for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3175 journals)

 A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

        1 2 3 4 5 6 7 8 | Last   [Sort by number of followers]   [Restore default list]

Showing 1 - 200 of 3175 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: 28, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 90, 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: 33, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 376, 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: 236, 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: 25, 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: 14)
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: 7)
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: 132, 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: 27, 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: 28, 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: 14)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 10)
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: 21)
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: 6)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 42, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
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: 15)
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: 7)
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: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 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: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 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: 15, 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: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 7)
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: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18, 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: 375, 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: 333, 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: 9, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 429, 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: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 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: 9, 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: 48, 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: 50, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 42, 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: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 42, 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: 189, 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: 61, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 14)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 39, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 164, 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: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, 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)

        1 2 3 4 5 6 7 8 | Last   [Sort by number of followers]   [Restore default list]

Journal Cover Acta Biomaterialia
  [SJR: 2.02]   [H-I: 104]   [27 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3175 journals]
  • Crystallinity of hydroxyapatite drives myofibroblastic activation and
           calcification in aortic valves
    • Authors: Jennifer M. Richards; Jennie A.M.R. Kunitake; Heather B. Hunt; Alexa N. Wnorowski; Debra W. Lin; Adele L. Boskey; Eve Donnelly; Lara A. Estroff; Jonathan T. Butcher
      Pages: 24 - 36
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Jennifer M. Richards, Jennie A.M.R. Kunitake, Heather B. Hunt, Alexa N. Wnorowski, Debra W. Lin, Adele L. Boskey, Eve Donnelly, Lara A. Estroff, Jonathan T. Butcher
      Calcific aortic valve disease (CAVD) is an inexorably degenerative pathology characterized by progressive calcific lesion formation on the valve leaflets. The interaction of valvular cells in advanced lesion environments is not well understood yet highly relevant as clinically detectable CAVD exhibits calcifications composed of non-stoichiometric hydroxyapatite (HA). In this study, Fourier transform infrared spectroscopic imaging was used to spatially analyze mineral properties as a function of disease progression. Crystallinity (size and perfection) increased with increased valve calcification. To study the relationship between crystallinity and cellular behavior in CAVD, valve cells were seeded into 3D mineral-rich collagen gels containing synthetic HA particles, which had varying crystallinities. Lower crystallinity HA drove myofibroblastic activation in both valve interstitial and endothelial cells, as well as osteoblastic differentiation in interstitial cells. Additionally, calcium accumulation within gels depended on crystallinity, and apoptosis was insufficient to explain differences in HA-driven cellular activity. The protective nature of endothelial cells against interstitial cell activation and calcium accumulation was completely inhibited in the presence of less crystalline HA particles. Elucidating valve cellular behavior post-calcification is of vital importance to better predict and treat clinical pathogenesis, and mineral-containing hydrogel models provide a unique 3D platform to evaluate valve cell responses to a later stage of valve disease. Statement of Significance We implement a 3D in vitro platform with embedded hydroxyapatite (HA) nanoparticles to investigate the interaction between valve interstitial cells, valve endothelial cells, and a mineral-rich extracellular environment. HA nanoparticles were synthesized based on analysis of the mineral properties of calcific regions of diseased human aortic valves. Our findings indicate that crystallinity of HA drives activation and differentiation in interstitial and endothelial cells. We also show that a mineralized environment blocks endothelial protection against interstitial cell calcification. Our HA-containing hydrogel model provides a unique 3D platform to evaluate valve cell responses to a mineralized ECM. This study additionally lays the groundwork to capture the diversity of mineral properties in calcified valves, and link these properties to progression of the disease.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.024
      Issue No: Vol. 71 (2018)
       
  • The in vitro effects of macrophages on the osteogenic capabilities of
           MC3T3-E1 cells encapsulated in a biomimetic poly(ethylene glycol) hydrogel
           
    • Authors: Leila S. Saleh; Maria Carles-Carner; Stephanie J. Bryant
      Pages: 37 - 48
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Leila S. Saleh, Maria Carles-Carner, Stephanie J. Bryant
      Poly(ethylene glycol) PEG-based hydrogels are promising for cell encapsulation and tissue engineering, but are known to elicit a foreign body response (FBR) in vivo. The goal of this study was to investigate the impact of the FBR, and specifically the presence of inflammatory macrophages, on encapsulated cells and their ability to synthesize new extracellular matrix. This study employed an in vitro co-culture system with murine macrophages and MC3T3-E1 pre-osteoblasts encapsulated in a bone-mimetic hydrogel, which were cultured in transwell inserts, and exposed to an inflammatory stimulant, lipopolysaccharide (LPS). The co-culture was compared to mono-cultures of the cell-laden hydrogels alone and with LPS over 28 days. Two macrophage cell sources, RAW 264.7 and primary derived, were investigated. The presence of LPS-stimulated primary macrophages led to significant changes in the cell-laden hydrogel by a 5.3-fold increase in percent apoptotic osteoblasts at day 28, 4.2-fold decrease in alkaline phosphatase activity at day 10, and 7-fold decrease in collagen deposition. The presence of LPS-stimulated RAW macrophages led to significant changes in the cell-laden hydrogel by 5-fold decrease in alkaline phosphatase activity at day 10 and 4-fold decrease in collagen deposition. Mineralization, as measured by von Kossa stain or quantified by calcium content, was not sensitive to macrophages or LPS. Elevated interleukin-6 and tumor necrosis factor-α secretion were detected in mono-cultures with LPS and co-cultures. Overall, primary macrophages had a more severe inhibitory effect on osteoblast differentiation than the macrophage cell line, with greater apoptosis and collagen I reduction. In summary, this study highlights the detrimental effects of macrophages on encapsulated cells for bone tissue engineering. Statement of Significance Poly(ethylene glycol) (PEG)-based hydrogels are promising for cell encapsulation and tissue engineering, but are known to elicit a foreign body response (FBR) in vivo. The impact of the FBR on encapsulated cells and their ability to synthesize tissue has not been well studied. This study utilizes thiol-ene click chemistry to create a biomimetic, enzymatically degradable hydrogel system with which to encapsulate MC3T3-E1 pre-osteoblasts. The osteogenic capabilities and differentiation of these cellswerestudied in co-culture with macrophages, known drivers of the FBR.This study demonstrates that macrophages reduce osteogenic capabilities of encapsulated cells in vitro and suggestthat the FBR should be considered for in vivo tissue engineering.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.026
      Issue No: Vol. 71 (2018)
       
  • Cancer cells biomineralize ionic gold into nanoparticles-microplates via
           secreting defense proteins with specific gold-binding peptides
    • Authors: Ajay Vikram Singh; Timotheus Jahnke; Vimal Kishore; Byung-Wook Park; Madu Batuwangala; Joachim Bill; Metin Sitti
      Pages: 61 - 71
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Ajay Vikram Singh, Timotheus Jahnke, Vimal Kishore, Byung-Wook Park, Madu Batuwangala, Joachim Bill, Metin Sitti
      Cancer cells have the capacity to synthesize nanoparticles (NPs). The detailed mechanism of this process is not very well documented. We report the mechanism of biomineralization of aqueous gold chloride into NPs and microplates in the breast-cancer cell line MCF7. Spherical gold NPs are synthesized in these cells in the presence of serum in the culture media by the reduction of HAuCl4. In the absence of serum, the cells exhibit gold microplate formation through seed-mediate growth albeit slower reduction. The structural characteristics of the two types of NPs under different media conditions were confirmed using scanning electron microscopy (SEM); crystallinity and metallic properties were assessed with transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). Gold-reducing proteins, related to cell stress initiate the biomineralization of HAuCl4 in cells (under serum free conditions) as confirmed by infrared (IR) spectroscopy. MCF7 cells undergo irreversible replicative senescence when exposed to a high concentration of ionic gold and conversely remain in a dormant reversible quiescent state when exposed to a low gold concentration. The latter cellular state was achievable in the presence of the rho/ROCK inhibitor Y-27632. Proteomic analysis revealed consistent expression of specific proteins under serum and serum-free conditions. A high-throughput proteomic approach to screen gold-reducing proteins and peptide sequences was utilized and validated by quartz crystal microbalance with dissipation (QCM-D). Statement of significance Cancer cells are known to synthesize gold nanoparticles and microstructures, which are promising for bioimaging and other therapeutic applications. However, the detailed mechanism of such biomineralization process is not well understood yet. Herein, we demonstrate that cancer cells exposed to gold ions (grown in serum/serum-free conditions) secrete shock and stress-related proteins with specific gold-binding/reducing polypeptides. Cells undergo reversible senescence and can recover normal physiology when treated with the senescence inhibitor depending on culture condition. The use of mammalian cells as microincubators for synthesis of such particles could have potential influence on their uptake and biocompatibility. This study has important implications for in-situ reduction of ionic gold to anisotropic micro-nanostructures that could be used in-vivo clinical applications and tumor photothermal therapy.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.022
      Issue No: Vol. 71 (2018)
       
  • A continuum of mineralization from human renal pyramid to stones on stems
    • Authors: Benjamin A. Sherer; Ling Chen; Misun Kang; Alex R. Shimotake; Scott V. Wiener; Tom Chi; Marshall L. Stoller; Sunita P. Ho
      Pages: 72 - 85
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Benjamin A. Sherer, Ling Chen, Misun Kang, Alex R. Shimotake, Scott V. Wiener, Tom Chi, Marshall L. Stoller, Sunita P. Ho
      The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralized volumes within the renal pyramid to larger interstitial plaques that ultimately lead into clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed. Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall’s plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall’s plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones. Statement of Significance Nephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall’s plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall’s plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall’s plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.01.040
      Issue No: Vol. 71 (2018)
       
  • Exogenous mineralization of hard tissues using photo-absorptive minerals
           and femto-second lasers; the case of dental enamel
    • Authors: A.D. Anastasiou; S. Strafford; C.L. Thomson; J. Gardy; T.J. Edwards; M. Malinowski; S.A. Hussain; N.K. Metzger; A. Hassanpour; C.T.A. Brown; A.P. Brown; M.S. Duggal; A. Jha
      Pages: 86 - 95
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): A.D. Anastasiou, S. Strafford, C.L. Thomson, J. Gardy, T.J. Edwards, M. Malinowski, S.A. Hussain, N.K. Metzger, A. Hassanpour, C.T.A. Brown, A.P. Brown, M.S. Duggal, A. Jha
      A radical new methodology for the exogenous mineralization of hard tissues is demonstrated in the context of laser-biomaterials interaction. The proposed approach is based on the use of femtosecond pulsed lasers (fs) and Fe3+-doped calcium phosphate minerals (specifically in this work fluorapatite powder containing Fe2O3 nanoparticles (NP)). A layer of the synthetic powder is applied to the surface of eroded bovine enamel and is irradiated with a fs laser (1040 nm wavelength, 1 GHz repetition rate, 150 fs pulse duration and 0.4 W average power). The Fe2O3 NPs absorb the light and may act as thermal antennae, dissipating energy to the vicinal mineral phase. Such a photothermal process triggers the sintering and densification of the surrounding calcium phosphate crystals thereby forming a new, dense layer of typically ∼20 μm in thickness, which is bonded to the underlying surface of the natural enamel. The dispersed iron oxide NPs, ensure the localization of temperature excursion, minimizing collateral thermal damage to the surrounding natural tissue during laser irradiation. Simulated brushing trials (pH cycle and mechanical force) on the synthetic layer show that the sintered material is more acid resistant than the natural mineral of enamel. Furthermore, nano-indentation confirms that the hardness and Young’s modulus of the new layers are significantly more closely matched to enamel than current restorative materials used in clinical dentistry. Although the results presented herein are exemplified in the context of bovine enamel restoration, the methodology may be more widely applicable to human enamel and other hard-tissue regenerative engineering. Statement of significance In this work we provide a new methodology for the mineralisation of dental hard tissues using femtosecond lasers and iron doped biomaterials. In particular, we demonstrate selective laser sintering of an iron doped fluorapatite on the surface of eroded enamel under low average power and mid-IR wavelength and the formation of a new layer to substitute the removed material. The new layer is evaluated through simulated brushing trials and nano-indentation. From the results we can conclude that is more acid resistant than natural enamel while, its mechanical properties are superior to that of current restorative materials. To the best of our knowledge this is the first time that someone demonstrated, laser sintering and bonding of calcium phosphate biomaterials on hard tissues. Although we here we discuss the case of dental enamel, similar approach can be adopted for other hard tissues, leading to new strategies for the fixation of bone/tooth defects.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.012
      Issue No: Vol. 71 (2018)
       
  • Hydroxyapatite nanobelt/polylactic acid Janus membrane with
           osteoinduction/barrier dual functions for precise bone defect repair
    • Authors: Baojin Ma; Jing Han; Shan Zhang; Feng Liu; Shicai Wang; Jiazhi Duan; Yuanhua Sang; Huaidong Jiang; Dong Li; Shaohua Ge; Jinghua Yu; Hong Liu
      Pages: 108 - 117
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Baojin Ma, Jing Han, Shan Zhang, Feng Liu, Shicai Wang, Jiazhi Duan, Yuanhua Sang, Huaidong Jiang, Dong Li, Shaohua Ge, Jinghua Yu, Hong Liu
      Controllable osteoinduction maintained in the original defect area is the key to precise bone repair. To meet the requirement of precise bone regeneration, a hydroxyapatite (HAp) nanobelt/polylactic acid (PLA) (HAp/PLA) Janus membrane has been successfully prepared in this study by coating PLA on a paper-like HAp nanobelt film by a casting-pervaporation method. The Janus membrane possesses dual functions: excellent osteoinduction from the hydrophilic HAp nanobelt side and barrier function originating from the hydrophobic PLA film. The cell viability and osteogenic differentiation ability of human adipose-derived stem cells (hADSCs) on the Janus membrane were assessed. The in vitro experimental results prove that the HAp nanobelt side presents high cell viability and efficient osteoinduction without any growth factor and that the PLA side can prohibit cell attachment. The in vivo repair experiments on a rat mandible defect model prove that the PLA side can prevent postoperative adhesion between bone and adjacent soft tissues. Most importantly, the HAp side has a strong ability to promote defect repair and bone regeneration. Therefore, the HAp/PLA Janus membrane will have wide applications as a kind of tissue engineering material in precise bone repair because of its unique dual osteoinduction/barrier functions, biocompatibility, low cost, and its ability to be mass-produced. State of Significance Precise bone defect repair to keeping tissue integrity and original outline shape is a very important issue for tissue engineering. Here, we have designed and prepared a novel HAp/PLA Janus membrane using a casting-pervaporation method to form a layer of PLA film on paper-like HAp nanobelt film. HAp nanobelt side of the Janus membrane can successfully promote osteogenic differentiation. PLA side of the Janus membrane exhibits good properties as a barrier for preventing the adhesion of cells in vitro. Mandible repair experiments in vivo have shown that the HAp/PLA Janus membrane can promote rat mandible repair on the HAp side and can successfully prevent postoperative adhesion on the PLA side at the same time. Therefore, the HAp/PLA Janus membrane with its osteoinduction/barrier dual functions can be applied to repair bone defect precisely.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.033
      Issue No: Vol. 71 (2018)
       
  • Inhibition of osteoclastogenesis by stem cell-derived extracellular matrix
           through modulation of intracellular reactive oxygen species
    • Authors: Mao Li; Xi Chen; Jinku Yan; Long Zhou; Yifan Wang; Fan He; Jun Lin; Caihong Zhu; Guoqing Pan; Jia Yu; Ming Pei; Huilin Yang; Tao Liu
      Pages: 118 - 131
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Mao Li, Xi Chen, Jinku Yan, Long Zhou, Yifan Wang, Fan He, Jun Lin, Caihong Zhu, Guoqing Pan, Jia Yu, Ming Pei, Huilin Yang, Tao Liu
      Decellularized extracellular matrix (ECM) derived from stem cells has been shown as a promising biomaterial for bone regeneration because of the promotion effect on osteogenesis in mesenchymal stem cells (MSCs). However, bone regeneration is also influenced by bone resorption and little is known about the effect of cell-derived ECM on osteoclast differentiation. In this study, ECM was deposited by MSCs and, after decellularization, the effect of ECM on osteoclastogenesis of bone marrow monocytes (BMMs) was investigated in comparison to standard tissue culture polystyrene. Our results showed that cell-derived ECM improved BMM proliferation but potently inhibited osteoclast differentiation, evidenced by down-regulation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells, areas of actin rings, and osteoclast-specific gene expression. ECM-mediated attenuation of intracellular reactive oxygen species (ROS) was suggested to play a rival role in the inhibition of osteoclastogenesis, because exogenous hydrogen peroxide supplementation partially rescued the ECM-inhibited osteoclastogenesis. Furthermore, rather than collagen type I, fibronectin in the ECM contributed to ECM-mediated anti-osteoclastogenesis. In conclusion, stem cell-derived decellularized ECM significantly suppressed osteoclastogenesis via the attenuation of intracellular ROS. The anti-osteoclastogenic property of cell-derived ECM may benefit its clinical use for modulating bone remodeling and promoting bone tissue engineering. Statement of Significance Decellularized extracellular matrix (ECM) derived from stem cells has been shown as a promising biomaterial for bone regeneration; however, bone remodeling is influenced by bone resorption and little is known about the effect of cell-derived ECM on osteoclast differentiation. Cell-derived ECM improved BMM proliferation but potently inhibited osteoclast differentiation. ECM-mediated attenuation of intracellular reactive oxygen species was suggested to play a rival role in osteoclastogenesis. Fibronectin in cell-derived ECM also contributed to ECM-mediated anti-osteoclastogenesis. The anti-osteoclastogenic property of cell-derived ECM may benefit clinically for modulating bone remodeling and promoting bone tissue engineering.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.003
      Issue No: Vol. 71 (2018)
       
  • Macrophage involvement affects matrix stiffness-related influences on cell
           osteogenesis under three-dimensional culture conditions
    • Authors: Xiao-Tao He; Rui-Xin Wu; Xin-Yue Xu; Jia Wang; Yuan Yin; Fa-Ming Chen
      Pages: 132 - 147
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Xiao-Tao He, Rui-Xin Wu, Xin-Yue Xu, Jia Wang, Yuan Yin, Fa-Ming Chen
      Accumulating evidence indicates that the physicochemical properties of biomaterials exert profound influences on stem cell fate decisions. However, matrix-based regulation selected through in vitro analyses based on a given cell population do not genuinely reflect the in vivo conditions, in which multiple cell types are involved and interact dynamically. This study constitutes the first investigation of how macrophages (Mφs) in stiffness-tunable transglutaminase cross-linked gelatin (TG-gel) affect the osteogenesis of bone marrow-derived mesenchymal stem cells (BMMSCs). When a single cell type was cultured, low-stiffness TG-gels promoted BMMSC proliferation, whereas high-stiffness TG-gels supported cell osteogenic differentiation. However, Mφs in high-stiffness TG-gels were more likely to polarize toward the pro-inflammatory M1 phenotype. Using either conditioned medium (CM)-based incubation or Transwell-based co-culture, we found that Mφs encapsulated in the low-stiffness matrix exerted a positive effect on the osteogenesis of co-cultured BMMSCs. Conversely, Mφs in high-stiffness TG-gels negatively affected cell osteogenic differentiation. When both cell types were cultured in the same TG-gel type and placed into the Transwell system, the stiffness-related influences of Mφs on BMMSCs were significantly altered; both the low- and high-stiffness matrix induced similar levels of BMMSC osteogenesis. Although the best material parameter for synergistically affecting Mφs and BMMSCs remains unknown, our data suggest that Mφ involvement in the co-culture system alters previously identified material-related influences on BMMSCs, such as matrix stiffness-related effects, which were identified based on a culture system involving a single cell type. Such Mφ-stem cell interactions should be considered when establishing proper matrix parameter-associated cell regulation in the development of biomimetic biomaterials for regenerative applications. Statement of Significance The substrate stiffness of a scaffold plays critical roles in modulating both reparative cells, such as mesenchymal stem cells (MSCs), and immune cells, such as macrophages (Mφs). Although the influences of material stiffness on either Mφs or MSCs, have been extensively described, how the two cell types respond to matrix cues to dynamically affect each other in a three-dimensional (3D) biosystem remains largely unknown. Here, we report our findings that, in a platform wherein Mφs and bone marrow-derived MSCs coexist, matrix stiffness can influence stem cell fate through both direct matrix-associated regulation and indirect Mφ-based modulation. Our data support future studies of the MSC-Mφ-matrix interplay in the 3D context to optimize matrix parameters for the development of the next biomaterial.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.015
      Issue No: Vol. 71 (2018)
       
  • Superior calvarial bone regeneration using pentenoate-functionalized
           hyaluronic acid hydrogels with devitalized tendon particles
    • Authors: Jakob M. Townsend; Brian T. Andrews; Yi Feng; Jinxi Wang; Randolph J. Nudo; Erik Van Kampen; Stevin H. Gehrke; Cory J. Berkland; Michael S. Detamore
      Pages: 148 - 155
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Jakob M. Townsend, Brian T. Andrews, Yi Feng, Jinxi Wang, Randolph J. Nudo, Erik Van Kampen, Stevin H. Gehrke, Cory J. Berkland, Michael S. Detamore
      Traumatic brain injury (TBI) is a life-threatening condition defined by internal brain herniation. Severe TBI is commonly treated by a two-stage surgical intervention, where decompressive craniectomy is first conducted to remove a large portion of calvarial bone and allow unimpeded brain swelling. In the second surgery, spaced weeks to months after the first, cranioplasty is performed to restore the cranial bone. Hydrogels with paste-like precursor solutions for surgical placement may potentially revolutionize TBI treatment by permitting a single-stage surgical intervention, capable of being implanted with the initial surgery, remaining pliable during brain swelling, and tuned to regenerate calvarial bone after brain swelling has subsided. The current study evaluated the use of photocrosslinkable pentenoate-functionalized hyaluronic acid (PHA) and non-crosslinking hyaluronic acid (HA) hydrogels encapsulating naturally derived tissue particles of demineralized bone matrix (DBM), devitalized cartilage (DVC), devitalized meniscus (DVM), or devitalized tendon (DVT) for bone regeneration in critical-size rat calvarial defects. All hydrogel precursors exhibited a yield stress for placement and addition of particles increased the average material compressive modulus. The HA-DBM (4–30%), PHA (4%), and PHA-DVT (4–30%) groups had 5 (p < 0.0001), 3.1, and 3.2 (p < 0.05) times greater regenerated bone volume compared to the sham (untreated defect) group, respectively. In vitro cell studies suggested that the PHA-DVT (4–10%) group would have the most desirable performance. Overall, hydrogels containing DVT particles outperformed other materials in terms of bone regeneration in vivo and calcium deposition in vitro. Hydrogels containing DVT will be further evaluated in future rat TBI studies. Statement of Significance Traumatic brain injury (TBI) is a life-threatening condition characterized by severe brain swelling and is currently treated by a two-stage surgical procedure. Complications associated with the two-stage surgical intervention include the occurrence of the condition termed syndrome of the trephined; however, the condition is completely reversible once the secondary surgery is performed. A desirable TBI treatment would include a single surgical intervention to avoid syndrome of the trephined altogether. The first hurdle in reaching the overall goal is to develop a pliable hydrogel material that can regenerate the patient’s bone. The development of a pliable hydrogel technology would greatly impact the field of bone regeneration for TBI application and other areas of bone regeneration.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.013
      Issue No: Vol. 71 (2018)
       
  • Histone-targeted gene transfer of bone morphogenetic protein-2 enhances
           mesenchymal stem cell chondrogenic differentiation
    • Authors: Erik V. Munsell; Deepa S. Kurpad; Theresa A. Freeman; Millicent O. Sullivan
      Pages: 156 - 167
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Erik V. Munsell, Deepa S. Kurpad, Theresa A. Freeman, Millicent O. Sullivan
      Skeletal tissue regeneration following traumatic injury involves a complex cascade of growth factor signals that direct the differentiation of mesenchymal stem cells (MSCs) within the fracture. The necessity for controlled and localized expression of these factors has highlighted the role gene therapy may play as a promising treatment option for bone repair. However, the design of nanocarrier systems that negotiate efficient intracellular trafficking and nuclear delivery represents a significant challenge. Recent investigations have highlighted the roles histone tail sequences play in directing nuclear delivery and activating DNA transcription. We previously established the ability to recapitulate these natural histone tail activities within non-viral nanocarriers, improving gene transfer and expression by enabling effective navigation to the nucleus via retrograde vesicular trafficking. Herein, we demonstrate that histone-targeting leads to ∼4-fold enhancements in osteogenic bone morphogenetic protein-2 (BMP-2) expression by MSCs over 6 days, as compared with standard polymeric transfection reagents. This improved expression augmented chondrogenesis, an essential first step in fracture healing. Importantly, significant enhancements of cartilage-specific protein expression were triggered by histone-targeted gene transfer, as compared with the response to treatment with equivalent amounts of recombinant BMP-2 protein. In fact, an ∼100-fold increase in recombinant BMP-2 was required to achieve similar levels of chondrogenic gene and protein expression. The enhancements in differentiation achieved using histone-targeting were in part enabled by an increase in transcription factor expression, which functioned to drive MSC chondrogenesis. These novel findings demonstrate the utility of histone-targeted gene transfer strategies to enable substantial reductions in BMP-2 dosing for bone regenerative applications. Statement of significance This contribution addresses significant limitations in non-viral gene transfer for bone regenerative applications by exploiting a novel histone-targeting approach for cell-triggered delivery that induces osteogenic BMP-2 expression coincident with the initiation of bone repair. During repair, proliferating MSCs respond to a complex series of growth factor signals that direct their differentiation along cellular lineages essential to mature bone formation. Although these MSCs are ideal targets for enhanced transfection during cellular mitosis, few non-viral delivery approaches exist to enable maximization of this effect. Accordingly, this contribution seeks to utilize our histone-targeted nanocarrier design strategy to stimulate BMP-2 gene transfer in dividing MSCs. This gene-based approach leads to significantly augmented MSC chondrogenesis, an essential first step in bone tissue repair.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.021
      Issue No: Vol. 71 (2018)
       
  • Exogenous stromal derived factor-1 releasing silk scaffold combined with
           intra-articular injection of progenitor cells promotes bone-ligament-bone
           regeneration
    • Authors: Yejun Hu; Jisheng Ran; Zefeng Zheng; Zhangchu Jin; Xiao Chen; Zi Yin; Chenqi Tang; Yangwu Chen; Jiayun Huang; Huihui Le; Ruijian Yan; Ting Zhu; Junjuan Wang; Junxin Lin; Kan Xu; Yiting Zhou; Wei Zhang; Youzhi Cai; Pioletti Dominique; Boon Chin Heng; Weishan Chen; Weiliang Shen; Hong-Wei Ouyang
      Pages: 168 - 183
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Yejun Hu, Jisheng Ran, Zefeng Zheng, Zhangchu Jin, Xiao Chen, Zi Yin, Chenqi Tang, Yangwu Chen, Jiayun Huang, Huihui Le, Ruijian Yan, Ting Zhu, Junjuan Wang, Junxin Lin, Kan Xu, Yiting Zhou, Wei Zhang, Youzhi Cai, Pioletti Dominique, Boon Chin Heng, Weishan Chen, Weiliang Shen, Hong-Wei Ouyang
      Anterior cruciate ligament (ACL) is one of the most difficult tissues to heal once injured. Ligament regeneration and tendon-bone junction healing are two major goals of ACL reconstruction. This study aimed to investigate the synergistic therapeutic effects of Stromal cell-derived factor 1 (SDF-1)-releasing collagen-silk (CSF) scaffold combined with intra-articular injection of ligament-derived stem/progenitor cells (LSPCs) for ACL regeneration and the amelioration in the long-term complication of osteoarthritis (OA). The stem cell recruitment ability of CSF scaffold and the multipotency, particularly the tendon forming ability of LSPCs from rabbits were characterized in vitro, while the synergistic effect of the CSF scaffold and LSPCs for ACL regeneration and OA amelioration were investigated in vivo at 1, 3, and 6 months with a rabbit ACL reconstruction model. The CSF scaffold was used as a substitute for the ACL, and LSPCs were injected into the joint cavity after 7 days of the ACL reconstruction. CSF scaffold displayed a controlled release pattern for the encapsulated protein for up to 7 days with an increased stiffness in the mechanical property. LSPCs, which exhibited highly I Collagen and CXCR4 expression, were attracted by SDF-1 and successfully relocated into the CSF scaffold at 1 month in vivo. At 3 and 6 months post-treatment, the CSF scaffold combined with LSPCs (CSFL group) enhanced the regeneration of ACL tissue, and promoted bone tunnel healing. Furthermore, the OA progression was impeded efficiently. Our findings here provided a new strategy that using stem cell recruiting CSF scaffold with tissue-specific stem cells, could be a promising solution for ACL regeneration. Statement of Significance In this study, we developed a silk scaffold with increased stiffness and SDF-1 controlled release capacity for ligament repair. This advanced scaffold transplantation combined with intra-articular injection of LSPCs (which was isolated from rabbit ligament for the first time in this study) promoted the regeneration of both the tendinous and bone tunnel portion of ACL. This therapeutic strategy also ameliorated cartilage degeneration and reduced the severity of arthrofibrosis. Hence, combining LSPCs injection with SDF-1-releasing silk scaffold is demonstrated as a therapeutic strategy for ACL regeneration and OA treatment in the clinic.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.019
      Issue No: Vol. 71 (2018)
       
  • Localization and promotion of recombinant human bone morphogenetic
           protein-2 bioactivity on extracellular matrix mimetic chondroitin
           sulfate-functionalized calcium phosphate cement scaffolds
    • Authors: Baolin Huang; Zihan Wu; Sai Ding; Yuan Yuan; Changsheng Liu
      Pages: 184 - 199
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Baolin Huang, Zihan Wu, Sai Ding, Yuan Yuan, Changsheng Liu
      Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) scaffolds through specific noncovalent interactions. CS, one of the core glycosaminoglycans, was covalently conjugated onto CPC scaffolds with the assistance of polydopamine (PDA) and further immobilized rhBMP-2 in a biomimetic form. The CPC-PDA-CS scaffolds not only controlled the release kinetics and presentation state of rhBMP-2 but also effectively increased the expression levels of bone morphogenetic protein receptors (BMPRs) and enhanced the recognitions of the remaining rhBMP-2 to BMPRs. Strikingly, the rhBMP-2-loaded CPC-PDA-CS significantly promoted the cellular surface translocation of BMPRs (especially BMPR-IA). In vivo studies demonstrated that, compared with the rhBMP-2 upon CPC and CPC-PDA, the rhBMP-2 upon CPC-PDA-CS exhibited sustained release and induced high quality and more ectopic bone formation. Collectively, these results suggest that rhBMP-2 can be localized within CS-functionalized CPC scaffolds and exert continuous, long-term, and effective osteogenic stimulation. Thus, this work could provide new avenues in mimicking bone extracellular matrix microenvironment and localizing growth factor activity for enhanced bone regeneration. Statement of Significance A bioinspired chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) platform was developed to tether recombinant human bone morphogenetic protein-2 (rhBMP-2), which could exhibit continuous, long-term, and effective osteogenic stimulation in bone tissue engineering. Compared with rhBMP-2-loaded CPC, the rhBMP-2-loaded CPC-polydopamine-CS scaffolds induced higher expression of bone morphogenetic protein receptors (BMPRs), greater cellular surface translocation of bone morphogenetic protein receptor-IA, higher binding affinity of BMPRs/rhBMP-2, and thus higher activation of the drosophila gene mothers against decapentaplegic protein-1/5/8 (Smad1/5/8) and extracellular-regulated protein kinases-1/2 (ERK1/2) signaling. This work can provide new guidelines for the design of BMP-2-based bioactive materials for bone regeneration.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.01.004
      Issue No: Vol. 71 (2018)
       
  • In vitro and in vivo studies on zinc-hydroxyapatite composites as novel
           biodegradable metal matrix composite for orthopedic applications
    • Authors: Hongtao Yang; Xinhua Qu; Wenjiao Lin; Cong Wang; Donghui Zhu; Kerong Dai; Yufeng Zheng
      Pages: 200 - 214
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Hongtao Yang, Xinhua Qu, Wenjiao Lin, Cong Wang, Donghui Zhu, Kerong Dai, Yufeng Zheng
      Recent studies indicate that there is a great demand to optimize pure Zn with tunable degradation rates and more desirable biocompatibility as orthopedic implants. Metal matrix composite (MMC) can be a promising approach for this purpose. In this study, MMC with pure Zn as a matrix and hydroxyapatite (HA) as reinforcements were prepared by spark plasma sintering (SPS). Feasibility of novel Zn-HA composites to be used as orthopedic implant applications was systematically evaluated. After sintering, HA distributed in the Zn particle boundaries uniformly. Corrosion tests indicated that the degradation rates of Zn-HA composites were adjustable due to the biphasic effects of HA. Zn-HA composites showed significantly improved cell viability of osteoblastic MC3T3-E1 cells compared with pure Zn. Both pure Zn and composites exhibited a low thrombosis risk and hemolysis rates while a Zn ion concentration-dependent effect was found on coagulation time. An effective antibacterial property was observed as well. The volume loss of pure Zn and Zn-5HA composite was 1.7% and 3.2% after 8 weeks’ implantation. Histological analysis found newly formed bone surrounding pure Zn and Zn-5HA composite at week 4 and increased bone mass over time. With prolonged implantation time, Zn-5HA composite was more effective on stimulating new bone formation than pure Zn. In summary, MMC is a feasible way to design Zn based materials with adjustable degradation rates and improved biocompatibility. Statement of Significance Biodegradable zinc materials are promising candidates for the new generation of orthopedic implants. However, the slow degradation rates and unsatisfactory cytocompatibility of pure Zn in bone environments limit its future clinical applications. Generally, alloying is a common way to improve the performance of pure Zn. In this study, metal matrix composite was chosen as a novel strategy to solve the problems. Hydroxyapatite, as a bioactive component, was added into Zn matrix via spark plasma sintering. We find that Zn-HA composites exhibited adjustable degradation rates and improved biocompatibility both in vitro and in vivo. This study provides exhaustive and significant information including microstructure, mechanical performance, degradation behavior, biocompatibility, hemocompatibility and antibacterial property for the future Zn based implants design.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.007
      Issue No: Vol. 71 (2018)
       
  • Binary polyhydroxyalkanoate systems for soft tissue engineering
    • Authors: Barbara Lukasiewicz; Pooja Basnett; Rinat Nigmatullin; Rupy Matharu; Jonathan C. Knowles; Ipsita Roy
      Pages: 225 - 234
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Barbara Lukasiewicz, Pooja Basnett, Rinat Nigmatullin, Rupy Matharu, Jonathan C. Knowles, Ipsita Roy
      Progress in tissue engineering is dependent on the availability of suitable biomaterials. In an effort to overcome the brittleness of poly(3-hydroxybutyrate), P(3HB), a natural biodegradable polyester, and widen its biomedical applications, plasticising of P(3HB) with oligomeric substances of related structure has been studied. A biosynthesised medium-chain-length polyhydroxyalkanoate (mcl-PHA) copolymer, the plasticiser precursor, was obtained using vegetable waste frying oil as a sole carbon source. The mcl-PHA was transformed into an oligomeric derivative by acid hydrolysis. The plasticising effect of the oligomeric mcl-PHA on P(3HB) was studied via characterisation of thermal and mechanical properties of the blends in the course of ageing at ambient conditions. Addition of oligomeric mcl-PHA to P(3HB) resulted in softer and more flexible materials based entirely on PHAs. It was shown that the oligomeric mcl-PHA transformed highly crystalline P(3HB) into materials with a dominant amorphous phase when the content of oligomeric mcl-PHA exceeded 10 wt%. In vitro biocompatibility studies of the new binary PHA materials showed high viability and proliferation of C2C12 myoblast cells. Thus, the proposed approach for P(3HB) plasticisation has the potential for the generation of more pliable biomaterials based on P(3HB) which can find application in unique soft tissue engineering applications where a balance between stiffness, tensile strength and ductility is required. Statement of Significance Polyhydroxyalkanoates, a broad family of natural biodegradable and biocompatible polymers, have emerged as highly promising biomaterials both for bulk and biomedical applications. Here we describe an approach to tune the mechanical properties of stiff and brittle poly(3-hydroxybutyrate) and thereby to expand its potential biomedical applications. Plasticisation, a common practice in the plastic industry to modify polymer mechanical properties, has been used very cautiously for biomedical applications due to plasticiser toxicity and migration. We have developed a plasticiser for poly(3-hydroxybutyrate) based on a structurally related but softer and pliable medium chain length polyhydroxyalkanoate. Additives of oligomeric derivatives of this polymer improved ductility of poly(3-hydroxybutyrate), greatly widening the future applicability of this well-established biomaterial. In parallel, the binary polyhydroxyalkanoate materials also exhibited improved cell attachment and proliferation, a highly desirable outcome.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.027
      Issue No: Vol. 71 (2018)
       
  • Human iPSC-derived mesenchymal stem cells encapsulated in PEGDA hydrogels
           mature into valve interstitial-like cells
    • Authors: Aline L.Y. Nachlas; Siyi Li; Rajneesh Jha; Monalisa Singh; Chunhui Xu; Michael E. Davis
      Pages: 235 - 246
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Aline L.Y. Nachlas, Siyi Li, Rajneesh Jha, Monalisa Singh, Chunhui Xu, Michael E. Davis
      Despite recent advances in tissue engineered heart valves (TEHV), a major challenge is identifying a cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. This study demonstrates that induced pluripotent stem cells (iPSC)-derived mesenchymal stem cells (iMSCs) can be derived from iPSCs using a feeder-free protocol and then further matured into VICs by encapsulation within 3D hydrogels. The differentiation efficiency was characterized using flow cytometry, immunohistochemistry staining, and trilineage differentiation. Using our feeder-free differentiation protocol, iMSCs were differentiated from iPSCs and had CD90+, CD44+, CD71+, αSMA+, and CD45− expression. Furthermore, iMSCs underwent trilineage differentiation when cultured in induction media for 21 days. iMSCs were then encapsulated in poly(ethylene glycol)diacrylate (PEGDA) hydrogels grafted with adhesion peptide (RGDS) to promote remodeling and further maturation into VIC-like cells. VIC phenotype was assessed by the expression of alpha-smooth muscle actin (αSMA), vimentin, and collagen production after 28 days. When MSC-derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, a decrease in αSMA expression and increase in vimentin was observed. In addition, iMSCs synthesized collagen type I after 28 days in 3D hydrogel culture. Thus, the results from this study suggest that iMSCs may be a promising cell source for TEHV. Statement of Significance Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.025
      Issue No: Vol. 71 (2018)
       
  • Modulation of macrophage phenotype and protein secretion via heparin-IL-4
           functionalized supramolecular elastomers
    • Authors: V. Bonito; A.I.P.M. Smits; O.J.G.M. Goor; B.D. Ippel; A. Driessen-Mol; T.J.A.G. Münker; A.W. Bosman; T. Mes; P.Y.W. Dankers; C.V.C. Bouten
      Pages: 247 - 260
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): V. Bonito, A.I.P.M. Smits, O.J.G.M. Goor, B.D. Ippel, A. Driessen-Mol, T.J.A.G. Münker, A.W. Bosman, T. Mes, P.Y.W. Dankers, C.V.C. Bouten
      Hallmark of the in situ tissue engineering approach is the use of bioresorbable, synthetic, acellular scaffolds, which are designed to modulate the inflammatory response and actively trigger tissue regeneration by the body itself at the site of implantation. Much research is devoted to the design of synthetic materials modulating the polarization of macrophages, which are essential mediators of the early stages of the inflammatory response. Here, we present a novel method for the functionalization of elastomers based on synthetic peptide chemistry, supramolecular self-assembly, and immobilization of heparin and interleukin 4 (IL-4), which is known to skew the polarization of macrophages into the wound healing “M2” phenotype. Ureido-pyrimidinone (UPy)-modified chain extended polycaprolactone (CE-UPy-PCL) was mixed with a UPy-modified heparin binding peptide (UPy-HBP) to allow for immobilization of heparin, and further functionalization with IL-4 via its heparin binding domain. As a first proof of principle, CE-UPy-PCL and UPy-HBP were premixed in solution, dropcast and exposed to primary human monocyte-derived macrophages, in the presence or absence of IL-4-heparin functionalization. It was demonstrated that the supramolecular IL-4-heparin functionalization effectively promoted macrophage polarization into an anti-inflammatory phenotype, in terms of morphology, immunohistochemistry and cytokine secretion. Moreover, the supramolecular functionalization approach used was successfully translated to 3D electrospun scaffolds for in situ tissue engineering purposes, where UPy-HBP retention, and heparin and IL-4 attachment to the supramolecular scaffolds were proven over 7 days. Lastly, human monocyte-derived macrophages were cultured on 3D scaffolds, which, in case of IL-4-heparin functionalization, were proven to promote of an anti-inflammatory environment on protein level. This study presents a novel method in designing a versatile class of functionalized elastomers that effectively harness the anti-inflammatory behavior of macrophages in vitro, and as such, may be instrumental for the development of a new class of synthetic materials for in situ tissue engineering purposes. Statement of Significance Macrophages and their phenotypic and functional plasticity play a pivotal role in metabolic homeostasis and tissue repair. Based on this notion, bioactivated materials modulating macrophage polarization were extensively investigated in the past. Here, we designed immunomodulating, synthetic materials based on supramolecular immobilization of a heparin binding peptide, and further bioactivation with heparin and IL-4, an anti-inflammatory cytokine responsible for M2 activation and polarization. Human monocyte-derived macrophages cultured on heparin-IL-4 bioactivated materials displayed an elongated morphology and an anti-inflammatory phenotype, with downregulation of pro-inflammatory cytokines and promotion of anti-inflammatory cytokines over time. This study represents the first step in designing a novel class of synthetic, bioactivated materials that harness the regenerative behavior of host macrophages towards in situ tissue regeneration.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.032
      Issue No: Vol. 71 (2018)
       
  • Controlled release of an HDAC inhibitor for reduction of inflammation in
           dry eye disease
    • Authors: Michelle L. Ratay; Stephen C. Balmert; Ethan J. Bassin; Steven R. Little
      Pages: 261 - 270
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Michelle L. Ratay, Stephen C. Balmert, Ethan J. Bassin, Steven R. Little
      Dry eye disease (DED), also known as keratoconjunctivitis sicca, is an ocular surface disease characterized by T-cell-mediated inflammation. Current therapeutics, such as immunosuppressive agents, act to suppress the clinical signs and inflammation. However, long-term usage of these treatments can cause severe side effects. In this study, we present an alternative therapeutic approach that utilizes a histone deacetylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. Specifically, HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs), enhancing FoxP3 acetylation and subsequently guarding the transcription factor from proteasomal degradation. Here, a specific HDACi known as SAHA (suberoylanilide hydroxamic acid) was formulated to controllably release in the lacrimal gland. Intralacrimal gland injection of PLGA-based SAHA microspheres prevented clinical signs of DED in mice with Concanavalin A-induced DED, reduced expression of pro-inflammatory cytokines, and increased expression of FoxP3 in the lacrimal glands. Murine T cell culture experiments also revealed that SAHA decreased effector T cell proliferation and enhanced suppressive function of Tregs in co-cultures of Tregs and effector T cells. Statement of Significance In this study, we demonstrate a therapeutic approach that utilizes a histone deactylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs). Here, HDACi microspheres composed of a biocompatible and biodegradable polymer (poly(lactic-co-glycolic acid) (PLGA)), were able to locally release the HDACi and prevent clinical signs of DED. This work is timely given the recent shift in treatments of DED towards immunological based therapies to reduce ocular inflammation. However, notably, many of these treatments require large amounts of drug, and non-specifically suppress the immune system, leading to several systemic side effects. Instead of merely suppressing or blocking inflammation, the formulation described herein intends to balance the microenvironment promoting immunological homeostasis. This particular drug delivery system may also have broad implications in the field of inflammatory mediated ocular disorders such as uveitis, Sjögren’s syndrome, allergic conjunctivitis.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.002
      Issue No: Vol. 71 (2018)
       
  • Mechanical stabilization of proteolytically degradable polyethylene glycol
           dimethacrylate hydrogels through peptide interaction
    • Authors: Hyun Ju Lim; Zara Khan; Xi Lu; T. Hiran Perera; Thomas S. Wilems; Krishna T. Ravivarapu; Laura A. Smith Callahan
      Pages: 271 - 278
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Hyun Ju Lim, Zara Khan, Xi Lu, T. Hiran Perera, Thomas S. Wilems, Krishna T. Ravivarapu, Laura A. Smith Callahan
      Balancing enhancement of neurite extension against loss of matrix support in synthetic hydrogels containing proteolytically degradable and bioactive signaling peptides to optimize tissue formation is difficult. Using a systematic approach, polyethylene glycol hydrogels containing concurrent continuous concentration gradients of the laminin derived bioactive signaling peptide, Ile-Lys-Val-Ala-Val (IKVAV), and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ, were fabricated and characterized. During proteolytic degradation of the concentration gradient hydrogels, the IKVAV and IWGQ cleavage fragment from GPQGIWGQ were found to interact and stabilize the bulk Young’s Modulus of the hydrogel. Further testing of discrete samples containing GPQGIWGQ or its cleavage fragments, GPQG and IWGQ, indicates hydrophobic interactions between the peptides are not necessary for mechanical stabilization of the hydrogel, but changes in the concentration ratio between the peptides tethered in the hydrogel and salts and ions in the swelling solution can affect the stabilization. Encapsulation of human induced pluripotent stem cell derived neural stem cells did not reduce the mechanical properties of the hydrogel over a 14 day neural differentiation culture period, and IKVAV was found to maintain concentration dependent effects on neurite extension and mRNA gene expression of neural cytoskeletal markers, similar to previous studies. As a result, this work has significant implications for the analysis of biological studies in matrices, as the material and mechanical properties of the hydrogel may be unexpectedly temporally changing during culture due to interactions between peptide signaling elements, underscoring the need for greater matrix characterization during the degradation and cell culture. Statement of significance Greater emulation of the native extracellular matrix is necessary for tissue formation. To achieve this, matrices are becoming more complex, often including multiple bioactive signaling elements. However, peptide signaling in polyethylene glycol matrices and amino acids interactions between peptides can affect hydrogel material and mechanical properties, but are rarely studied. The current study identifies such an interaction between laminin derived peptide, IKVAV, and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ. Previous studies using these peptides did not identify their interactions’ ability to mechanically stabilize the hydrogel during degradation. This work underscores the need for greater matrix characterization and consideration of bioactive signaling element effects temporally on the matrix’s material and mechanical properties, as they can contribute to cellular response.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.001
      Issue No: Vol. 71 (2018)
       
  • Sulfated zwitterionic poly(sulfobetaine methacrylate) hydrogels promote
           complete skin regeneration
    • Authors: Jiang Wu; Zecong Xiao; Anqi Chen; Huacheng He; Chaochao He; Xintao Shuai; Xiaokun Li; Shengfu Chen; Yanxian Zhang; Baiping Ren; Jie Zheng; Jian Xiao
      Pages: 293 - 305
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Jiang Wu, Zecong Xiao, Anqi Chen, Huacheng He, Chaochao He, Xintao Shuai, Xiaokun Li, Shengfu Chen, Yanxian Zhang, Baiping Ren, Jie Zheng, Jian Xiao
      Skin wound healing is a still long-history challenging problem and impeded by the foreign-body reaction including severe inflammation response, poor neovascularization, incomplete re-epithelialization and defective ECM remodeling. Development of biocompatible polymers, in combination with specific drugs or growth factors, has been considered as a promising strategy to treat skin wounds. Significant research efforts have been made to develop poly(ethylene glycol) PEG-based polymers for wound healing, however less efforts has been paid to zwitterionic materials, some of which have demonstrated their super low-fouling property in vitro and anti-inflammatory property in vivo. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied them to full-thickness cutaneous wounds in mice. The healing effects of SBMA hydrogels on the wound closure, re-epithelialization ratio, ECM remodeling, angiogenesis, and macrophage responses during wound healing processes were histologically evaluated by in vivo experiments. Collective results indicate that SBMA hydrogels promote full-thickness excisional acute wound regeneration in mice by enhancing angiogenesis, decreasing inflammation response, and modulating macrophage polarization. Consistently, the incorporation of SBMA into PEG hydrogels also improved the overall wound healing efficiency as compared to pure PEG hydrogels. This work demonstrates zwitterionic SBMA hydrogels as promising wound dressings for treating full-thickness excisional skin wounds. Statement of Significance Development of highly effective wound regeneration system is practically important for biomedical applications. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied it to full-thickness cutaneous wounds in mice, in comparison with PEG hydrogels as a control. We are the first to examine and reveal the difference between zwitterionic SBMA hydrogels and PEG hydrogels using a full-thickness excisional mice model. Overall, a series of in vivo systematic tests demonstrated that zwitterionic SBMA hydrogels exhibited superior wound healing property in almost all aspects as compared to PEG hydrogels.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.034
      Issue No: Vol. 71 (2018)
       
  • Substrate fiber alignment mediates tendon cell response to inflammatory
           signaling
    • Authors: Angelina D. Schoenenberger; Jasper Foolen; Pascal Moor; Unai Silvan; Jess G. Snedeker
      Pages: 306 - 317
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Angelina D. Schoenenberger, Jasper Foolen, Pascal Moor, Unai Silvan, Jess G. Snedeker
      Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures. We confirmed that fibroblast morphology, phenotype, and markers of matrix turnover could be significantly affected by matrix topography. More strikingly, the TF response to paracrine signals from polarized macrophages or by stimulation with pro-inflammatory cytokines featured significant downregulation of signaling related to extracellular synthesis, with significant concomitant upregulation of gene and protein expression of matrix degrading enzymes. Critically, this tendency towards degenerative re-regulation was exacerbated on randomly oriented PCL substrates. These novel findings indicate that highly aligned tendon cell scaffolds not only promote tendon matrix synthesis, but also play a previously unappreciated role in mitigating adverse resident fibroblast response within an inflammatory milieu. Statement of Significance Use of biomaterial scaffolds for tendon repair often results in tissue formation characteristic of scar tissue, rather than the highly aligned type-1 collagen matrix of healthy tendons. We hypothesized that non-optimal biomaterial surfaces may play a role in these outcomes, specifically randomly oriented biomaterial surfaces that unintentionally mimic structure of pathological tendon. We observed that disorganized scaffold surfaces do adversely affect early cell attachment and gene expression. We further identified that disorganized fiber surfaces can prime tendon cells toward pro-inflammatory signaling. These findings represent provocative evidence unstructured fiber surfaces may underlie inflammatory responses that drive aberrant collagen matrix turnover. This work could be highly relevant for the design of cell instructive biomaterial therapies that yield positive clinical outcomes.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.004
      Issue No: Vol. 71 (2018)
       
  • Fibrin glue mesh fixation combined with mesenchymal stem cells or exosomes
           modulates the inflammatory reaction in a murine model of incisional hernia
           
    • Authors: Rebeca Blázquez; Francisco Miguel Sánchez-Margallo; Verónica Álvarez; Alejandra Usón; Federica Marinaro; Javier G. Casado
      Pages: 318 - 329
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Rebeca Blázquez, Francisco Miguel Sánchez-Margallo, Verónica Álvarez, Alejandra Usón, Federica Marinaro, Javier G. Casado
      Surgical meshes are effective and frequently used to reinforce soft tissues. Fibrin glue (FG) has been widely used for mesh fixation and is also considered an optimal vehicle for stem cell delivery. The aim of this preclinical study was to evaluate the therapeutic effect of MSCs and their exosomes combined with FG for the treatment of incisional hernia. A murine incisional hernia model was used to implant surgical meshes and different treatments with FG, MSCs and exo-MSCs were applied. The implanted meshes were evaluated at day 7 by anatomopathology, cellular analysis of infiltrating leukocytes and gene expression analysis of TH1/TH2 cytokines, MMPs, TIMPs and collagens. Our results demonstrated a significant increase of anti-inflammatory M2 macrophages and TH2 cytokines when MSCs or exo-MSCs were used. Moreover, the analysis of MMPs, TIMPs and collagen exerted significant differences in the extracellular matrix and in the remodeling process. Our in vivo study suggests that the fixation of surgical meshes with FG and MSCs or exo-MSCs will have a beneficial effect for the treatment of incisional hernia in terms of improved outcomes of damaged tissue, and especially, in the modulation of inflammatory responses towards a less aggressive and pro-regenerative profile. Statement of Significance The implantation of surgical meshes is the standard procedure to reinforce tissue defects such as hernias. However, an exacerbated and persistent inflammatory response secondary to this implantation is frequently observed, leading to a strong discomfort and chronic pain in the patients. In many cases, an additional surgical intervention is needed to remove the mesh. This study shows that mesenchymal stem cells and their exosomes, combined with a fibrin sealant, can be used for the successful fixation of these meshes. This new therapeutic approach, assayed in a murine model of incisional hernia, favors the modulation of the inflammatory response towards a less aggressive and pro-regenerative profile.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.014
      Issue No: Vol. 71 (2018)
       
  • Recovery of low volumes of wear debris from rat stifle joint tissues using
           a novel particle isolation method
    • Authors: J. Patel; S. Lal; K. Nuss; S.P. Wilshaw; B. von Rechenberg; R.M. Hall; J.L. Tipper
      Pages: 339 - 350
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): J. Patel, S. Lal, K. Nuss, S.P. Wilshaw, B. von Rechenberg, R.M. Hall, J.L. Tipper
      Less than optimal particle isolation techniques have impeded analysis of orthopaedic wear debris in vivo. The purpose of this research was to develop and test an improved method for particle isolation from tissue. A volume of 0.018 mm3 of clinically relevant CoCrMo, Ti-6Al-4V or Si3N4 particles was injected into rat stifle joints for seven days of in vivo exposure. Following sacrifice, particles were located within tissues using histology. The particles were recovered by enzymatic digestion of periarticular tissue with papain and proteinase K, followed by ultracentrifugation using a sodium polytungstate density gradient. Particles were recovered from all samples, observed using SEM and the particle composition was verified using EDX, which demonstrated that all isolated particles were free from contamination. Particle size, aspect ratio and circularity were measured using image analysis software. There were no significant changes to the measured parameters of CoCrMo or Si3N4 particles before and after the recovery process (KS tests, p > 0.05). Titanium particles were too few before and after isolation to analyse statistically, though size and morphologies were similar. Overall the method demonstrated a significant improvement to current particle isolation methods from tissue in terms of sensitivity and efficacy at removal of protein, and has the potential to be used for the isolation of ultra-low wearing total joint replacement materials from periprosthetic tissues. Statement of Significance This research presents a novel method for the isolation of wear particles from tissue. Methodology outlined in this work would be a valuable resource for future researchers wishing to isolate particles from tissues, either as part of preclinical testing, or from explants from patients for diagnostic purposes. It is increasingly recognised that analysis of wear particles is critical to evaluating the safety of an orthopaedic device.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.030
      Issue No: Vol. 71 (2018)
       
  • Targeting tumor hypoxia with stimulus-responsive nanocarriers in
           overcoming drug resistance and monitoring anticancer efficacy
    • Authors: Zhiqi Xie; Wangwei Guo; Ningning Guo; Mingyi Huangfu; Huina Liu; Mengting Lin; WenHong Xu; Jiejian Chen; TianTian Wang; Qichun Wei; Min Han; Jianqing Gao
      Pages: 351 - 362
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Zhiqi Xie, Wangwei Guo, Ningning Guo, Mingyi Huangfu, Huina Liu, Mengting Lin, WenHong Xu, Jiejian Chen, TianTian Wang, Qichun Wei, Min Han, Jianqing Gao
      Although existing nanomedicines have focused on the tumor microenvironment with the goal of improving the effectiveness of conventional chemotherapy, the penetration of a tumor’s core still represents a formidable barrier for existing drug delivery systems. Therefore, a novel multifunctional hypoxia-induced size-shrinkable nanoparticle has been designed to increase the penetration of drugs, nucleic acids, or probes into tumors. This cooperative strategy relies on three aspects: (i) the responsiveness of nanoparticles to hypoxia, which shrink when triggered by low oxygen concentrations; (ii) the core of a nanoparticle involves an internal cavity and strong positive charges on the surface to deliver both doxorubicin and siRNA; and (iii) a reactive oxygen species (ROS) probe is incorporated in the nanoparticle to monitor its preliminary therapeutic response in real time, which is expected to realize the enhanced efficacy together with the ability to self-monitor the anticancer activity. A more effective inhibition of tumor growth was observed in tumor-bearing zebrafish, demonstrating the feasibility of this cooperative strategy for in vivo applications. This research highlights a promising value in delivering drugs, nucleic acids, or probes to a tumor’s core for cancer imaging and treatment. Statement of Significance Hypoxia-induced chemoresistance of tumor cells still represents a formidable barrier, as it is difficult for existing drug delivery systems to penetrate the tumor hypoxia core. This study involves the hypoxia-responsive size-shrinkable nanoparticle co-delivery of DOX and siRNA to enhance the penetration of DOX deep within tumors and subsequently disturb crucial pathways of cancer development induced by hypoxia and to improve sensitization to DOX chemotherapy. Furthermore, the nanopreparation can combine the ROS probe as a self-reporting nanopreparation to realize the function of real-time feedback efficacy, which has a good application prospect in the diagnosis and treatment of cancer.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.013
      Issue No: Vol. 71 (2018)
       
  • Investigation of adhesive interactions in the specific targeting of
           Triptorelin-conjugated PEG-coated magnetite nanoparticles to breast cancer
           cells
    • Authors: Jingjie Hu; Sina Youssefian; John Obayemi; Karen Malatesta; Nima Rahbar; Winston Soboyejo
      Pages: 363 - 378
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Jingjie Hu, Sina Youssefian, John Obayemi, Karen Malatesta, Nima Rahbar, Winston Soboyejo
      The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers. Statement of Significance Systematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.011
      Issue No: Vol. 71 (2018)
       
  • Characterizing viscoelastic mechanical properties of highly compliant
           polymers and biological tissues using impact indentation
    • Authors: Aleksandar S. Mijailovic; Bo Qing; Daniel Fortunato; Krystyn J. Van Vliet
      Pages: 388 - 397
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Aleksandar S. Mijailovic, Bo Qing, Daniel Fortunato, Krystyn J. Van Vliet
      Precise and accurate measurement of viscoelastic mechanical properties becomes increasingly challenging as sample stiffness decreases to elastic moduli <1 kPa, largely due to difficulties detecting initial contact with the compliant sample surface. This limitation is particularly relevant to characterization of biological soft tissues and compliant gels. Here, we employ impact indentation which, in contrast to shear rheology and conventional indentation, does not require contact detection a priori, and present a novel method to extract viscoelastic moduli and relaxation time constants directly from the impact response. We first validate our approach by using both impact indentation and shear rheology to characterize polydimethylsiloxane (PDMS) elastomers of stiffness ranging from 100 s of Pa to nearly 10 kPa. Assuming a linear viscoelastic constitutive model for the material, we find that the moduli and relaxation times obtained from fitting the impact response agree well with those obtained from fitting the rheological response. Next, we demonstrate our validated method on hydrated, biological soft tissues obtained from porcine brain, murine liver, and murine heart, and report the equilibrium shear moduli, instantaneous shear moduli, and relaxation time constants for each tissue. Together, our findings provide a new and straightforward approach capable of probing local mechanical properties of highly compliant viscoelastic materials with millimeter scale spatial resolution, mitigating complications involving contact detection or sample geometric constraints. Statement of significance Characterization and optimization of mechanical properties can be essential for the proper function of biomaterials in diverse applications. However, precise and accurate measurement of viscoelastic mechanical properties becomes increasingly difficult with increased compliance (particularly for elastic moduli <1 kPa), largely due to challenges detecting initial contact with the compliant sample surface and measuring response at short timescale or high frequency. By contrast, impact indentation has highly accurate contact detection and can be used to measure short timescale (glassy) response. Here, we demonstrate an experimental and analytical method that confers significant advantages over existing approaches to extract spatially resolved viscoelastic moduli and characteristic time constants of biological tissues (e.g., brain and heart) and engineered biomaterials.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.017
      Issue No: Vol. 71 (2018)
       
  • Beyond the protein corona – lipids matter for biological response of
           nanocarriers
    • Authors: Julius Müller; Domenik Prozeller; Artur Ghazaryan; Maria Kokkinopoulou; Volker Mailänder; Svenja Morsbach; Katharina Landfester
      Pages: 420 - 431
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Julius Müller, Domenik Prozeller, Artur Ghazaryan, Maria Kokkinopoulou, Volker Mailänder, Svenja Morsbach, Katharina Landfester
      The interaction of nanocarriers with blood plasma components influences the biological response, and therefore, it needs to be controlled. Whereas protein adsorption to nanocarriers has been investigated to a large extent, the role of lipid interaction for drug delivery and its biological effect is not yet clear. However, lipids represent an important constituent of blood plasma and are usually bound in the form of lipoproteins. Because already for many nanocarrier systems an enrichment of apolipoproteins in their protein corona was reported, we examine the interaction of lipoproteins with nanocarriers. If interaction occurs in terms of lipoprotein adsorption, two scenarios are possible: adsorption of intact lipoprotein complexes or disintegration of the complexes with adsorption of the single components. To investigate the interaction and clarify which scenario occurs, polymeric model nanoparticles and different lipoprotein types have been studied by isothermal titration calorimetry, transmission electron microscopy, and other methods. Our data indicate that upon contact with polymeric nanoparticles, disintegration of lipoproteins and adsorption of lipids occurs. Further, the effect of lipoprotein adsorption on cell uptake has been examined, and a major effect of the lipoproteins has been found. Statement of Significance It is now well accepted that nanomaterials developed as diagnostic or therapeutic carrier systems need to be well characterized in terms of biological responses inside an organism. Many studies have already shown that proteins adsorb to the surface of a nanomaterial and create a new interface that define the identity of the material. However, the presence of other surface-active components of the blood plasma and how they interact with nanomaterials has been much less investigated. Thus, this study aims at providing a significant contribution to understanding the interaction mechanism between lipoproteins and nanomaterials. Since lipoproteins transport a high amount of lipids, which are surface-active molecules, the demonstrated interactions can go as far as complete lipoprotein disintegration.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.036
      Issue No: Vol. 71 (2018)
       
  • Protein machineries defining pathways of nanocarrier exocytosis and
           transcytosis
    • Authors: Jonas Reinholz; Christopher Diesler; Susanne Schöttler; Maria Kokkinopoulou; Sandra Ritz; Katharina Landfester; Volker Mailänder
      Pages: 432 - 443
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Jonas Reinholz, Christopher Diesler, Susanne Schöttler, Maria Kokkinopoulou, Sandra Ritz, Katharina Landfester, Volker Mailänder
      The transport of nanocarriers through barriers like the gut in a living organism involves the transcytosis of these nanocarriers through the cell layer dividing two compartments. Understanding how this process works is not only essential to further developing strategies for a more effective nanocarrier transport system but also for providing fundamental insights into the barrier function as a means of protection against micro- and nanoplastics in the food chain. We therefore set out to investigate the different uptake mechanisms, intracellular trafficking and the routes for exocytosis for small polystyrene nanoparticles (PS-NPs ca. 100 nm) as mimicking nanocarriers in a Caco-2 cell model for gut-blood transition. We used label-free, quantitative mass spectrometry (MS) for determining the proteome that adhered to transversed nanoparticles. From this rich proteomics dataset, as well as previous studies, we generated stable-transfected Caco-2 cell lines carrying the green fluorescent protein (GFP) coupled to proteins of interest for uptake, early, late and exocytotic endosomes. We detected the spatial and temporal overlap of such marked endosomes with the nanocarrier signal in confocal laser scanning and super-resolution microscopy. There was a clear distinction in the time course of nanoparticle trafficking between groups of proteins for endocytosis, intracellular storage and putatively transcytosis and we identified several key transcytotic markers like Rab3 and Copine1. Moreover, we postulate the necessity of a certain protein composition on endosomes for successful transcytosis of nanocarriers. Finally, we define the two-sided impasse of the lysosome as a dead end for nano-plastic and the limit of nanocarriers in the 100 nm range. Statement of Significance Here we focus on mechanisms of transcytosis and how we can follow these with methods not used before. First, we use mass spectrometry of transcytosed nanoparticles to pick proteins of the transcytosis machinery describing key proteins involved. We can detect the complex mixtures of proteins. As this is a dynamic process involving whole families of proteins interacting with each other and as this is an orchestrated process we coined the term protein machineries for this active interplay. By genetically modifying the proteins attaching GFP we are able to follow the transcytosis pathway. We evaluate the process in a quantitative manner over time. This reveals that the most obvious obstacle to transcytosis is a routing of the nanocarriers to the lysosomes.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.03.006
      Issue No: Vol. 71 (2018)
       
  • Glaucomatous cell derived matrices differentially modulate
           non-glaucomatous trabecular meshwork cellular behavior
    • Authors: Vijay Krishna Raghunathan; Julia Benoit; Ramesh Kasetti; Gulab Zode; Michelle Salemi; Brett S. Phinney; Kate E. Keller; Julia A. Staverosky; Christopher J. Murphy; Ted Acott; Janice Vranka
      Pages: 444 - 459
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Vijay Krishna Raghunathan, Julia Benoit, Ramesh Kasetti, Gulab Zode, Michelle Salemi, Brett S. Phinney, Kate E. Keller, Julia A. Staverosky, Christopher J. Murphy, Ted Acott, Janice Vranka
      Ocular hypertension is a causal risk-factor to developing glaucoma. This is associated with stiffening of the trabecular meshwork (TM), the primary site of resistance to aqueous-humor-outflow. The mechanisms underlying this stiffening or how pathologic extracellular matrix (ECM) affects cell function are poorly understood. It is recognized that mechanotransduction systems allow cells to sense and translate the intrinsic biophysical properties of ECM into intracellular signals to control gene transcription, protein expression, and cell behavior. Using an anterior segment perfusion model, we document that there are significantly more low flow regions that are much stiffer, and fewer high flow regions that are less stiff in glaucomatous TM (GTM) when compared to non-glaucomatous TMs (NTM). GTM tissue also has fewer cells overall when compared with NTM tissue. In order to study the role of pathologic ECM in glaucoma disease progression, we conducted studies using cell derived matrices (CDM). First, we characterized the mechanics, composition and organization of fibronectin in ECM deposited by GTM and NTM cells treated with glucocorticosteroids. Then, we determined that these GTM-derived ECM are able to induce stiffening of normal NTM cells, and alter their gene/protein expression to resemble that of a glaucomatous phenotype. Further, we demonstrate that GTM-derived ECM causes endoplasmic reticular stress in NTM. They also became resistant to being reorganized by these NTM cells. These phenomena were exacerbated by ECMs obtained from steroid treated glaucoma model groups. Collectively, our data demonstrates that CDMs represent a novel tool for the study of bidirectional interactions between TM cells and their immediate microenvironment. Statement of Significance Extracellular matrix (ECM) changes are prevalent in a number of diseases. The precise mechanisms by which changes in the ECM contribute to disease progression is unclear, primarily due to absence of appropriate models. Here, using glaucoma as a disease model, we document changes in cell derived matrix (CDM) and tissue mechanics that contribute to the pathology. Subsequently, we determine the effect that ECMs from diseased and healthy individuals have on healthy cell behaviors. Data emanating from this study demonstrate that CDMs are a potent tool for the study of cell-ECM interactions.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.037
      Issue No: Vol. 71 (2018)
       
  • Puncturing of lyophilized tissue engineered vascular matrices enhances the
           efficiency of their recellularization
    • Authors: Agnieszka A. Książek; Laura Frese; Petra E. Dijkman; Bart Sanders; Sarah E. Motta; Benedikt Weber; Simon P. Hoerstrup
      Pages: 474 - 485
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Agnieszka A. Książek, Laura Frese, Petra E. Dijkman, Bart Sanders, Sarah E. Motta, Benedikt Weber, Simon P. Hoerstrup
      Data on in vitro engineered “off the shelf” matrices support the concept of endogenous cellular repopulation driving the graft’s remodeling via immune-mediated response. This seems important to further accelerate the cell reconstitution and may play a crucial role when mononuclear cells are used. Nevertheless, studies on decellularized xenogeneic grafts showed only limited host cell repopulation post-implantation. This study aims at a systematic comparison of reseeding methods (dripping, injection, bathing in a cell suspension and combined puncturing-dripping method) to define the most efficient technique enhancing recellularization of tissue engineered vascular matrices (patches, vessels, small diameter and standard size valves) prior implantation. The constructs were analyzed histologically, biochemically and biomechanically. Various preconditioning treatments (wet, lyophilized and air-dried) combined with reseeding methods demonstrated the highest cell loading efficiency, despite applied crimping and flow stress, of lyophilization followed by puncturing-dripping technique. This novel seeding method allows for an efficient, time-saving graft reseeding that can be used within a one-step cardiovascular clinical intervention. Statement of Significance The concept of living tissue engineered, self-repairing, autologous cardiovascular replacements, was proposed alternatively to existing synthetic/xenogeneic prostheses. Recent studies in animal models demonstrate faster in vivo recellularization after grafts pre-seeding with cells prior implantation. Pre-seeded cells hold either, the ability to differentiate directionally or attract host cells, crucial for graft integration and remodeling. It is unclear, however, how efficient the pre-loading is and how well cells withstand the flow. The study presents a systematic overview of cell loading techniques of different cardiovascular constructs, tested under static and dynamic conditions. Comparison illustrates a significantly higher efficiency of cells loading in lyophilized tissues punctured before their standard seeding. This technique may beneficially accelerate remodeling of cardiovascular grafts in further in vivo studies.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.029
      Issue No: Vol. 71 (2018)
       
  • Manipulation of VEGF-induced angiogenesis by 2-N, 6-O-sulfated chitosan
    • Authors: Yuanman Yu; Rui Chen; Yi Sun; Yuanzhong Pan; Wei Tang; Shuang Zhang; Lingyan Cao; Yuan Yuan; Jing Wang; Changsheng Liu
      Pages: 510 - 521
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Yuanman Yu, Rui Chen, Yi Sun, Yuanzhong Pan, Wei Tang, Shuang Zhang, Lingyan Cao, Yuan Yuan, Jing Wang, Changsheng Liu
      Emerging evidence suggests that vascular endothelial growth facto (VEGF) is important in the treatment of various ischemic and cardiovascular diseases. However, it often suffers from high cost and easy deactivation with a short half-life. Here, we describe a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF promoting the binding of the signaling protein to its VEGF receptor 2 (VEGFR2), activating receptor phosphorylation and pro-angiogenic related genes expression, and further stimulating downstream VEGF-dependent endothelial cell viability, migration, tube formation and rat aortic rings outgrowth. Interestingly, the obvious recruitment of mural cells were occurred to stabilize the sprouted microvessels. In addition, the pro-angiogenic potential of 26SCS composited VEGF was confirmed in vivo using the chick embryo chorioallantoic membrane (CAM) assay with an extensive perfusable vascular network. A longer monitoring was administered subcutaneously to mice in a biocompatible gelatin sponge and showed that VEGF with 26SCS had the capability to efficiently enhance neovascularization. These findings highlight that 26SCS, the semi-synthetic natural polymer, may be a promising coagent with VEGF for vascular therapy. Statement of significance Vascular endothelial growth factor (VEGF) is crucial for facilitating angiogenesis to supply oxygen and nutrient during wound healing and tissue regeneration. However, appropriate use of VEGF is an ongoing challenge due to its rapidly clearance and severe side effects at higher dosage. In this study, we described a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF, which could significantly promote its binding capacity to VEGF receptor 2 and further stimulate the angiogenic behavior of endothelial cells. We further confirmed that 26SCS was spatially combined with VEGF in a “lying manner”, and this spatial arrangement was more conducive to exposure of the receptor binding domain of VEGF. Additionally, it also promoted in vivo angiogenesis in a chicken chorioallantoic membrane assay and mouse subcutaneous implant model. This strategy may afford a new avenue to enhance pro-angiogenic capacity of VEGF.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.02.031
      Issue No: Vol. 71 (2018)
       
  • Corrigendum to “One step fabrication of hydrogel microcapsules with
           hollow core for assembly and cultivation of hepatocyte spheroids” [Acta
           Biomater. 50 (2017) 428–436]
    • Authors: Christian Siltanen; Michalitsa Diakatou; Jeremy Lowen; Amranul Haque; Ali Rahimian; Gulnaz Stybayeva; Alexander Revzin
      First page: 522
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Christian Siltanen, Michalitsa Diakatou, Jeremy Lowen, Amranul Haque, Ali Rahimian, Gulnaz Stybayeva, Alexander Revzin


      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2017.10.023
      Issue No: Vol. 71 (2018)
       
  • Corrigendum to “pH-triggered chitosan nanogels via an ortho ester-based
           linkage for efficient chemotherapy” [Acta Biomater. 60 (2017) 232–243]
           
    • Authors: Guanqing Yang; Xin Wang; Shengxiang Fu; Rupei Tang; Jun Wang
      Pages: 523 - 524
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Guanqing Yang, Xin Wang, Shengxiang Fu, Rupei Tang, Jun Wang


      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2017.12.015
      Issue No: Vol. 71 (2018)
       
  • Corrigendum to “Tailoring surface nanoroughness of electrospun scaffolds
           for skeletal tissue engineering” Acta Biomater. 59 (2017) 82–93
    • Authors: Honglin Chen; Xiaobin Huang; Minmin Zhang; Febriyani Damanik; Matthew B. Baker; Anne Leferink; Huipin Yuan; Roman Truckenmüller; Clemens van Blitterswijk; Lorenzo Moroni
      First page: 525
      Abstract: Publication date: 15 April 2018
      Source:Acta Biomaterialia, Volume 71
      Author(s): Honglin Chen, Xiaobin Huang, Minmin Zhang, Febriyani Damanik, Matthew B. Baker, Anne Leferink, Huipin Yuan, Roman Truckenmüller, Clemens van Blitterswijk, Lorenzo Moroni


      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.01.030
      Issue No: Vol. 71 (2018)
       
  • Estrone-modified pH-sensitive Glycol Chitosan Nanoparticles for Drug
           Delivery in Breast Cancer
    • Authors: Huan Yang; Cui Tang; Chunhua Yin
      Abstract: Publication date: Available online 14 April 2018
      Source:Acta Biomaterialia
      Author(s): Huan Yang, Cui Tang, Chunhua Yin
      Estrone-modified glycol chitosan nanoparticles (GCNP-ES) based on the mechanisms of ES-mediated endocytosis and intracellular pH-responsive drug release were developed for the treatment of breast cancer. GCNP-ES were prepared by grafting copolymerization of glycol chitosan with 2-(diisopropylamino)ethyl methacrylate to generate GCNP prior to ES conjugation. The particle size, zeta potential, and paclitaxel (PTX) encapsulation efficiency of GCNP-ES were characterized. In particular, GCNP-ES exhibited pH-responsive dissociation properties while maintaining stability under long-term storage and lyophilization. The drug release of PTX-loaded GCNP-ES (PTX/GNCP-ES) was modestly prolonged with considerable pH sensitivity. GCNP-ES promoted internalization in breast cancer MCF-7 cells by approximately 5-fold as compared to GCNP, and the internalized GCNP-ES was mainly localized in the endosomes of MCF-7 cells. PTX/GNCP-ES exhibited higher cytotoxicity and cell apoptosis ratio than GCNP. In mice with MCF-7 breast cancer xenograft, PTX/GCNP-ES showed higher accumulation at the tumor site, which resulted in a higher tumor inhibition ratio (81.4%) than that achieved by PTX/GCNP (69.4%) and PTX solution (48.8%). Furthermore, no histological and hematological toxicity was detected in in vivo studies of PTX/GCNP-ES. Overall, these results suggested the potential applicability of GCNP-ES as a drug delivery system for breast cancer therapy. Statement of significance Most breast cancers are hormone dependent. Herein, we developed a estrone-modified glycol chitosan nanoparticles (GCNP-ES) as a drug delivery system to overcome the drawbacks of chemotherpeutic drugs, including poor water solubility and lack of specifity. GCNP-ES could provide efficient drug delivery in breast cancer cells. The study demonstrated that GCNP-ES could dissociate under mildly acidic conditions, leading to the timely payload release of the drug in target tumor cells following internalization. The conjugated estrone of the nanoparticles could significantly increase drug accumulation in the tumor site and result in enhanced therapeutic effect. Thus, the potential applicability of GCNP-ES was suggested.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.04.020
       
  • Comparative adsorption profiles of basal lamina proteome and gingival
           cells onto dental and titanium surfaces
    • Authors: Mohamed-Nur Abdallah; Ghada Abughanam; Simon D Tran; Zeeshan Sheikh; Mohamed A. Mezour; Tayebah basiri; Yizhi Xiao; Marta Cerruti; Walter L Siqueira; Faleh Tamimi
      Abstract: Publication date: Available online 13 April 2018
      Source:Acta Biomaterialia
      Author(s): Mohamed-Nur Abdallah, Ghada Abughanam, Simon D Tran, Zeeshan Sheikh, Mohamed A. Mezour, Tayebah basiri, Yizhi Xiao, Marta Cerruti, Walter L Siqueira, Faleh Tamimi
      Titanium (Ti) dental implants are susceptible to bacterial infections and failure due to lack of proper epithelial seal. Epithelial cells establish a strong epithelial seal around natural teeth by the deposition of basal lamina (BL) proteins that adsorb on the tooth surface. This seal can even be re-established onto cementum or dentin following injury or periodontal therapy. However, it is unclear how tooth surfaces promote this cell attachment and protein adsorption. Understanding the interactions between BL proteins and epithelial cells with dentin and Ti will facilitate the development of implant surfaces that promote the formation of an epithelial seal and improve the success of periodontal therapy and wound healing on natural teeth. To study these interactions, we used a surface proteomic approach to decipher the adsorption profile of BL proteins onto Ti and dentin, and correlated these adsorption profiles with in vitro interactions of human gingival fibroblasts and epithelial cells. Results showed that dentin adsorbed higher amounts of key BL proteins, particularly laminin and nidogen-1, and promoted more favorable interactions with epithelial cells than Ti. Next, dentin specimens were deproteinized or partially demineralized to determine if its mineral or protein component was responsible for BL adsorption and cell attachment. Deproteinized (mineral-rich) and partially demineralized (protein-rich) dentin specimens revealed BL proteins (i.e. laminin and nidogen-1) and epithelial cells interact preferentially with dentinal proteins rather than dentin mineral. These findings suggest that, unlike Ti, dentin and, in particular, dentinal proteins have a selective affinity to BL proteins that enhance epithelial cell attachment. Statement of Significance It is remains unclear why natural teeth, unlike titanium dental implants, promote the formation of an epithelial seal that protects them against the external environment. This study used a surface screening approach to analyze the adsorption of proteins produced by epithelial tissues onto tooth-dentin and titanium surfaces, and correlate it with the behaviour of cells. This study shows that tooth-dentin, in particular its proteins, has a higher selective affinity to certain adhesion proteins, and subsequently allows more favourable interactions with epithelial cells than titanium. This knowledge could help in developing new approaches for re-establishing and maintaining the epithelial seal around teeth, and could pave the way for developing implants with surfaces that allow the formation of a true epithelial seal.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.04.017
       
  • 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
      Abstract: Publication date: Available online 13 April 2018
      Source:Acta Biomaterialia
      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 24h of incubation at drug concentration up to 600μM. 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, 69nmol 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 69nmol 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.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.04.019
       
  • 3D-printed scaffolds with bioactive elements-induced photothermal effect
           for bone tumor therapy
    • Authors: Yaqin Liu; Tao Li; Hongshi Ma; Dong Zhai; Cuijun Deng; Jinwu Wang; Shangjun Zhuo; Jiang Chang; Chengtie Wu
      Abstract: Publication date: Available online 13 April 2018
      Source:Acta Biomaterialia
      Author(s): Yaqin Liu, Tao Li, Hongshi Ma, Dong Zhai, Cuijun Deng, Jinwu Wang, Shangjun Zhuo, Jiang Chang, Chengtie Wu
      For treatment of bone tumor and regeneration of bone defects, the biomaterials should possess the ability to kill tumor cells and regenerate bone defect simultaneously. To date, there are a few biomaterials possessing such dual functions, the disadvantages, however, such as long-term toxicity and degradation, restrict their application. Although bioactive elements have been incorporated into biomaterials to improve their osteogenic activity, there is no report about elements-induced functional scaffolds for photothermal tumor therapy. Herein, the elements (Cu, Fe, Mn, Co)-doped bioactive glass-ceramic (BGC) scaffolds with photothermal effect and osteogenic differentiation ability were prepared via 3D-printing method. Moreover, the photothermal anti-tumor effect and osteogenic activity of these scaffolds were systematically investigated. The prepared elements-doped scaffolds possessed excellent photothermal performance, which displayed a trend, 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC, in this study. The final temperature of elements-doped scaffolds can be well controlled by altering the doping element categories, contents and laser power density. Additionally, the hyperthermia induced by 5Cu-BGC, 5Fe-BGC and 5Mn-BGC effectively killed tumor cells in vitro and inhibited tumor growth in vivo. More importantly, 5Fe-BGC and 5Mn-BGC scaffolds could promote rabbit bone mesenchymal stem cells (rBMSCs) adhesion, and the ionic products released from elements-doped scaffolds significantly stimulated the osteogenic differentiation of bone-forming cells. These results suggested that 5Fe-BGC and 5Mn-BGC scaffolds possessed promising potential for photothermal treatment of bone tumor and at the same time for stimulating bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds. Statement of significance The major innovation of this study is that we fabricated the elements (Cu, Fe, Mn, Co)-doped bioactive scaffolds via 3D printing technique and found that they possess distinct photothermal performance and osteogenic differentiation ability. To the best of our knowledge, there is no report about elements-doped scaffolds for photothermal therapy of bone tumor. This is an important research advance by combining the photothermal effect and osteogenic differentiation activity of bioactive elements in the scaffold system for potential bone tumor therapy and bone reconstruction. We optimized the elements-doped scaffolds and found the photothermal effect of elements-doped scaffolds (5Cu-BGC, 5Fe-BGC, 5Mn-BGC) could effectively kill tumor cells in vivo. The photothermal performance of elements-doped scaffolds follows a trend: 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC > BGC. Compared to traditional nano-sized photothermal agents, bioactive elements-induced functional scaffolds have better biosecurity and bioactivity. Furthermore, 5Fe-BGC and 5Mn-BGC scaffolds displayed excellent bone-forming activity by stimulating the osteogenic differentiation of bone-forming cells. The major significance of the study is that the elements-doped bioactive glass-ceramics (5Fe-BGC, 5Mn-BGC) have great potential to be used as bifunctional scaffolds for photothermal tumor therapy and bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.
      Graphical abstract image

      PubDate: 2018-04-15T07:07:33Z
      DOI: 10.1016/j.actbio.2018.04.014
       
  • Photooxidatively crosslinked acellular tumor extracellular matrices as
           potential tumor engineering scaffolds
    • Authors: Wei-Dong Lü; Rui-Fang Sun; Ye-Rong Hu; Jan-Rong Lu; Lu Gu; Zhi-Gang Liu; Guang-Yan Lei; Zhun Qiang; Lin Cai
      Abstract: Publication date: Available online 17 March 2018
      Source:Acta Biomaterialia
      Author(s): Wei-Dong Lü, Rui-Fang Sun, Ye-Rong Hu, Jan-Rong Lu, Lu Gu, Zhi-Gang Liu, Guang-Yan Lei, Zhun Qiang, Lin Cai
      Acellular tumor extracellular matrices (ECMs) have limitations when employed as three-dimensional scaffolds for tumor engineering. In this work, methylene blue-mediated photooxidation was used to crosslink acellular tumor ECMs. Photooxidative crosslinking greatly increased the stiffness of acellular tumor ECM scaffolds but barely altered the Amide III band of the secondary structure of polypeptides and proteins. MCF-7, HepG2 and A549 cells cultured on photooxidatively crosslinked acellular tumor ECM scaffolds exhibited greater cell number per scaffold, more IL-8 and VEGF secretion, and increase migration and invasion abilities than cells cultured on uncrosslinked acellular tumor ECM scaffolds. The three tumor cell lines cultured on the stiffer photooxidatively crosslinked acellular matrices acquire mesenchymal properties (mesenchymal shift) and dedifferentiated phenotypes. Furthermore, the malignant phenotypes induced in vitro when cultured on the crosslinked scaffold promoted the in vivo tumor growth of BALB/c nude mice. Finally, the dedifferentiated cancer cells, including MCF-7, HepG2 and A549 cells, were less sensitive to chemotherapeutics. Thus, photooxidatively crosslinked acellular tumor ECMs have potentials as three-dimensional (3D) tumor engineering scaffolds for cancer research. Statement of Significance Natural material scaffolds have been successfully used as 3D matrices to study the in vitro tumor cell growth and mimic the in vivo tumor microenvironment. Acellular tumor extracellular matrices (ECMs) are developed as 3D scaffolds for tumor engineering but have limitations in terms of elastic modulus and cell spheroid formation. Here we use methylene blue-mediated photooxidation to crosslink acellular tumor ECMs and investigate the influence of photooxidative crosslinking on structural, mechanical and biological characteristics of acellular tumor ECM scaffolds. It is the first study to evaluate the feasibility of photooxidatively crosslinked acellular tumor ECMs as 3D scaffolds for cancer research and the results are encouraging. Moreover, this study provides new research areas in regard to photodynamic therapy (PDT) for Cancer.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.020
       
  • Long-term in vivo evolution of high-purity Mg screw degradation — Local
           and systemic effects of Mg degradation products
    • Authors: Yiqiang Yu; Hua Lu; Jiao Sun
      Abstract: Publication date: Available online 17 March 2018
      Source:Acta Biomaterialia
      Author(s): Yiqiang Yu, Hua Lu, Jiao Sun
      Magnesium (Mg) based materials are the focus of research for use as degradable materials in orthopedics and cranio-maxillofacial surgery. However, corrosion rate control and biosecurity are still the key issues that need to be solved prior to their clinical applications. In the present study, as-rolled high-purity magnesium (HP Mg, 99.99 wt%) screws were implanted in rabbit tibiae for up to 52 weeks in order to investigate their long-term in vivo degradation and the local and systemic effects of their degradation products. A series of long-term monitoring were performed at various time points (4w, 12w, 26w and 52w) after implantation using numerous investigations such as micro-CT assay, histomorphometric analysis, local micro-environment testing and biochemical analysis of serum and urine. It was revealed that HP Mg screws had a uniform degradation morphology and a slow degradation rate in vivo during the period of 52 weeks. Their degradation products not only increased the local pH values but also changed the local Mg2+ ions concentration and gas cavity area in the peri-implant tissues in a dynamic manner. More importantly, both the new bone formation and bone-implant contact rate were increased at bone-implant interfaces at 26 weeks and 52 weeks post-implantation. Furthermore, neither abnormal elevation of serum magnesium and urine magnesium level, nor liver and kidney dysfunction were detected during the monitoring period of 26 weeks. All these results of long-term investigation suggest that HP Mg screws possess a slow degradation rate, desirable bone repair capacity and long-term local/systemic biosafety, and consequently may have good potential for application as bone fixation devices. Statement of significance The corrosion resistance control and biosecurity issues of Mg alloys limited their clinical applications in some extent. Mg purification is another effective way to improve corrosion resistance of Mg-based materials. However, the long-term in vivo degradation of high-purity magnesium (HP Mg) and the local and systemic effects of its degradation products have not been fully investigated yet, which are the key factors to determine the clinical application prospect of HP Mg. Especially the changes in peri-implant microenvironment may greatly influence the local physiological response and bone repair. In this study, the long-term evolution tendency of in vivo degradation behavior of HP Mg screws was discovered from the view of space-time. Furthermore, not only the dynamic changes of local microenvironment and the long-term evolution process of bone repair, but also the dynamic systemic responses were systematically revealed. Conclusions of this study may help us to further understand the long-term in vivo evolution of HP Mg degradation and the local/systemic effects of its degradation products and help to guide the design of biodegradable bone fixation material.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.02.023
       
  • Effects of Tunable, 3D-Bioprinted Hydrogels on Human Brown Adipocyte
           Behavior and Metabolic Function
    • Authors: Mitchell Kuss; Jiyoung Kim; Dianjun Qi; Shaohua Wu; Yuguo Lei; Soonkyu Chung; Bin Duan
      Abstract: Publication date: Available online 16 March 2018
      Source:Acta Biomaterialia
      Author(s): Mitchell Kuss, Jiyoung Kim, Dianjun Qi, Shaohua Wu, Yuguo Lei, Soonkyu Chung, Bin Duan
      Obesity and its related health complications cause billions of dollars in healthcare costs annually in the United States, and there are yet to be safe and long-lasting anti-obesity approaches. Using brown adipose tissue (BAT) is a promising approach, as it uses fats for energy expenditure. However, the effect of the microenvironment on human thermogenic brown adipogenesis and how to generate clinically relevant sized and functioning BAT are still unknown. In our current study, we evaluated the effects of endothelial growth medium exposure on brown adipogenesis of human brown adipose progenitors (BAP). We found that pre-exposing BAP to angiogenic factors promoted brown adipogenic differentiation and metabolic activity. We further 3D bioprinted brown and white adipose progenitors within hydrogel-based bioink with controllable physicochemical properties and evaluated the cell responses in 3D bioprinted environments. We used soft, stiff, and stiff-porous constructs to encapsulate the cells. All three types had high cell viability and allowed for varying levels of function for both white and brown adipocytes. We found that the soft hydrogel constructs promoted white adipogenesis, while the stiff-porous hydrogel constructs improved both white and brown adipogenesis and were the optimal condition for promoting brown adipogenesis. Consistently, stiff-porous hydrogel constructs showed higher metabolic activities than stiff hydrogel constructs, as assessed by 2-deoxy glucose uptake (2-DOG) and oxygen consumption rate (OCR). These findings show that the physicochemical environments affect the brown adipogenesis and metabolic function, and further tuning will be able to optimize their functions. Our results also demonstrate that 3D bioprinting of brown adipose tissues with clinically relevant size and metabolic activity has the potential to be a viable option in the treatment of obesity and type 2 diabetes. Statement of Significance One promising strategy for the treatment or prevention of obesity-mediated health complications is augmenting brown adipose tissues (BAT), which is a specialized fat that actively dissipate energy in the form of heat and maintain energy balance. In this study, we determined how pre-exposing human brown adipose progenitors (BAP) to angiogenic factors in 2D and how bioprinted microenvironments in 3D affected brown adipogenic differentiation and metabolic activity. We demonstrated that white and brown adipogenesis, and thermogenesis were regulated by tuning the bioprintable matrix stiffness and construct structure. This study not only unveils the interaction between BAP and 3D physiological microenvironments, but also presents a novel tissue engineered strategy to manage obesity and other related metabolic disorders.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.021
       
  • Genipin cross-linked type II collagen/chondroitin sulfate composite
           hydrogel-like cell delivery system induces differentiation of
           adipose-derived stem cells and regenerates degenerated nucleus pulposus
    • Authors: Xiaopeng Zhou; Jingkai Wang; Weijing Fang; Yiqing Tao; Tengfei Zhao; Kaishun Xia; Chengzhen Liang; Jianming Hua; Fangcai Li; Qixin Chen
      Abstract: Publication date: Available online 16 March 2018
      Source:Acta Biomaterialia
      Author(s): Xiaopeng Zhou, Jingkai Wang, Weijing Fang, Yiqing Tao, Tengfei Zhao, Kaishun Xia, Chengzhen Liang, Jianming Hua, Fangcai Li, Qixin Chen
      Nucleus pulposus (NP) degeneration is usually the origin of intervertebral disc degeneration and consequent lower back pain. Although adipose-derived stem cell (ADSC)-based therapy is regarded to be promising for the treatment of degenerated NP, there is a lack of viable cell carriers to transplant ADSCs into the NP while maintaining cell function. In this study, we developed a type II collagen/chondroitin sulfate (CS) composite hydrogel-like ADSC (CCSA) delivery system with genipin as the cross-linking agent. The induction effect of the scaffold on ADSC differentiation was studied in vitro, and a rat coccygeal vertebrae degeneration model was used to investigate the regenerative effect of the CCSA system on the degenerated NP in vivo. The results showed that the CCSA delivery system cross-linked with 0.02% genipin was biocompatible and promoted the expressions of NP-specific genes. After the injection of the CCSA system, the disc height, water content, extracellular matrix synthesis, and structure of the degenerated NP were partly restored. Our CCSA delivery system uses minimally invasive approaches to promote the regeneration of degenerated NP and provides an exciting new avenue for the treatment of degenerative disc disease. Statement of significance Nucleus pulposus (NP) degeneration is usually the origin of intervertebral disc degeneration and consequent low back pain. Stem cell-based tissue engineering is a promising method in NP regeneration, but there is a lack of viable cell carriers to transplant ADSCs into the NP while maintaining cell function. In this study, we developed a type II collagen/chondroitin sulfate (CS) composite hydrogel-like ADSCs (CCSA) delivery system with genipin cross-linking. Although several research groups have studied the fabrication of injectable hydrogel with biological matrix, our study differs other works. We chose type II collagen and CS, the two primary native components in the NP, as the main materials and combined them according to the natural ratio of collagen and sGAG in the NP. The delivery system is pre-loaded with ADSCs and can be injected into the NP with needle, followed by in situ gelation. Genipin is used as a cross-linker to improve the bio-stability of scaffold, with low cytotoxicity. We investigated the stimulatory effects of our scaffold on ADSCs differentiation in vitro and the regenerative effect of the CCSA delivery system on degenerated NP in vivo.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.019
       
  • Magnetically actuated mechanical stimuli on Fe3O4/mineralized collagen
           coatings to enhance osteogenic differentiation of the MC3T3-E1 cells
    • Authors: Junjun Zhuang; Suya Lin; Lingqing Dong; Kui Cheng; Wenjian Weng
      Abstract: Publication date: Available online 15 March 2018
      Source:Acta Biomaterialia
      Author(s): Junjun Zhuang, Suya Lin, Lingqing Dong, Kui Cheng, Wenjian Weng
      Mechanical stimuli at the bone–implant interface are considered to activate the mechanotransduction pathway of the cell to improve the initial osseointegration establishment and to guarantee clinical success of the implant. However, control of the mechanical stimuli at the bone–implant interface still remains a challenge. In this study, we have designed a strategy of a magnetically responsive coating on which the mechanical stimuli is controlled because of coating deformation under static magnetic field (SMF). The iron oxide nanoparticle/mineralized collagen (IOP-MC) coatings were electrochemically codeposited on titanium substrates in different quantities of IOPs and distributions; the resulting coatings were verified to possess swelling behavior with flexibility same as that of hydrogel. The relative quantity of IOP to collagen and the IOP distribution in the coatings were demonstrated to play a critical role in mediating cell behavior. The cells present on the outer layer of the distributed IOP-MC (O-IOP-MC) coating with a mass ratio of 0.67 revealed the most distinct osteogenic differentiation activity being promoted, which could be attributed to the maximized mechanical stimuli with exposure to SMF. Furthermore, the enhanced osteogenic differentiation of the stimulated MC3T3-E1 cells originated from magnetically actuated mechanotransduction signaling pathway, embodying the upregulated expression of osteogenic-related and mechanotransduction-related genes. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone–implant interface and thus to promote osseointegration. Statement of significance The magnetically actuated coating is designed to produce mechanical stimuli to cells for promoting osteogenic differentiation based on the coating deformation. Iron oxide nanoparticles (IOPs) were incorporated into the mineralized collagen coatings (MC) forming the composite coatings (IOP-MC) with spatially distributed IOPs, and the IOP-MC coatings with outer distributed IOPs (O-IOPs-MC) shows the maximized mechanical stimuli to cells with enhanced osteogenic differentiation under static magnetic field. The upregulated expression of the associated genes reveals that the enabled mechanotransduction signaling pathway is responsible for the promoted cellular osteogenic differentiation. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone–implant interface to promote osseointegration.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.009
       
  • Fatigue of soft fibrous tissues: multi-scale mechanics and constitutive
           modeling
    • Authors: Kevin Linka; Markus Hillgärtner; Mikhail Itskov
      Abstract: Publication date: Available online 15 March 2018
      Source:Acta Biomaterialia
      Author(s): Kevin Linka, Markus Hillgärtner, Mikhail Itskov
      In recent experimental studies a possible damage mechanism of collagenous tissues mainly caused by fatigue was disclosed. In this contribution, a multi-scale constitutive model ranging from the tropocollagen (TC) molecule level up to bundles of collagen fibers is proposed and utilized to predict the elastic and inelastic long-term tissue response. Material failure of collagen fibrils is elucidated by a permanent opening of the triple helical collagen molecule conformation, triggered either by overstretching or reaction kinetics of non-covalent bonds. This kinetics is described within a probabilistic framework of adhesive detachments of molecular linkages providing collagen fiber integrity. Both intramolecular and interfibrillar linkages are considered. The final constitutive equations are validated against recent experimental data available in literature for both uniaxial tension to failure and the evolution of fatigue for subsequent loading cycles. All material parameters of the proposed model have a clear physical interpretation. Statement of significance Irreversible changes take place at different length scales of soft fibrous tissues tissues under supra-physiological loading and alter their macroscopic mechanical properties. Understanding the evolution of those histologic pathologies under loading and incorporating them into a continuum mechanical framework appears to be crucial in order to predict long-term evolution of various diseases and to support the development of tissue engineering.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.010
       
  • Urethane-based Low-temperature Curing, Highly-Customized and
           Multifunctional Poly(glycerol sebacate)-co-Poly(ethylene glycol)
           Copolymers
    • Authors: Zihao Wang; Yifan Ma; YanXiang Wang; Yutong Liu; Kai Chen; Zihan Wu; Shuang Yu; Yuan Yuan; Changsheng Liu
      Abstract: Publication date: Available online 14 March 2018
      Source:Acta Biomaterialia
      Author(s): Zihao Wang, Yifan Ma, YanXiang Wang, Yutong Liu, Kai Chen, Zihan Wu, Shuang Yu, Yuan Yuan, Changsheng Liu
      Poly (glycerol sebacate) (PGS), a tough elastomer, has been widely explored in tissue engineering due to the desirable mechanical properties and biocompatibility. However, the complex curing procedure (high temperature and vacuum) and limited hydrophilicity (∼90° of wetting angle) greatly impede its functionalities. To address these challenges, a urethane-based low-temperature setting, PEGylated PGS bioelastomer was developed with and without solvent. By simultaneously tailoring PEG and hexamethylene diisocyanate (HDI) contents, the elastomers X-P-mUs (X referred to the PEG content and m referred to HDI content) with a broad ranging mechanical properties and customized hydrophilicity were constructed. The X-P-mUs synthesized exhibited adjustable tensile Young’s modulus, ultimate tensile strength and elongation at break in the range of 1.0 MPa–14.2 MPa, 0.3 MPa–7.6 MPa and 53.6%–272.8%, with the water contact angle varying from 28.6° to 71.5°, respectively. Accordingly, these elastomers showed favorable biocompatibility in vitro and mild host response in vivo. Furthermore, the potential applications of X-P-mU elastomers prepared with solvent-base and solvent-free techniques in biomedical fields were investigated. The results showed that these X-P-mU elastomers with high molding capacity at mild temperature could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity, demonstrating that the X-P-mU elastomers could be tailored as potential building blocks for diverse applications in biomedical research. Statement of Significance Poly(glycerol sebacate) (PGS), a tough biodegradable elastomer, has received great attentions in biomedical field. But the complex curing procedure and limited hydrophilicity greatly hamper its functionality. Herein, a urethane-based low-temperature setting, PEGylated PGS (PEGS-U) bioelastomer with highly-customized mechanical properties, hydrophilicty and biodegradability was first explored. The synthesized PEGS-U showed favorable biocompatibility both in vitro and in vivo. Furthermore, the PEGS-U elastomer could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity. This versatile, user-tunable bioelastomers should be a promising biomaterials for biomedical applications.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.011
       
  • 3D-printed IFN-γ-loading calcium silicate-β-tricalcium phosphate
           scaffold sequentially activates M1 and M2 polarization of macrophages to
           promote vascularization of tissue engineering bone
    • Authors: Tao Li; Mingzheng Peng; Zezheng Yang; Xiaojun Zhou; Yuan Deng; Chuan Jiang; Ming Xiao; Jinwu Wang
      Abstract: Publication date: Available online 14 March 2018
      Source:Acta Biomaterialia
      Author(s): Tao Li, Mingzheng Peng, Zezheng Yang, Xiaojun Zhou, Yuan Deng, Chuan Jiang, Ming Xiao, Jinwu Wang
      To promote vascularization of tissue-engineered bone, IFN-γ polarizing macrophages to M1 was loaded on 5% calcium silicate/β-tricalcium phosphate (CaSiO3-β-TCP) scaffolds. IFN-γ and Si released from the scaffold were designed to polarize M1 and M2 macrophages, respectively. β-TCP, CaSiO3-β-TCP, and IFN-γ@CaSiO3-β-TCP were fabricated and biocompatibilities were evaluated. Polarizations of macrophages were detected by flow cytometry. Human umbilical vein endothelial cells with GFP were cultured and induced on Matrigel with conditioned culture medium extracted from culture of macrophages loaded on scaffolds for evaluating angiogenesis. Four weeks after the scaffolds were subcutaneously implanted into C57B1/6, vascularization was evaluated by visual observation, hematoxylin and eosin staining, as well as immunohistochemistry of CD31. The results showed that IFN-γ@CaSiO3-β-TCP scaffolds released IFN-γ in the early stage (1–3 days) to stimulate macrophages to M1 polarization, followed by release of Si inducing macrophages to M2 polarization while scaffolds degraded. The activation of M1/M2 allows macrophages to secrete more cytokines, including VEGF, CXCL12 and PDGF-BB. The IFN-γ@CaSiO3-β-TCP scaffolds formed more blood vessels in vitro and in vivo compared to the control groups. The study indicated that the design of tissue-engineered scaffolds with immunomodulatory function utilized host macrophages to increase vascularization of tissue-engineered bone, providing a new strategy for accelerating vascularization and osteogenesis of tissue-engineered scaffolds and showing the potential for treatment of major bone defects. Statement of significance A 3-D printed immunomodulatory scaffold was designed for repair of massive bone defects. Through the release of interferon γ and silicon ions, the new immunomodulatory scaffold promoted the M1 and M2 polarization of macrophages, boosting angiogenesis. This scaffold provided a new strategy for accelerating vascularization and osteogenesis of tissue-engineered scaffolds and showing the potential for treatment of major bone defects.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.012
       
  • New findings confirm the viscoelastic behaviour of the inter-lamellar
           matrix of the disc annulus fibrosus in radial and circumferential
           directions of loading
    • Authors: J. Tavakoli; J.J. Costi
      Abstract: Publication date: Available online 14 March 2018
      Source:Acta Biomaterialia
      Author(s): J. Tavakoli, J.J. Costi
      While few studies have improved our understanding of composition and organization of elastic fibres in the inter-lamellar matrix (ILM), its clinical relevance is not fully understood. Moreover, no studies have measured the direct tensile and shear failure and viscoelastic properties of the ILM. Therefore, the aim of this study was, for the first time, to measure the viscoelastic and failure properties of the ILM in both the tension and shear directions of loading. Using an ovine model, isolated ILM samples were stretched to 40% of their initial length at three strain rates of 0.1%s−1 (slow), 1%s−1 (medium) and 10%s−1 (fast) and a ramp test to failure was performed at a strain rate of 10%s−1. The findings from this study identified that the stiffness of the ILM was significantly larger at faster strain rates, and energy absorption significantly smaller, compared to slower strain rates, and the viscoelastic and failure properties were not significantly different under tension and shear loading. We found a strain rate dependent response of the ILM during dynamic loading, particularly at the fastest rate. The ILM demonstrated a significantly higher capability for energy absorption at slow strain rates compared to medium and fast strain rates. A significant increase in modulus was found in both loading directions and all strain rates, having a trend of larger modulus in tension and at faster strain rates. The finding of no significant difference in failure properties in both loading directions, was consistent with our previous ultra-structural studies that revealed a well-organized (±45°) elastic fibre orientation in the ILM. The results from this study can be used to develop and validate finite element models of the AF at the tissue scale, as well as providing new strategies for fabricating tissue engineered scaffolds. Statement of significance While few studies have improved our understanding of composition and organization of elastic fibres in the inter-lamellar matrix (ILM) of the annulus in the disc no studies have measured the direct mechanical failure and viscoelastic properties of the ILM. The findings from this study identified that the stiffness of the ILM was significantly larger at faster strain rates, and energy absorption significantly smaller, compared to slower strain rates. The failure properties of the ILM were not significantly different under tension and shear.
      Graphical abstract image

      PubDate: 2018-03-19T21:44:39Z
      DOI: 10.1016/j.actbio.2018.03.015
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.198.78.121
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-