for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3044 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 3044 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 22, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 21, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 84, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 24, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 342, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 215, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 23, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 3)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 25, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in 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: 26, 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: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 5)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 40, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 48, 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: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in 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: 35, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 15, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 61)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 350, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 317, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 411, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 39, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 47, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 48, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 45, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 39, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 16, 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: 24, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 192, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 56, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 4)
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: 24, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 55, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 9)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 167, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 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  
Animal Behaviour     Hybrid Journal   (Followers: 160, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 1, SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

        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]   [25 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3044 journals]
  • Carbon nanotube, graphene and boron nitride nanotube reinforced bioactive
           ceramics for bone repair
    • Authors: Chengde Gao; Pei Feng; Shuping Peng; Cijun Shuai
      Pages: 1 - 20
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Chengde Gao, Pei Feng, Shuping Peng, Cijun Shuai
      The high brittleness and low strength of bioactive ceramics have severely restricted their application in bone repair despite the fact that they have been regarded as one of the most promising biomaterials. In the last few years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have gained increasing attention owing to their favorable biocompatibility, large surface specific area and super mechanical properties. These qualities make LDNs potential nanofillers in reinforcing bioactive ceramics. In this review, the types, characteristics and applications of the commonly used LDNs in ceramic composites are summarized. In addition, the fabrication methods for LDNs/ceramic composites, such as hot pressing, spark plasma sintering and selective laser sintering, are systematically reviewed and compared. Emphases are placed on how to obtain the uniform dispersion of LDNs in a ceramic matrix and maintain the structural stability of LDNs during the high-temperature fabrication process of ceramics. The reinforcing mechanisms of LDNs in ceramic composites are then discussed in-depth. The in vitro and in vivo studies of LDNs/ceramic in bone repair are also summarized and discussed. Finally, new developments and potential applications of LDNs/ceramic composites are further discussed with reference to experimental and theoretical studies. Statement of Significance Despite bioactive ceramics having been regarded as promising biomaterials, their high brittleness and low strength severely restrict their application in bone scaffolds. In recent years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have shown great potential in reinforcing bioactive ceramics owing to their unique structures and properties. However, so far it has been difficult to maintain the structural stability of LDNs during fabrication of LDNs/ceramic composites, due to the lengthy, high-temperature process involved. This review presents a comprehensive overview of the developments and applications of LDNs in bioactive ceramics. The newly-developed fabrication methods for LDNs/ceramic composites, the reinforcing mechanisms and the in vitro and in vivo performance of LDNs are also summarized and discussed in detail.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.05.020
      Issue No: Vol. 61 (2017)
       
  • Polymer materials for prevention of postoperative adhesion
    • Authors: Jiannan Li; Xiangru Feng; Baichun Liu; Yingjie Yu; Leming Sun; Tongjun Liu; Yongheng Wang; Jianxun Ding; Xuesi Chen
      Pages: 21 - 40
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Jiannan Li, Xiangru Feng, Baichun Liu, Yingjie Yu, Leming Sun, Tongjun Liu, Yongheng Wang, Jianxun Ding, Xuesi Chen
      Postoperative adhesion (POA) is a common complication that often occurs after a variety of surgeries, such as plastic surgery, repair operations of abdominal, pelvic, and tendon, and so forth. Moreover, POA leads to chronic abdominal pain, secondary infertility in women, intestinal obstruction, and other severe complications, which significantly reduce the life quality of patients. In order to prevent the formation of POA, a number of strategies have been developed, among which an emerging method is physical barriers consisting of polymer materials. This review highlights the most commonly used natural and synthetic polymer materials in anti-adhesion physical barriers. The specific features of polymer materials are analyzed and compared, and the possible prospect is also predicted. Statement of Significance Postoperative adhesion (POA) is a serious complication accompanied with various surgeries. Polymer material-based physical barriers have attracted a large amount of attention in POA prevention. The polymer barriers can effectively avoid the formation of fibrous tissues among normal organs by reducing the interconnection of injured tissues. In this review, specific features of the natural and synthetic polymer materials for application in POA prevention were presented, and the possible prospects were predicted. All in all, our work can provide inspiration for researchers to choose proper polymer materials for preclinical and even clinical anti-adhesion studies.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.002
      Issue No: Vol. 61 (2017)
       
  • The bio in the ink: cartilage regeneration with bioprintable hydrogels and
           articular cartilage-derived progenitor cells
    • Authors: Riccardo Levato; William R. Webb; Iris A. Otto; Anneloes Mensinga; Yadan Zhang; Mattie van Rijen; René van Weeren; Ilyas M. Khan; Jos Malda
      Pages: 41 - 53
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Riccardo Levato, William R. Webb, Iris A. Otto, Anneloes Mensinga, Yadan Zhang, Mattie van Rijen, René van Weeren, Ilyas M. Khan, Jos Malda
      Cell-laden hydrogels are the primary building blocks for bioprinting, and, also termed bioinks, are the foundations for creating structures that can potentially recapitulate the architecture of articular cartilage. To be functional, hydrogel constructs need to unlock the regenerative capacity of encapsulated cells. The recent identification of multipotent articular cartilage-resident chondroprogenitor cells (ACPCs), which share important traits with adult stem cells, represents a new opportunity for cartilage regeneration. However, little is known about the suitability of ACPCs for tissue engineering, especially in combination with biomaterials. This study aimed to investigate the potential of ACPCs in hydrogels for cartilage regeneration and biofabrication, and to evaluate their ability for zone-specific matrix production. Gelatin methacryloyl (gelMA)-based hydrogels were used to culture ACPCs, bone marrow mesenchymal stromal cells (MSCs) and chondrocytes, and as bioinks for printing. Our data shows ACPCs outperformed chondrocytes in terms of neo-cartilage production and unlike MSCs, ACPCs had the lowest gene expression levels of hypertrophy marker collagen type X, and the highest expression of PRG4, a key factor in joint lubrication. Co-cultures of the cell types in multi-compartment hydrogels allowed generating constructs with a layered distribution of collagens and glycosaminoglycans. By combining ACPC- and MSC-laden bioinks, a bioprinted model of articular cartilage was generated, consisting of defined superficial and deep regions, each with distinct cellular and extracellular matrix composition. Taken together, these results provide important information for the use of ACPC-laden hydrogels in regenerative medicine, and pave the way to the biofabrication of 3D constructs with multiple cell types for cartilage regeneration or in vitro tissue models. Statement of Significance Despite its limited ability to repair, articular cartilage harbors an endogenous population of progenitor cells (ACPCs), that to date, received limited attention in biomaterials and tissue engineering applications. Harnessing the potential of these cells in 3D hydrogels can open new avenues for biomaterial-based regenerative therapies, especially with advanced biofabrication technologies (e.g. bioprinting). This study highlights the potential of ACPCs to generate neo-cartilage in a gelatin-based hydrogel and bioink. The ACPC-laden hydrogel is a suitable substrate for chondrogenesis and data shows it has a bias in directing cells towards a superficial zone phenotype. For the first time, ACPC-hydrogels are evaluated both as alternative for and in combination with chondrocytes and MSCs, using co-cultures and bioprinting for cartilage regeneration in vitro. This study provides important cues on ACPCs, indicating they represent a promising cell source for the next generation of cartilage constructs with increased biomimicry.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.005
      Issue No: Vol. 61 (2017)
       
  • Lipogels responsive to near-infrared light for the triggered release of
           therapeutic agents
    • Authors: Francisco Martín-Saavedra; Eduardo Ruiz-Hernández; Clara Escudero-Duch; Martín Prieto; Manuel Arruebo; Negar Sadeghi; Roel Deckers; Gert Storm; Wim E. Hennink; Jesús Santamaría; Nuria Vilaboa
      Pages: 54 - 65
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Francisco Martín-Saavedra, Eduardo Ruiz-Hernández, Clara Escudero-Duch, Martín Prieto, Manuel Arruebo, Negar Sadeghi, Roel Deckers, Gert Storm, Wim E. Hennink, Jesús Santamaría, Nuria Vilaboa
      Here we report a composite system based on fibrin hydrogels that incorporate in their structure near-infrared (NIR) responsive nanomaterials and thermosensitive liposomes (TSL). Polymerized fibrin networks entrap simultaneously gold-based nanoparticles (NPs) capable of transducing NIR photon energy into heat, and lysolipid-incorporated TSL (LTSL) loaded with doxorubicin hydrochloride (DOX). NIR irradiation of the resulting hydrogels (referred to as “lipogels”) with 808nm laser light increased the temperature of the illuminated areas, leading to the release of the liposomal cargo. Levels of DOX that release from the “smart” composites were dependent on the concentration of NIR nanotransducers loaded in the lipogel, the intensity of the electromagnetic energy deposited and the irradiation regime. Released DOX retained its bioactivity, as shown in cultures of epithelial carcinoma cells. Finally, the developed drug delivery platform was refined by using NIR-photoabsorbers based on copper sulfide NPs to generate completely biodegradable composites as well as through the incorporation of cholesterol (Ch) in LTSL formulation, which lessens leakiness of the liposomal cargo at physiological temperature. This remotely controlled system may suit well for those therapies that require precise control over the dose of delivered drug in a defined spatiotemporal framework. Statement of Significance Hydrogels composed of fibrin embedding nanoparticles responsive to near infrared (NIR) energy and thermosensitive liposomes loaded with doxorubicin hydrochloride (DOX), were prepared by in situ polymerization. NIR-light irradiation of these constructs, referred to as “NIR responsive lipogels”, results in the controlled release of DOX to the surrounding medium. This technology may use fully degradable components and can preserve the bioactivity of liposomal cargo after remote triggering to finely regulate the dose and bioavailability of delivered payloads. NIR responsive lipogels technology overcomes the limitations of drug release systems based on the combination of liposomes and degradable polymeric materials, which in many cases lead to insufficient release at therapy onset or to overdose during high degradation period.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.010
      Issue No: Vol. 61 (2017)
       
  • Self-defensive antibiotic-loaded layer-by-layer coatings: Imaging of
           
    • Authors: Victoria Albright; Iryna Zhuk; Yuhao Wang; Victor Selin; Betsy van de Belt-Gritter; Henk J. Busscher; Henny C. van der Mei; Svetlana A. Sukhishvili
      Pages: 66 - 74
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Victoria Albright, Iryna Zhuk, Yuhao Wang, Victor Selin, Betsy van de Belt-Gritter, Henk J. Busscher, Henny C. van der Mei, Svetlana A. Sukhishvili
      Self-defensive antibiotic-loaded coatings have shown promise in inhibiting growth of pathogenic bacteria adhering to biomaterial implants and devices, but direct proof that their antibacterial release is triggered by bacterially-induced acidification of the immediate environment under buffered conditions remained elusive. Here, we demonstrate that Staphylococcus aureus and Escherichia coli adhering to such coatings generate highly localized acidification, even in buffered conditions, to activate pH-triggered, self-defensive antibiotic release. To this end, we utilized chemically crosslinked layer-by-layer hydrogel coatings of poly(methacrylic acid) with a covalently attached pH-sensitive SNARF-1 fluorescent label for imaging, and unlabeled-antibiotic (gentamicin or polymyxin B) loaded coatings for antibacterial studies. Local acidification of the coatings induced by S. aureus and E. coli adhering to the coatings was demonstrated by confocal-laser-scanning-microscopy via wavelength-resolved imaging. pH-triggered antibiotic release under static, small volume conditions yielded high bacterial killing efficiencies for S. aureus and E. coli. Gentamicin-loaded films retained their antibacterial activity against S. aureus under fluid flow in buffered conditions. Antibacterial activity increased with the number of polymer layers in the films. Altogether, pH-triggered, self-defensive antibiotic-loaded coatings become activated by highly localized acidification in the immediate environment of an adhering bacterium, offering potential for clinical application with minimized side-effects. Statement of significance Polymeric coatings were created that are able to uptake and selectively release antibiotics upon stimulus by adhering bacteria in order to understand the fundamental mechanisms behind pH-triggered antibiotic release as a potential way to prevent biomaterial-associated infections. Through fluorescent imaging studies, this work importantly shows that adhering bacteria produce highly localized pH changes even in buffer. Accordingly such coatings only demonstrate antibacterial activity by antibiotic release in the presence of adhering bacteria. This is clinically important, because ad libitum releasing antibiotic coatings usually show a burst release and have often lost their antibiotic content when bacteria adhere.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.012
      Issue No: Vol. 61 (2017)
       
  • Microcontact printing of polydopamine on thermally expandable hydrogels
           for controlled cell adhesion and delivery of geometrically defined
           microtissues
    • Authors: Yu Bin Lee; Se-jeong Kim; Eum Mi Kim; Hayeon Byun; Hyung-kwan Chang; Jungyul Park; Yu Suk Choi; Heungsoo Shin
      Pages: 75 - 87
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Yu Bin Lee, Se-jeong Kim, Eum Mi Kim, Hayeon Byun, Hyung-kwan Chang, Jungyul Park, Yu Suk Choi, Heungsoo Shin
      Scaffold-free harvest of microtissue with a defined structure has received a great deal of interest in cell-based assay and regenerative medicine. In this study, we developed thermally expandable hydrogels with spatially controlled cell adhesive patterns for rapid harvest of geometrically controlled microtissue. We patterned polydopamine (PD) on to the hydrogel via microcontact printing (μCP), in linear shapes with widths of 50, 100 and 200μm. The hydrogels facilitated formation of spatially controlled strip-like microtissue of human dermal fibroblasts (HDFBs). It was possible to harvest and translocate microtissues with controlled widths of 61.4±14.7, 104.3±15.6, and 186.6±22.3μm from the hydrogel to glass substrates by conformal contact upon expansion of the hydrogel in response to a temperature change from 37 to 4°C, preserving high viability, extracellular matrix, and junction proteins. Microtissues were readily translocated in vivo to the subcutaneous tissue of mouse. The microtissues were further utilized as a simple assay model for monitoring of contraction in response to ROCK1 inhibitor. Collectively, micro-sized patterning of PD on the thermally expandable hydrogels via μCP holds promise for the development of microtissue harvesting systems that can be employed to ex vivo tissue assay and cell-based therapy. Statement of significance Harvest of artificial tissue with controlled cellular arrangement independently from external materials has been widely studied in cell-based assay and regenerative medicine. In this study, we developed scaffold-free harvest system of microtissues with anisotropic arrangement and controlled width by exploiting thermally expandable hydrogels with cell-adhesive patterns of polydopamine formed by simple microcontact printing. Cultured strips of human dermal fibroblasts on the hydrogels were rapidly delivered to various targets ranging from flat coverglass to mice subcutaneous tissue by thermal expansion of the hydrogel at 4°C for 10min. These were further utilized as a drug screening model responding to ROCK1 inhibitor, which imply its versatile applicability.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.07.040
      Issue No: Vol. 61 (2017)
       
  • Facile encapsulation of hydroxycamptothecin nanocrystals into zein-based
           nanocomplexes for active targeting in drug delivery and cell imaging
    • Authors: Hongdi Wang; Wei Zhu; Yunna Huang; Zhixian Li; Yanbin Jiang; Qiuling Xie
      Pages: 88 - 100
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Hongdi Wang, Wei Zhu, Yunna Huang, Zhixian Li, Yanbin Jiang, Qiuling Xie
      Nano-drug delivery systems that integrate inorganic and organic or even bioactive components into a single nanoscale platform are playing a hugely important role in cancer treatment. In this article, the fabrication of a versatile nanocarrier based on self-assembled structures of gold nanoparticles (AuNPs)-zein is reported, which displays high drug-loading efficiency for needle-shaped hydroxycamptothecin (HCPT) nanocrystals. The surface modification with folate-conjugated polydopamine (PFA) renders them stable and also facilitates their selective cellular internalization and enhancement of endocytosis. The release of payloads from nanocomplexes (NCs) was shown to be limited at physiological pH (17.1±2.8%) but significantly elevated at endosomal/lysosomal pH (58.4±3.0%) and at enzymatic environment (81.4±4.2%). Compared to free HCPT and its non-targeting equivalent, HCPT@AuNPs-Zein-PFA exerted a superior tumor suppression capacity as well as low side effects due to its active and passive targeting delivery both in vitro and in vivo. These results suggest that the NCs with well-defined core@shell nanostructures encapsulated with HCPT nanocrystals hold great promise to improve cancer therapy with high efficiency in the clinic. Statement of significance A novel nanocomplex with HCPT nanocrystals encapsulated was designed to achieve selective cellular uptake by endocytosis, acid responsive release in the tumor microenvironment and excellent tumor suppression without toxicity. This nanocomplex with conjugation of folate was stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in tumor tissues. The entrapment of a nanocrystal drug into nanomaterials might be capable of delivering drugs in a predictable and controllable manner.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.04.017
      Issue No: Vol. 61 (2017)
       
  • Thermosensitive chitosan-based hydrogels releasing stromal cell derived
           factor-1 alpha recruit MSC for corneal epithelium regeneration
    • Authors: Qiaomei Tang; Chenqi Luo; Bing Lu; Qiuli Fu; Houfa Yin; Zhenwei Qin; Danni Lyu; Lifang Zhang; Zhi Fang; Yanan Zhu; Ke Yao
      Pages: 101 - 113
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Qiaomei Tang, Chenqi Luo, Bing Lu, Qiuli Fu, Houfa Yin, Zhenwei Qin, Danni Lyu, Lifang Zhang, Zhi Fang, Yanan Zhu, Ke Yao
      Corneal epithelium integrity depends on continuous self-renewing of epithelium and connections between adjacent cells or between the cells and the basement membrane. Self-renewing epithelium cells mainly arise from the continuous proliferation and differentiation of the basal layer and limbal stem cells. The aim of the present study was to generate a bioactive, thermosensitive chitosan–gelatin hydrogel (CHI hydrogel) by incorporating exogenous recombinant human stromal cell–derived factor-1 alpha (SDF-1 alpha) for corneal epithelium regeneration. The exogenous SDF-1 alpha could enhance the stem cells proliferation, chemotaxis and migration, and the expression levels of related genes were significantly elevated in LESCs and mesenchymal stem cells (MSCs) in vitro. Moreover, the MSCs promoted the proliferation and maintained the corneal fate of the LESCs. The rat alkali injury model was used for in vivo study. The injured eyes were covered with CHI hydrogel alone or rhSDF-1 alpha-loaded CHI hydrogel. All rats were followed for 13days. Histological examination showed that the SDF-1 alpha/CHI hydrogel complex group had a nearly normal thickness; moreover, it was also found that this group could upregulate the expression of some genes and had more ΔNp63-positive cells. The SDF-1 alpha/CHI hydrogel complex group had a more tightly arranged epithelium compared with the control group using transmission electron microscopy (TEM). The mechanism for this may have involved the activation of stem cell homing and the secretion of growth factors via the SDF-1/CXCR4 chemokine axis. Therefore, SDF-1 alpha/CHI hydrogel complexes could provide a new idea for the clinical application. Statement of significance The clarity of cornea is important for normal vision. The loss or dysfunction of LESCs leads to the impairment of corneal epithelium. The complete regeneration of corneal epithelium has not been achieved. Our study demonstrated that the incorporation of rhSDF-1 alpha with CHI hydrogel accelerated corneal epithelium reconstruction with more native structural and functional properties. The mechanism may involve in inducing proliferation and migration of the LESCs and MSCs to the injury site via the SDF-1/CXCR4 chemokine axis. Therefore, SDF-1 alpha/CHI hydrogel complexes could be a practical application for clinical therapy.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.001
      Issue No: Vol. 61 (2017)
       
  • Combined delivery of a TGF-β inhibitor and an adenoviral vector
           expressing interleukin-12 potentiates cancer immunotherapy
    • Authors: Jiayu Jiang; Yuandong Zhang; Ke Peng; Qin Wang; Xiaoyu Hong; Hanmei Li; Gerui Fan; Zhirong Zhang; Tao Gong; Xun Sun
      Pages: 114 - 123
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Jiayu Jiang, Yuandong Zhang, Ke Peng, Qin Wang, Xiaoyu Hong, Hanmei Li, Gerui Fan, Zhirong Zhang, Tao Gong, Xun Sun
      Cancer immunotherapy appears to have a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-β (TGF-β), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-β inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-β inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. In addition, it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4+ and CD8+ T cells, natural killer cells and interferon-γ secretion in the tumor microenvironment. Statement of Significance To weaken immune resistance of tumors and simultaneously strengthen tumors' immune responses, we synthesized a structurally simple, low-toxic but functional polymer β-cyclodextrin-PEI to encapsulate a hydrophobic TGF-β inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This is the first report demonstrating that combining TGF-β inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drugs and therapeutic genes for treating cancer, providing a new approach for cancer immunotherapy.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.05.009
      Issue No: Vol. 61 (2017)
       
  • Gamma-irradiated human amniotic membrane decellularised with sodium
           dodecyl sulfate is a more efficient substrate for the ex vivo expansion of
           limbal stem cells
    • Authors: G.S. Figueiredo; S. Bojic; P. Rooney; S.-P. Wilshaw; C.J. Connon; R.M. Gouveia; C. Paterson; G. Lepert; H.S. Mudhar; F.C. Figueiredo; M. Lako
      Pages: 124 - 133
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): G.S. Figueiredo, S. Bojic, P. Rooney, S.-P. Wilshaw, C.J. Connon, R.M. Gouveia, C. Paterson, G. Lepert, H.S. Mudhar, F.C. Figueiredo, M. Lako
      The gold standard substrate for the ex vivo expansion of human limbal stem cells (LSCs) remains the human amniotic membrane (HAM) but this is not a defined substrate and is subject to biological variability and the potential to transmit disease. To better define HAM and mitigate the risk of disease transmission, we sought to determine if decellularisation and/or γ-irradiation have an adverse effect on culture growth and LSC phenotype. Ex vivo limbal explant cultures were set up on fresh HAM, HAM decellularised with 0.5M NaOH, and 0.5% (w/v) sodium dodecyl sulfate (SDS) with or without γ-irradiation. Explant growth rate was measured and LSC phenotype was characterised by histology, immunostaining and qRT-PCR (ABCG2, ΔNp63, Ki67, CK12, and CK13). Ƴ-irradiation marginally stiffened HAM, as measured by Brillouin spectromicroscopy. HAM stiffness and γ-irradiation did not significantly affect the LSC phenotype, however LSCs expanded significantly faster on Ƴ-irradiated SDS decellularised HAM (p<0.05) which was also corroborated by the highest expression of Ki67 and putative LSC marker, ABCG2. Colony forming efficiency assays showed a greater yield and proportion of holoclones in cells cultured on Ƴ-irradiated SDS decellularised HAM. Together our data indicate that SDS decellularised HAM may be a more efficacious substrate for the expansion of LSCs and the use of a γ-irradiated HAM allows the user to start the manufacturing process with a sterile substrate, potentially making it safer. Statement of Significance Despite its disadvantages, including its biological variability and its ability to transfer disease, human amniotic membrane (HAM) remains the gold standard substrate for limbal stem cell (LSC) culture. To address these disadvantages, we used a decellularised HAM sterilised by gamma-irradiation for LSC culture. We cultured LSCs on fresh HAM, HAM decellularised with NaOH, HAM decellularised with sodium dodecyl sulfate (SDS) and HAM decellularised with SDS and sterilised with gamma-irradiation. We demonstrated that although HAM decellularised with SDS and sterilised with gamma-irradiation is significantly stiffer this does not affect LSC culture growth rate or the phenotype of cultured LSCs. We therefore recommend the use of SDS decellularised gamma-irradiated HAM in future LSC clinical trials.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.07.041
      Issue No: Vol. 61 (2017)
       
  • Effects of the incorporation of ε-aminocaproic acid/chitosan particles to
           fibrin on cementoblast differentiation and cementum regeneration
    • Authors: Chan Ho Park; Joung-Hwan Oh; Hong-Moon Jung; Yoonnyoung Choi; Saeed Ur Rahman; Sungtae Kim; Tae-Il Kim; Hong-In Shin; Yun-Sil Lee; Frank H. Yu; Jeong-Hwa Baek; Hyun-Mo Ryoo; Kyung Mi Woo
      Pages: 134 - 143
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Chan Ho Park, Joung-Hwan Oh, Hong-Moon Jung, Yoonnyoung Choi, Saeed Ur Rahman, Sungtae Kim, Tae-Il Kim, Hong-In Shin, Yun-Sil Lee, Frank H. Yu, Jeong-Hwa Baek, Hyun-Mo Ryoo, Kyung Mi Woo
      Cementum formation on the exposed tooth-root surface is a critical process in periodontal regeneration. Although various therapeutic approaches have been developed, regeneration of integrated and functional periodontal complexes is still wanting. Here, we found that the OCCM30 cementoblasts cultured on fibrin matrix express substantial levels of matrix proteinases, leading to the degradation of fibrin and the apoptosis of OCCM30 cells, which was reversed upon treatment with a proteinase inhibitor, ε-aminocaproic acid (ACA). Based on these findings, ACA-releasing chitosan particles (ACP) were fabricated and ACP-incorporated fibrin (fibrin-ACP) promoted the differentiation of cementoblasts in vitro, as confirmed by bio-mineralization and expressions of molecules associated with mineralization. In a periodontal defect model of beagle dogs, fibrin-ACP resulted in substantial cementum formation on the exposed root dentin in vivo, compared to fibrin-only and enamel matrix derivative (EMD) which is used clinically for periodontal regeneration. Remarkably, the fibrin-ACP developed structural integrations of the cementum-periodontal ligament-bone complex by the Sharpey’s fiber insertion. In addition, fibrin-ACP promoted alveolar bone regeneration through increased bone volume of tooth roof-of-furcation defects and root coverage. Therefore, fibrin-ACP can promote cementogenesis and osteogenesis by controlling biodegradability of fibrin, implicating the feasibility of its therapeutic use to improve periodontal regeneration. Statement of Significance Cementum, the mineralized layer on root dentin surfaces, functions to anchor fibrous connective tissues on tooth-root surfaces with the collagenous Sharpey’s fibers integration, of which are essential for periodontal functioning restoration in the complex. Through the cementum-responsible fiber insertions on tooth-root surfaces, PDLs transmit various mechanical responses to periodontal complexes against masticatory/occlusal stimulations to support teeth. In this study, periodontal tissue regeneration was enhanced by use of modified fibrin biomaterial which significantly promoted cementogenesis within the periodontal complex with structural integration by collagenous Sharpey’s fiber insertions in vivo by controlling fibrin degradation and consequent cementoblast apoptosis. Furthermore, the modified fibrin could improve repair and regeneration of tooth roof-of-furcation defects, which has spatial curvatures and geometrical difficulties and hardly regenerates periodontal tissues.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.07.039
      Issue No: Vol. 61 (2017)
       
  • Primum non nocere – The effects of sodium hypochlorite on dentin as
           used in endodontics
    • Authors: Li-sha Gu; Xue-qing Huang; Brandon Griffin; Brian R. Bergeron; David H. Pashley; Li-na Niu; Franklin R. Tay
      Pages: 144 - 156
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Li-sha Gu, Xue-qing Huang, Brandon Griffin, Brian R. Bergeron, David H. Pashley, Li-na Niu, Franklin R. Tay
      The medical literature is replete with the maxim ‘primum non nocere’, cautioning health care providers to avoid doing any harm to human subjects in their delivery of medical care. Sodium hypochlorite (NaOCl) is a well-established irrigant for root canal treatment because of its antimicrobial and organic tissue remnant dissolution capability. However, little is known about the deleterious effect of this strong oxidizing agent on the integrity of human mineralized dentin. Iatrogenically-induced loss of dentin integrity may precipitate post-treatment root fracture and has potential medico-legal complications. In the present work, transmission electron microscopy provided evidence for collagen destruction in the surface/subsurface of dentin treated with high NaOCl concentrations and long contact times. Size exclusion chromatography showed that the hypochlorite anion, because of its small size, penetrated the water compartments of apatite-encapsulated collagen fibrils, degraded the collagen molecules and produced a 25–35µm thick, non-uniform “ghost mineral layer” with enlarged, coalesced dentinal tubules and their lateral branches. Fourier transform-infrared spectroscopy identified increases in apatite/collagen ratio in NaOCl-treated dentin. The apatite-rich, collagen-sparse dentin matrix that remained after NaOCl treatment is more brittle, as shown by the reductions in flexural strength. Understanding the deleterious effects of NaOCl on mineralized dentin enables one to balance the risks and benefits in using high NaOCl concentrations for lengthy periods in root canal debridement. Delineating the mechanism responsible for such a phenomenon enables high molecular weight, polymeric antimicrobial and tissue dissolution irrigants to be designed that abides by the maxim of ‘primum non nocere’ in contemporary medical practices. Statement of Significance The antimicrobial and tissue-dissolution capacities of NaOCl render it a well-accepted agent for root canal debridement. These highly desirable properties, however, appear to be intertwined with the untoward effect of collagen matrix degradation within mineralized dentin. Because of its small size, the hypochlorite anion is capable of infiltrating mineralized collagen and destroying the collagen fibrils, producing a mineral-rich, collagen sparse ghost mineral matrix with reduced flexural strength. Findings from the present work challenge the biosafety of NaOCl when it is used in high concentrations and for lengthy time periods during root canal treatment, and laid the background work for future biomaterials design in debridement of the canal space.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.008
      Issue No: Vol. 61 (2017)
       
  • Calcium ion coordinated dexamethasone supramolecular hydrogel as
           therapeutic alternative for control of non-infectious uveitis
    • Authors: Wei Wu; Zhaoliang Zhang; Taotao Xiong; Wenguang Zhao; Rou Jiang; Hao Chen; Xingyi Li
      Pages: 157 - 168
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Wei Wu, Zhaoliang Zhang, Taotao Xiong, Wenguang Zhao, Rou Jiang, Hao Chen, Xingyi Li
      Supramolecular hydrogels formed by the self-assembly of therapeutic agents have received considerable attention due to their high drug payload and carrier-free features. Herein, we constructed a dexamethasone sodium phosphate (Dex) supramolecular hydrogel in combination with Dex and calcium ion (Ca2+) and further demonstrated its therapeutic efficacy in the control of ocular inflammation. The developed supramolecular hydrogel was thoroughly characterized by rheology, TEM, FTIR and XRD. Calcium ions and Dex concentration had a marked influence on the sol-gel transition behaviour of hydrogel and the proposed Dex supramolecular hydrogel displayed thixotropic properties. The drug release rate from Dex supramolecular hydrogel was dependent on the Ca2+ concentration. In comparison with Dex aqueous solution, single intravitreal injections of Dex supramolecular hydrogel up to 30μg/eye were well tolerated without causing undesirable complications of fundus blood vessel tortuosity and lens opacity, as indicated by electroretinograms (ERGs), fundus photography and histopathology. Moreover, the administration by Dex supramolecular hydrogel exhibited a comparable anti-inflammatory efficacy to native Dex solution on an experimental autoimmune uveitis (EAU) model induced in Lewis rats with IRBP peptide and the therapeutic efficacy had in a dosage-dependent manner. Histological observation and cytokines measurements indicated that both Dex solution and Dex supramolecular hydrogel (30μg/eye) treatment could significantly attenuate the inflammatory response in both anterior and posterior chambers via the downregulation of Th1 and Th17 effector responses. All these data suggested that the developed Dex supramolecular hydrogel might be a therapeutic alternative for non-infectious uveitis with minimal risk of the induction of lens opacity and fundus blood vessel tortuosity. Statement of Significance A facile ionic cross-linking strategy was exploited to construct a dexamethasone sodium phosphate (Dex) supramolecular hydrogel composed of Dex and calcium ion. Intravitreal injection of Dex hydrogel displayed excellent intraocular biocompatibility without causing the complications of fundus blood vessel tortuosity and lens opacity. More importantly, the proposed Dex hydrogel exhibited a comparative anti-inflammatory response to native Dex formulation on an experimental autoimmune uveitis (EAU) model via the downregulation of Th1 and Th17 effector responses.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.05.024
      Issue No: Vol. 61 (2017)
       
  • Zwitterionic sulfobetaine polymer-immobilized surface by simple
           tyrosinase-mediated grafting for enhanced antifouling property
    • Authors: Ho Joon Kwon; Yunki Lee; Le Thi Phuong; Gyeung Mi Seon; Eunsuk Kim; Jong Chul Park; Hyunjin Yoon; Ki Dong Park
      Pages: 169 - 179
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Ho Joon Kwon, Yunki Lee, Le Thi Phuong, Gyeung Mi Seon, Eunsuk Kim, Jong Chul Park, Hyunjin Yoon, Ki Dong Park
      Introducing antifouling property to biomaterial surfaces has been considered an effective method for preventing the failure of implanted devices. In order to achieve this, the immobilization of zwitterions on biomaterial surfaces has been proven to be an excellent way of improving anti-adhesive potency. In this study, poly(sulfobetaine-co-tyramine), a tyramine-conjugated sulfobetaine polymer, was synthesized and simply grafted onto the surface of polyurethane via a tyrosinase-mediated reaction. Surface characterization by water contact angle measurements, X-ray photoelectron spectroscopy and atomic force microscopy demonstrated that the zwitterionic polymer was successfully introduced onto the surface of polyurethane and remained stable for 7days. In vitro studies revealed that poly(sulfobetaine-co-tyramine)-coated surfaces dramatically reduced the adhesion of fibrinogen, platelets, fibroblasts, and S. aureus by over 90% in comparison with bare surfaces. These results proved that polyurethane surfaces grafted with poly(sulfobetaine-co-tyramine) via a tyrosinase-catalyzed reaction could be promising candidates for an implantable medical device with excellent bioinert abilities. Statement of Significance Antifouling surface modification is one of the key strategy to prevent the thrombus formation or infection which occurs on the surface of biomaterial after transplantation. Although there are many methods to modify the surface have been reported, necessity of simple modification technique still exists to apply for practical applications. The purpose of this study is to modify the biomaterial’s surface by simply immobilizing antifouling zwitterion polymer via enzyme tyrosinase-mediated reaction which could modify versatile substrates in mild aqueous condition within fast time period. After modification, pSBTA grafted surface becomes resistant to various biological factors including proteins, cells, and bacterias. This approach appears to be a promising method to impart antifouling property on biomaterial surfaces.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.007
      Issue No: Vol. 61 (2017)
       
  • Investigation of cationized triblock and diblock
           poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers for oral
           delivery of enoxaparin: In vitro approach
    • Authors: Pimchanok Charoongchit; Jiraphong Suksiriworapong; Shirui Mao; Anne Sapin-Minet; Philippe Maincent; Varaporn Buraphacheep Junyaprasert
      Pages: 180 - 192
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Pimchanok Charoongchit, Jiraphong Suksiriworapong, Shirui Mao, Anne Sapin-Minet, Philippe Maincent, Varaporn Buraphacheep Junyaprasert
      In this study, poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL)2-PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200–450nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX. Statement of Significance The anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.006
      Issue No: Vol. 61 (2017)
       
  • Positron emission tomography (PET) guided glioblastoma targeting by a
           fullerene-based nanoplatform with fast renal clearance
    • Authors: Yayun Peng; Dongzhi Yang; Weifei Lu; Xiongwei Hu; Hao Hong; Ting Cai
      Pages: 193 - 203
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Yayun Peng, Dongzhi Yang, Weifei Lu, Xiongwei Hu, Hao Hong, Ting Cai
      Various carbonaceous nanomaterials, including fullerene, carbon nanotube, graphene, and carbon dots, have attracted increasing attention during past decades for their potential applications in biological imaging and therapy. In this study, we have developed a fullerene-based tumor-targeted positron emission tomography (PET) imaging probe. Water-soluble functionalized C60 conjugates were radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for targeting of integrin α vβ3 in glioblastoma. The specificity of fluorescein-labeled C60 conjugates against cellular integrin α vβ3 was evaluated in U87MG (integrin α vβ3 positive) and MCF-7 cells (integrin α vβ3 negative) by confocal fluorescence microscopy and flow cytometry. Our results indicated that cRGD-conjugated C60 derivatives showed better cellular internalization compared with C60 derivatives without the cRGD attachment. Moreover, an interesting finding on intra-nuclei transportation of cRGD-conjugated C60 derivatives was observed in U87MG cells. In vivo serial PET studies showed preferential accumulation of cRGD-conjugated C60 derivatives at in U87MG tumors. In addition, the pharmacokinetic profiles of these fullerene-based nanoparticles conjugated with cRGD and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) fit well with the three compartment model. The renal clearance of C60-based nanoparticles is remarkably fast, which makes this material very promising for safer cancer theranostic applications. Statement of significance Safety is one of the major concerns for nanomedicine and nanomaterials with fast clearance profile are highly desirable. Fullerene is a distinct type of zero-dimensional carbon nanomaterial with ultrasmall size, uniform dispersity, and versatile reactivity. Here we have developed a fullerene-based tumor-targeted positron emission tomography imaging probe using water-soluble functionalized C60 conjugates radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for glioblastoma targeting. The improved tumor targeting property along with fast renal clearance behavior of C60-based nanoparticles makes this material very promising for future safer cancer theranostic applications.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.011
      Issue No: Vol. 61 (2017)
       
  • Flexible bipolar nanofibrous membranes for improving gradient
           microstructure in tendon-to-bone healing
    • Authors: Xiaoxi Li; Ruoyu Cheng; Zhiyong Sun; Wei Su; Guoqing Pan; Song Zhao; Jinzhong Zhao; Wenguo Cui
      Pages: 204 - 216
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Xiaoxi Li, Ruoyu Cheng, Zhiyong Sun, Wei Su, Guoqing Pan, Song Zhao, Jinzhong Zhao, Wenguo Cui
      Enthesis is a specialized tissue interface between the tendon and bone. Enthesis structure is very complex because of gradient changes in its composition and structure. There is currently no strategy to create a suitable environment and to regenerate the gradual-changing enthesis because of the modular complexities between two tissue types. Herein, a dual-layer organic/inorganic flexible bipolar fibrous membrane (BFM) was successfully fabricated by electrospinning to generate biomimetic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. The growth of the in situ apatite nanoparticle layer was induced on the nano hydroxyapatite-poly-l-lactic acid (nHA-PLLA) fibrous layer in simulated body solution, and the poly-l-lactic acid (PLLA) fibrous layer retained its original properties to induce tendon regeneration. The in vivo results showed that BFM significantly increased the area of glycosaminoglycan staining at the tendon–bone interface and improved collagen organization when compared to the simplex fibrous membrane (SFM) of PLLA. Implanting the bipolar membrane also induced bone formation and fibrillogenesis as assessed by micro-CT and histological analysis. Biomechanical testing showed that the BFM group had a greater ultimate load-to-failure and stiffness than the SFM group at 12weeks after surgery. Therefore, this flexible bipolar nanofibrous membrane improves the healing and regeneration process of the enthesis in rotator cuff repair. Statement of Significance In this study, we generated a biomimetic dual-layer organic/inorganic flexible bipolar fibrous membrane by sequential electrospinning and in situ biomineralization, producing integrated bipolar fibrous membranes of PLLA fibrous membrane as the upper layer and nHA-PLLA fibrous membrane as the lower layer to mimic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. Flexible bipolar nanofibrous membranes could be easily fabricated with gradient microstructure for enthesis regeneration in rotator cuff tears.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.07.044
      Issue No: Vol. 61 (2017)
       
  • The synergistic effects of Sr and Si bioactive ions on osteogenesis,
           osteoclastogenesis and angiogenesis for osteoporotic bone regeneration
    • Authors: Lixia Mao; Lunguo Xia; Jiang Chang; Jiaqiang Liu; Lingyong Jiang; Chengtie Wu; Bing Fang
      Pages: 217 - 232
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Lixia Mao, Lunguo Xia, Jiang Chang, Jiaqiang Liu, Lingyong Jiang, Chengtie Wu, Bing Fang
      Bioactive ions released from bioceramics play important roles in bone regeneration; however, it is unclear how each ionic composition in complex bioceramics exerts its specific effect on bone regeneration. The aim of this study is to elucidate the functional effects of Sr and Si ions in bioceramics on the regeneration of osteoporotic bone. A model bioceramic with Sr- and Si-containing components (SMS) was successfully fabricated and the effects of ionic products from SMS bioceramics on the osteogenic, osteoclastic and angiogenic differentiation of rBMSCs-OVX and RANKL-induced osteoclasts were investigated. The results showed that SMS bioceramics could enhance ALP activity and expression of Col 1, OCN, Runx2, and angiogenic factors including VEGF and Ang-1. SMS bioceramics not only rebalanced the OPG/RANKL ratio of rBMSCs-OVX at early stage, but also repressed RANKL-induced osteoclast formation and expression of TRAP, DC-STAMP, V-ATPase a3, and NFATc1. The synergistic effects of Sr and Si ions were further investigated as compared with those of similar concentrations of Sr and Si ions alone. Sr and Si ions possessed synergistic effects on osteogenesis, osteoclastogenesis, and angiogenesis, attributed to the dominant effects of Sr ions on enhancing angiogenesis and repressing osteoclastogenesis, and the dominant effects of Si ions on stimulating osteogenesis. The in vivo study using critical-size mandibular defects of OVX rat models showed that SMS bioceramics could significantly enhance bone formation and mineralization compared with β-TCP bioceramics. Our results are the first to elucidate the specific effect of each ion from bioceramics on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration, paving the way for the design of functional biomaterials with complex compositions for tissue engineering and regenerative medicine. Statement of significance Bioactive ions released from bioceramics play important roles for bone regeneration; however, it is unclear how each of ionic compositions in complex bioceramics exerts its specific effect on bone regeneration. The aim of present study is to elucidate the functional effects of Sr and Si ions in complex bioceramics on the regeneration of osteoporotic bone. A model bioceramic with Sr and Si-containing components (SMS) was successfully fabricated and the effects of ionic products from SMS bioceramics on the osteogenic, osteoclastic and angiogenic differentiation of rBMSCs-OVX and RANKL-induced osteoclasts were investigated. The results showed that SMS bioceramics could enhance ALP activity and expression of Col 1, OCN, Runx2 and angiogenic factors including VEGF and Ang-1. SMS bioceramics not only rebalanced the ratio of OPG/RANKL of OVX-BMSCs at early stage, but also repressed RANKL-induced osteoclast formation and expression of TRAP, DC-STAMP, V-ATPase a3, and NFATc1. The synergistic effects of Sr and Si ions were further investigated as compared with the similar concentration of Sr and Si ions alone. It was found that Sr and Si ions possessed synergistic effects on osteogenesis, osteoclastogenesis and angiogenesis, attributed to the dominant effects of Sr ions on enhancing angiogenesis and repressing osteoclastogenesis, and the dominant effects of Si ions on stimulating osteogenesis. The in vivo study using critical-size mandibular defects of OVX rat models showed that SMS bioceramics could significantly enhance bone formation and mineralization as compared with β-TCP bioceramics. It is suggested that SMS bioceramics may be a promising biomaterial for osteoporotic bone regeneration. To our knowledge, this is the first time to elucidate the specific effect of each ion from bioceramics on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration, paving the way to design functional biomaterials with complex compositions for tissue engineering and regenerative medicine.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.08.015
      Issue No: Vol. 61 (2017)
       
  • Adiponectin improves the osteointegration of titanium implant under
           diabetic conditions by reversing mitochondrial dysfunction via the AMPK
           pathway in vivo and in vitro
    • Authors: Xiao-Fan Hu; Lin Wang; Yi-Zhao Lu; Geng Xiang; Zi-Xiang Wu; Ya-Bo Yan; Yang Zhang; Xiong Zhao; Yuan Zang; Lei Shi; Wei Lei; Ya-Fei Feng
      Pages: 233 - 248
      Abstract: Publication date: 1 October 2017
      Source:Acta Biomaterialia, Volume 61
      Author(s): Xiao-Fan Hu, Lin Wang, Yi-Zhao Lu, Geng Xiang, Zi-Xiang Wu, Ya-Bo Yan, Yang Zhang, Xiong Zhao, Yuan Zang, Lei Shi, Wei Lei, Ya-Fei Feng
      Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat-derived adipocytokine with strong antioxidant, mitochondrial-protective and anti-diabetic efficacies. We hypothesized that mitochondrial dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM+APN, DM+AICAR (AMPK activator) and DM+APN+Compound C (AMPK inhibitor). In vivo, APN or APN+Compound C were administered to diabetic db/db mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterial-engineering to improve clinical performance of TI in diabetic patients. Statement of Significance The loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients.
      Graphical abstract image

      PubDate: 2017-09-17T17:34:18Z
      DOI: 10.1016/j.actbio.2017.06.020
      Issue No: Vol. 61 (2017)
       
  • Paths to Open Access: An update from Acta Materialia, Inc.
    • Authors: Christopher A. Schuh; Kazuhiro Hono; William R. Wagner; Baptiste Gault; Joseph D'Angelo; George T. Gray
      Pages: 1 - 2
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Christopher A. Schuh, Kazuhiro Hono, William R. Wagner, Baptiste Gault, Joseph D'Angelo, George T. Gray


      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.08.020
      Issue No: Vol. 60 (2017)
       
  • Current status and future direction of biodegradable metallic and
           polymeric vascular scaffolds for next-generation stents
    • Authors: Seung Hyuk Im; Youngmee Jung; Soo Hyun Kim
      Pages: 3 - 22
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Seung Hyuk Im, Youngmee Jung, Soo Hyun Kim
      Because of the increasing incidence of coronary artery disease, the importance of cardiovascular stents has continuously increased as a treatment of this disease. Biodegradable scaffolds fabricated from polymers and metals have emerged as promising materials for vascular stents because of their biodegradability. Although such stent framework materials have shown good clinical efficacy, it is difficult to decide whether polymers or metals are better vascular scaffolds because their properties are different. Therefore, there are still obstacles in the development of biodegradable vascular scaffolds in terms of improving clinical efficacy. This review analyzes the pros and cons of current stent materials with respect to five key factors for next-generation stent and discusses methods of improvement. Furthermore, we discuss biodegradable electronic stents with electrical conductivity, which has been considered unimportant until now, and highlight electrical conductivity as a key factor in the development of next-generation stents.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.019
      Issue No: Vol. 60 (2017)
       
  • Exploring the role of peptides in polymer-based gene delivery
    • Authors: Yanping Sun; Zhen Yang; Chunxi Wang; Tianzhi Yang; Cuifang Cai; Xiaoyun Zhao; Li Yang; Pingtian Ding
      Pages: 23 - 37
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Yanping Sun, Zhen Yang, Chunxi Wang, Tianzhi Yang, Cuifang Cai, Xiaoyun Zhao, Li Yang, Pingtian Ding
      Polymers are widely studied as non-viral gene vectors because of their strong DNA binding ability, capacity to carry large payload, flexibility of chemical modifications, low immunogenicity, and facile processes for manufacturing. However, high cytotoxicity and low transfection efficiency substantially restrict their application in clinical trials. Incorporating functional peptides is a promising approach to address these issues. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we systematically summarize the role of peptides in polymer-based gene delivery, and elaborate how to rationally design polymer-peptide based gene delivery vectors. Statement of Significance Polymers are widely studied as non-viral gene vectors, but suffer from high cytotoxicity and low transfection efficiency. Incorporating short, bioactive peptides into polymer-based gene delivery systems can address this issue. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we highlight the peptides’ roles in polymer-based gene delivery, and elaborate how to utilize various functional peptides to enhance the transfection efficiency of polymers. The optimized peptide-polymer vectors should be able to alter their structures and functions according to biological microenvironments and utilize inherent intracellular pathways of cells, and consequently overcome the barriers during gene delivery to enhance transfection efficiency.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.043
      Issue No: Vol. 60 (2017)
       
  • Biomimetically grown apatite spheres from aggregated bioglass
           nanoparticles with ultrahigh porosity and surface area imply potential
           drug delivery and cell engineering applications
    • Authors: Ahmed El-Fiqi; Jennifer O. Buitrago; Sung Hee Yang; Hae-Won Kim
      Pages: 38 - 49
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Ahmed El-Fiqi, Jennifer O. Buitrago, Sung Hee Yang, Hae-Won Kim
      Here we communicate the generation of biomimetically grown apatite spheres from aggregated bioglass nanoparticles and the potential properties applicable for drug delivery and cell/tissue engineering. Ion releasing nanoparticulates of bioglass (85%SiO2-15%CaO) in a mineralizing medium show an intriguing dynamic phenomenon – aggregation, mineralization to apatite, integration and growth into micron-sized (1.5–3μm) spheres. During the progressive ionic dissolution/precipitation reactions, nano-to-micro-morphology, glass-to-crystal composition, and the physico-chemical properties (porosity, surface area, and charge) change dynamically. With increasing reaction period, the apatite becomes more crystallized with increased crystallinity and crystal size, and gets a composition closer to the stoichiometry. The developed microspheres exhibit hierarchical surface nanostructure, negative charge (ς-potential of −20mV), and ultrahigh mesoporosity (mesopore size of 6.1nm, and the resultant surface area of 63.7m2/g and pore volume of 0.153cm3/g) at 14days of mineralization, which are even higher than those of its precursor bioglass nanoparticles. Thanks to these properties, the biomimetic mineral microspheres take up biological molecules effectively, i.e., loading capacity of positive-charged protein is over 10%. Of note, the release is highly sustainable at a constant rate, i.e., profiling almost ‘zero-order’ kinetics for 4weeks, suggesting the potential usefulness as protein delivery systems. The biomimetic mineral microspheres hold some remnant Si in the core region, and release calcium, phosphate, and silicate ions over the test period, implying the long-term ionic-related therapeutic functions. The mesenchymal stem cells favour the biomimetic spheres with an excellent viability. Due to the merit of sizes (a few micrometers), the spheres can be intercalated into cells, mediating cellular interactions in 3D cell-spheroid engineering, and also can stimulate osteogenic differentiation of cells when incorporated into cell-laden gels. The intriguing properties observed in this study, including biomimetic composition, high mesoporosity, release of therapeutic ions, effective loading and long-term release of proteins, and diverse yet favorable 3D cellular interactions, suggest great potential of the newly developed biomimetic microspheres in biomedical applications, such as drug delivery and cell/tissue engineering. Statement of Significance This work reports the generation of apatite spheres with a few micrometers in size biomimetically grown from bioactive glass nanoparticles, through a series of intriguing yet unprecedented phenomenon involving aggregation of nanoparticles, mineralization and sphere growth. The mineral microspheres possess some unique physico-chemical properties including mesoporosity, ultrahigh surface area, and therapeutic ionic release. Furthermore, the spheres show excellent loading and delivery capacity of protein molecules, and mediate favorable cellular interactions in 2D and 3D culture conditions, demonstrating a future multifunctional microcarrier platform for the therapeutics delivery and cell/tissue engineering.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.036
      Issue No: Vol. 60 (2017)
       
  • In-situ tissue regeneration through SDF-1α driven cell recruitment and
           stiffness-mediated bone regeneration in a critical-sized segmental femoral
           defect
    • Authors: Amaia Cipitria; Kathrin Boettcher; Sophia Schoenhals; Daniela S. Garske; Katharina Schmidt-Bleek; Agnes Ellinghaus; Anke Dienelt; Anja Peters; Manav Mehta; Christopher M. Madl; Nathaniel Huebsch; David J. Mooney; Georg N. Duda
      Pages: 50 - 63
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Amaia Cipitria, Kathrin Boettcher, Sophia Schoenhals, Daniela S. Garske, Katharina Schmidt-Bleek, Agnes Ellinghaus, Anke Dienelt, Anja Peters, Manav Mehta, Christopher M. Madl, Nathaniel Huebsch, David J. Mooney, Georg N. Duda
      In-situ tissue regeneration aims to utilize the body’s endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent chemoattractant. Here we use a cell-free biomaterial-based approach to (i) deliver SDF-1α for the recruitment of endogenous bone marrow-derived stromal cells (BMSC) into a critical-sized segmental femoral defect in rats and to (ii) induce hydrogel stiffness-mediated osteogenic differentiation in-vivo. Ionically crosslinked alginate hydrogels with a stiffness optimized for osteogenic differentiation were used. Fast-degrading porogens were incorporated to impart a macroporous architecture that facilitates host cell invasion. Endogenous cell recruitment to the defect site was successfully triggered through the controlled release of SDF-1α. A trend for increased bone volume fraction (BV/TV) and a significantly higher bone mineral density (BMD) were observed for gels loaded with SDF-1α, compared to empty gels at two weeks. A trend was also observed, albeit not statistically significant, towards matrix stiffness influencing BV/TV and BMD at two weeks. However, over a six week time-frame, these effects were insufficient for bone bridging of a segmental femoral defect. While mechanical cues combined with ex-vivo cell encapsulation have been shown to have an effect in the regeneration of less demanding in-vivo models, such as cranial defects of nude rats, they are not sufficient for a SDF-1α mediated in-situ regeneration approach in segmental femoral defects of immunocompetent rats, suggesting that additional osteogenic cues may also be required. Statement of Significance Stromal cell-derived factor-1α (SDF-1α) is a chemoattractant used to recruit host cells for tissue regeneration. The concept that matrix stiffness can direct mesenchymal stromal cell (MSC) differentiation into various lineages was described a decade ago using in-vitro experiments. Recently, alginate hydrogels with an optimized stiffness and ex-vivo encapsulated MSCs were shown to have an effect in the regeneration of skull defects of nude rats. Here, we apply this material system, loaded with SDF-1α and without encapsulated MSCs, to (i) recruit endogenous cells and (ii) induce stiffness-mediated osteogenic differentiation in-vivo, using as model system a load-bearing femoral defect in immunocompetent rats. While a cell-free approach is of great interest from a translational perspective, the current limitations are described.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.032
      Issue No: Vol. 60 (2017)
       
  • Scaffold curvature-mediated novel biomineralization process originates a
           continuous soft tissue-to-bone interface
    • Authors: Michael Paris; Andreas Götz; Inga Hettrich; Cécile M. Bidan; John W.C. Dunlop; Hajar Razi; Ivo Zizak; Dietmar W. Hutmacher; Peter Fratzl; Georg N. Duda; Wolfgang Wagermaier; Amaia Cipitria
      Pages: 64 - 80
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Michael Paris, Andreas Götz, Inga Hettrich, Cécile M. Bidan, John W.C. Dunlop, Hajar Razi, Ivo Zizak, Dietmar W. Hutmacher, Peter Fratzl, Georg N. Duda, Wolfgang Wagermaier, Amaia Cipitria
      A myriad of shapes are found in biological tissues, often naturally evolved to fulfill a particular function. In the field of tissue engineering, substrate geometry influences cell behavior and tissue formation in vitro, yet little is known how this translates to an in vivo scenario. Here we investigate scaffold curvature-induced tissue growth, without additional growth factors or cells, in an ovine animal model. We show that soft tissue formation follows a curvature-driven tissue growth model. The highly organized endogenous soft matrix, potentially under mechanical strain, leads to a non-standard form of biomineralization, whereby the pre-existing organic matrix is mineralized without collagen remodeling and without an intermediate cartilage ossification phase. Micro- and nanoscale characterization of the tissue microstructure using histology, backscattered electron (BSE) and second-harmonic generation (SHG) imaging and synchrotron small angle X-ray scattering (SAXS) revealed (i) continuous collagen fibers across the soft-hard tissue interface on the tip of mineralized cones, and (ii) bone remodeling by basic multicellular units (BMUs) in regions adjacent to the native cortical bone. Thus, features of soft tissue-to-bone interface resembling the insertion sites of ligaments and tendons into bone were created, using a scaffold that did not mimic the structural or biological gradients across such a complex interface at its mature state. This study provides fundamental knowledge for biomimetic scaffold design in the fields of bone regeneration and soft tissue-to-bone interface tissue engineering. Statement of significance Geometry influences cell behavior and tissue formation in vitro. However, little is known how this translates to an in vivo scenario. Here we investigate the influence of scaffold mean surface curvature on in vivo tissue growth using an ovine animal model. Based on a multiscale tissue microstructure characterization, we show a seamless integration of soft tissue into newly formed bone, resembling the insertion sites of ligaments and tendons into bone. This interface was created using a scaffold without additional growth factors or cells that did not recapitulate the structural or biological gradients across such a complex tissue interface at its mature state. These findings have important implications for biomimetic scaffold design for bone regeneration and soft tissue-to-bone interface tissue engineering.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.029
      Issue No: Vol. 60 (2017)
       
  • In vitro degradation of calcium phosphates: Effect of multiscale porosity,
           textural properties and composition
    • Authors: A. Diez-Escudero; M. Espanol; S. Beats; M.-P. Ginebra
      Pages: 81 - 92
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): A. Diez-Escudero, M. Espanol, S. Beats, M.-P. Ginebra
      The capacity of calcium phosphates to be replaced by bone is tightly linked to their resorbability. However, the relative importance of some textural parameters on their degradation behavior is still unclear. The present study aims to quantify the effect of composition, specific surface area (SSA), and porosity at various length scales (nano-, micro- and macroporosity) on the in vitro degradation of different calcium phosphates. Degradation studies were performed in an acidic medium to mimic the osteoclastic environment. Small degradations were found in samples with interconnected nano- and micropores with sizes below 3µm although they were highly porous (35–65%), with maximum weight loss of 8wt%. Biomimetic calcium deficient hydroxyapatite, with high SSA and low crystallinity, presented the highest degradation rates exceeding even the more soluble β-TCP. A dependence of degradation on SSA was indisputable when porosity and pore sizes were increased. The introduction of additional macroporosity with pore interconnections above 20µm significantly impacted degradation, more markedly in the substrates with high SSA (>15m2/g), whereas in sintered substrates with low SSA (<1m2/g) it resulted just in a linear increase of degradation. Up to 30 % of degradation was registered in biomimetic substrates, compared to 15 % in β-TCP or 8 % in sintered hydroxyapatite. The incorporation of carbonate in calcium deficient hydroxyapatite did not increase its degradation rate. Overall, the study highlights the importance of textural properties, which can modulate or even outweigh the effect of other features such as the solubility of the compounds. Statement of Significance The physicochemical features of calcium phosphates are crucial to tune biological events like resorption during bone remodeling. Understanding in vitro resorption can help to predict the in vivo behavior. Besides chemical composition, other parameters such as porosity and specific surface area have a strong influence on resorption. The complexity of isolating the contribution of each parameter lies in the close interrelation between them. In this work, a multiscale study was proposed to discern the extent to which each parameter influences degradation in a variety of calcium phosphates, using an acidic medium to resemble the osteoclastic environment. The results emphasize the importance of textural properties, which can modulate or even outweigh the effect of the intrinsic solubility of the compounds.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.033
      Issue No: Vol. 60 (2017)
       
  • Intracellular co-delivery of Sr ion and phenamil drug through mesoporous
           bioglass nanocarriers synergizes BMP signaling and tissue mineralization
    • Authors: Jung-Hwan Lee; Nandin Mandakhbayar; Ahmed El-Fiqi; Hae-Won Kim
      Pages: 93 - 108
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Jung-Hwan Lee, Nandin Mandakhbayar, Ahmed El-Fiqi, Hae-Won Kim
      Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification. Herein Sr ion is structurally doped to MBN while drug Phenamil is externally loaded as a small molecule activator of BMP signaling, for the stimulation of osteo/odontogenesis and mineralization of human MSCs derived from dental pulp. The Sr-doped MBN (85Si:10Ca:5Sr) sol-gel processed presents a high mesoporosity with a pore size of ∼6nm. In particular, Sr ion is released slowly at a daily rate of ∼3ppm per mg nanoparticles for up to 7days, a level therapeutically effective for cellular stimulation. The Sr-MBN is internalized to most MSCs via an ATP dependent macropinocytosis within hours, increasing the intracellular levels of Sr, Ca and Si ions. Phenamil is loaded maximally ∼30% into Sr-MBN and then released slowly for up to 7days. The co-delivered molecules (Sr ion and Phenamil drug) have profound effects on the differentiation and maturation of cells, i.e., significantly enhancing expression of osteo/odontogenic genes, alkaline phosphatase activity, and mineralization of cells. Of note, the stimulation is a result of a synergism of Sr and Phenamil, through a Trb3-dependent BMP signaling pathway. This biological synergism is further evidenced in vivo in a mal-calcification condition involving an extracted tooth implantation in dorsal subcutaneous tissues of rats. Six weeks post operation evidences the osseous-dentinal hard tissue formation, which is significantly stimulated by the Sr/Phenamil delivery, based on histomorphometric and micro-computed tomographic analyses. The bioactive nanoparticles releasing both Sr ion and Phenamil drug are considered to be a promising therapeutic nanocarrier platform for hard tissue regeneration. Furthermore, this novel ion/drug co-delivery concept through nanoparticles can be extensively used for other tissues that require different therapeutic treatment. Statement of Significance This study reports a novel design concept in inorganic nanoparticle delivery system for hard tissues – the co-delivery of therapeutic molecules comprised of ion (Sr) and drug (Phenamil) through a unique nanoparticle of mesoporous bioactive glass (MBN). The physico-chemical and biological properties of MBN enabled an effective loading of both therapeutic molecules and a subsequently sustained/controlled release. The co-delivered Sr and Phenamil demonstrated significant stimulation of adult stem cell differentiation in vitro and osseous/dentinal regeneration in vivo, through BMP signaling pathways. We consider the current combination of Sr ion with Phenamil is suited for the osteo/odontogenesis of stem cells for hard tissue regeneration, and further, this ion/drug co-delivery concept can extend the applications to other areas that require specific cellular and tissue functions.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.021
      Issue No: Vol. 60 (2017)
       
  • Structural and physico-chemical analysis of calcium/strontium substituted,
           near-invert phosphate based glasses for biomedical applications
    • Authors: U. Patel; R.M. Moss; K.M.Z Hossain; A.R. Kennedy; E.R. Barney; I. Ahmed; A.C. Hannon
      Pages: 109 - 127
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): U. Patel, R.M. Moss, K.M.Z Hossain, A.R. Kennedy, E.R. Barney, I. Ahmed, A.C. Hannon
      Neutron diffraction, 23Na and 31P NMR, and FTIR spectroscopy have been used to investigate the structural effects of substituting CaO with SrO in a 40P2O5·(16-x)CaO·20Na2O·24MgO·xSrO glass, where x is 0, 4, 8, 12 and 16mol%. The 31P solid-state NMR results showed similar amounts of Q1 and Q2 units for all of the multicomponent glasses investigated, showing that the substitution of Sr for Ca has no effect on the phosphate network. The M-O coordinations (M=Mg, Ca, Sr, Na) were determined for binary alkali and alkaline earth metaphosphates using neutron diffraction and broad asymmetric distributions of bond length were observed, with coordination numbers that were smaller and bond lengths that were shorter than in corresponding crystals. The Mg-O coordination number was determined most reliably as 5.0(2). The neutron diffraction results for the multicomponent glasses are consistent with a structural model in which the coordination of Ca, Sr and Na is the same as in the binary metaphosphate glass, whereas there is a definite shift of Mg-O bonds to longer distance. There is also a small but consistent increase in the Mg-O coordination number and the width of the distribution of Mg-O bond lengths, as Sr substitutes for Ca. Functional properties, including glass transition temperatures, thermal processing windows, dissolution rates and ion release profiles were also investigated. Dissolution studies showed a decrease in dissolution rate with initial addition of 4mol% SrO, but further addition of SrO showed little change. The ion release profiles followed a similar trend to the observed dissolution rates. The limited changes in structure and dissolution rates observed for substitution of Ca with Sr in these fixed 40mol% P2O5 glasses were attributed to their similarities in terms of ionic size and charge. Statement of Significance Phosphate based glasses are extremely well suited for the delivery of therapeutic ions in biomedical applications, and in particular strontium plays an important role in the treatment of osteoporosis. We show firstly that the substitution of strontium for calcium in bioactive phosphate glasses can be used to control the dissolution rate of the glass, and hence the rate at which therapeutic ions are delivered. We then go on to examine in detail the influence of Sr/Ca substitution on the atomic sites in the glass, using advanced structural probes, especially neutron diffraction. The environments of most cations in the glass are unaffected by the substitution, with the exception of Mg, which becomes more disordered.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.002
      Issue No: Vol. 60 (2017)
       
  • A conducive bioceramic/polymer composite biomaterial for diabetic wound
           healing
    • Authors: Fang Lv; Jie Wang; Peng Xu; Yiming Han; Hongshi Ma; He Xu; Shijie Chen; Jiang Chang; Qinfei Ke; Mingyao Liu; Zhengfang Yi; Chengtie Wu
      Pages: 128 - 143
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Fang Lv, Jie Wang, Peng Xu, Yiming Han, Hongshi Ma, He Xu, Shijie Chen, Jiang Chang, Qinfei Ke, Mingyao Liu, Zhengfang Yi, Chengtie Wu
      Diabetic wound is a common complication of diabetes. Biomaterials offer great promise in inducing tissue regeneration for chronic wound healing. Herein, we reported a conducive Poly (caprolactone) (PCL)/gelatin nanofibrous composite scaffold containing silicate-based bioceramic particles (Nagelschmidtite, NAGEL, Ca7P2Si2O16) for diabetic wound healing. NAGEL bioceramic particles were well distributed in the inner of PCL/gelatin nanofibers via co-electrospinning process and the Si ions maintained a sustained release from the composite scaffolds during the degradation process. The nanofibrous scaffolds significantly promoted the adhesion, proliferation and migration of human umbilical vein endothelial cells (HUVECs) and human keratinocytes (HaCaTs) in vitro. The in vivo study demonstrated that the scaffolds distinctly induced the angiogenesis, collagen deposition and re-epithelialization in the wound sites of diabetic mice model, as well as inhibited inflammation reaction. The mechanism for nanofibrous composite scaffolds accelerating diabetic wound healing is related to the activation of epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) pathway in vivo and in vitro. Our results suggest that the released Si ions and nanofibrous structure of scaffolds have a synergetic effect on the improved efficiency of diabetic wound healing, paving the way to design functional biomaterials for tissue engineering and wound healing applications. Statement of Significance In order to stimulate tissue regeneration for chronic wound healing, a new kind of conducive nanofibrous composite scaffold containing silicate-based bioceramic particles (Nagelschmidtite, NAGEL, Ca7P2Si2O16) were prepared via co-electrospinning process. Biological assessments revealed that the NAGEL bioceramic particles could active epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) pathway in vitro and in vivo. The new composite scaffold had potential as functional biomaterials for tissue engineering and wound healing applications. The strategy of introducing controllable amount of therapeutic ions instead of loading expensive drugs/growth factors on nanofibrous composite scaffold provides new options for bioactive biomaterials.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.020
      Issue No: Vol. 60 (2017)
       
  • Nanofiber-structured hydrogel yarns with pH-response capacity and
           cardiomyocyte-drivability for bio-microactuator application
    • Authors: Shaohua Wu; Bin Duan; Xiaohong Qin; Jonathan T. Butcher
      Pages: 144 - 153
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Shaohua Wu, Bin Duan, Xiaohong Qin, Jonathan T. Butcher
      Polymeric hydrogels have great potential in soft biological micro-actuator applications. However, inappropriate micro-architecture, non-anisotropy, weak biomechanics, and inferior response behaviors limit their development. In this study, we designed and manufactured novel polyacrylonitrile (PAN)-based hydrogel yarns composed with uniaxially aligned nanofibers. The nanofibrous hydrogel yarns possessed anisotropic architecture and robust mechanical properties with flexibility, and could be assembled into defined scaffold structures by subsequent processes. The as-prepared hydrogel yarns showed excellent pH response behaviors, with around 100% maximum length and 900% maximum diameter changes, and the pH response was completed within several seconds. Moreover, the hydrogel yarns displayed unique cell-responsive abilities to promote the cell adhesion, proliferation, and smooth muscle differentiation of human adipose derived mesenchymal stem cells (HADMSC). Chicken cardiomyocytes were further seeded onto our nanofibrous hydrogel yarns to engineer living cell-based microactuators. Our results demonstrated that the uniaxially aligned nanofibrous networks within the hydrogel yarns were the key characteristics leading to the anisotropic organization of cardiac cells, and improved sarcomere organization, mimicking the cardiomyocyte bundles in the native myocardium. The construct is capable of sustaining spontaneous cardiomyocyte pumping behaviors for 7days. Our PAN-based nanofibrous hydrogel yarns are attractive for creating linear microactuators with pH-response capacity and biological microactuators with cardiomyocyte-drivability. Statement of Significance A mechanically robust polyacrylonitrile-based nanofibrous hydrogel yarn is fabricated by using a modified electrospinning setup in combination with chemical modification processes. The as-prepared hydrogel yarn possesses a uniaxially aligned nanofiber microarchitecture and supports a rapid, pH-dependent expansion/contraction response within a few seconds. Embryonic cardiomyocytes-seeded hydrogel yarn improves the sarcomere organization and mimics the cardiomyocyte bundles in the native myocardium, which sustains spontaneous cardiomyocyte pumping behaviors. The nanofibrous hydrogel yarn has several advantages over traditional bulk hydrogel scaffolds in terms of robust biomechanics, anisotropic aligned architecture, and superior pH response behaviors. Our nanofibrous hydrogel yarn holds the potential to be developed into novel linear and biological microactuators for various biomedical applications.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.023
      Issue No: Vol. 60 (2017)
       
  • Peptide modification of polyimide-insulated microwires: Towards improved
           biocompatibility through reduced glial scarring
    • Authors: Sangita Sridar; Matthew A. Churchward; Vivian K. Mushahwar; Kathryn G. Todd; Anastasia L. Elias
      Pages: 154 - 166
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Sangita Sridar, Matthew A. Churchward, Vivian K. Mushahwar, Kathryn G. Todd, Anastasia L. Elias
      The goal of this study is to improve the integration of implanted microdevices with tissue in the central nervous system (CNS). The long-term utility of neuroprosthetic devices implanted in the CNS is affected by the formation of a scar by resident glial cells (astrocytes and microglia), limiting the viability and functional stability of the devices. Reduction in the proliferation of glial cells is expected to enhance the biocompatibility of devices. We demonstrate the modification of polyimide-insulated microelectrodes with a bioactive peptide KHIFSDDSSE. Microelectrode wires were functionalized with (3-aminopropyl) triethoxy silane (APTES); the peptide was then covalently bonded to the APTES. The soluble peptide was tested in 2D mixed cultures of astrocytes and microglia, and reduced the proliferation of both cell types. The interactions of glial cells with the peptide-modified wires was then examined in 3D cell-laden hydrogels by immunofluorescence microscopy. As expected for uncoated wires, the microglia were first attracted to the wire (7days) followed by astrocyte recruitment and hypertrophy (14days). For the peptide-treated wires, astrocytes coated the wires directly (24h), and formed a thin, stable coating without evidence of hypertrophy, and the attraction of microglia to the wire was significantly reduced. The results suggest a mechanism to improve tissue integration by promoting uniform coating of astrocytes on a foreign body while lessening the reactive response of microglia. We conclude that the bioactive peptide KHIFSDDSSE may be effective in improving the biocompatibility of neural interfaces by both reducing acute glial reactivity and generating stable integration with tissue. Statement of significance The peptide KHIFSDDSSE has previously been shown in vitro to both reduce the proliferation of astrocytes, and to increase the adhesion of astrocyte to glass substrates. Here, we demonstrate a method to apply uniform coatings of peptides to microwires, which could readily be generalized to other peptides and surfaces. We then show that when peptide-modified wires are inserted into 3D cell-laden hydrogels, the normal cellular reaction (microglial activation followed by astrocyte recruitment and hypertrophy) does not occur, rather astrocytes are attracted directly to the surface of the wire, forming a relatively thin and uniform coating. This suggests a method to improve tissue integration of implanted devices to reduce glial scarring and ultimately reduce failure of neural interfaces.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.026
      Issue No: Vol. 60 (2017)
       
  • Regulated viral BDNF delivery in combination with Schwann cells promotes
           axonal regeneration through capillary alginate hydrogels after spinal cord
           injury
    • Authors: Shengwen Liu; Beatrice Sandner; Thomas Schackel; LaShae Nicholson; Abdelwahed Chtarto; Liliane Tenenbaum; Radhika Puttagunta; Rainer Müller; Norbert Weidner; Armin Blesch
      Pages: 167 - 180
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Shengwen Liu, Beatrice Sandner, Thomas Schackel, LaShae Nicholson, Abdelwahed Chtarto, Liliane Tenenbaum, Radhika Puttagunta, Rainer Müller, Norbert Weidner, Armin Blesch
      Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord. Statement of Significance Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4weeks does not further increase the number of regenerating axons.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.024
      Issue No: Vol. 60 (2017)
       
  • Hydrogel elasticity and microarchitecture regulate dental-derived
           mesenchymal stem cell-host immune system cross-talk
    • Authors: Sahar Ansari; Chider Chen; Mohammad Mahdi Hasani-Sadrabadi; Bo Yu; Homayoun H. Zadeh; Benjamin M. Wu; Alireza Moshaverinia
      Pages: 181 - 189
      Abstract: Publication date: 15 September 2017
      Source:Acta Biomaterialia, Volume 60
      Author(s): Sahar Ansari, Chider Chen, Mohammad Mahdi Hasani-Sadrabadi, Bo Yu, Homayoun H. Zadeh, Benjamin M. Wu, Alireza Moshaverinia
      The host immune system (T-lymphocytes and their pro-inflammatory cytokines) has been shown to compromise bone regeneration ability of mesenchymal stem cells (MSCs). We have recently shown that hydrogel, used as an encapsulating biomaterial affects the cross-talk among host immune cells and MSCs. However, the role of hydrogel elasticity and porosity in regulation of cross-talk between dental-derived MSCs and immune cells is unclear. In this study, we demonstrate that the modulus of elasticity and porosity of the scaffold influence T-lymphocyte-dental MSC interplay by regulating the penetration of inflammatory T cells and their cytokines. Moreover, we demonstrated that alginate hydrogels with different elasticity and microporous structure can regulate the viability and determine the fate of the encapsulated MSCs through modulation of NF-kB pathway. Our in vivo data show that alginate hydrogels with smaller pores and higher elasticity could prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascades, leading to higher amounts of ectopic bone regeneration. Additionally, dental-derived MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. Taken together, our findings demonstrate that the mechanical characteristics and microarchitecture of the microenvironment encapsulating MSCs, in addition to presence of T-lymphocytes and their pro-inflammatory cytokines, affect the fate of encapsulated dental-derived MSCs. Statement of significance In this study, we demonstrate that alginate hydrogel regulates the viability and the fate of the encapsulated dental-derived MSCs through modulation of NF-kB pathway. Alginate hydrogels with smaller pores and higher elasticity prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascade, leading to higher amounts of ectopic bone regeneration. MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. These findings confirm that the fate of encapsulated MSCs are affected by the stiffness and microarchitecture of the encapsulating hydrogel biomaterial, as well as presence of T-lymphocytes/pro-inflammatory cytokines providing evidence concerning material science, stem cell biology, the molecular mechanism of dental-derived MSC-associated therapies, and the potential clinical therapeutic impact of MSCs.
      Graphical abstract image

      PubDate: 2017-09-06T11:34:44Z
      DOI: 10.1016/j.actbio.2017.07.017
      Issue No: Vol. 60 (2017)
       
  • Design, Development and Characterization of Synthetic Bruch’s
           Membranes
    • Authors: Denver C. Surrao; Ursula Greferath; Yu-Qian Chau; Stuart J. Skabo; Mario Huynh; Kinnari J. Shelat; Ioannis J. Limnios; Erica L. Fletcher; Qin Liu
      Abstract: Publication date: Available online 23 September 2017
      Source:Acta Biomaterialia
      Author(s): Denver C. Surrao, Ursula Greferath, Yu-Qian Chau, Stuart J. Skabo, Mario Huynh, Kinnari J. Shelat, Ioannis J. Limnios, Erica L. Fletcher, Qin Liu
      Age-related macular degeneration (AMD) is a leading cause of blindness, and dry AMD has no effective treatment. Retinal constructs comprising retinal pigment epithelium (RPE) cells supported by electrospun scaffolds have been investigated to treat dry AMD. However, electrospun scaffolds studied to-date do not mimic the structural microenvironment of human Bruch’s membrane (BM), essential for native-like RPE monolayers. The aim of this study was to develop a structurally biomimetic scaffold designed to support a functional RPE monolayer, comprising porous, electrospun nanofibrous membranes (ENMs), coated with laminin, mimicking the inner collagenous layer (ICL) and basal RPE lamina respectively, the cell supporting layers of the BM. In vitro evaluation showed 70 nm PLLA ENMs adsorbed high amounts of laminin and supported functional RPE monolayers, exhibiting 3D polygonal-cobblestone morphology, apical microvilli, basal infoldings, high transepithelial resistance (TER), phagocytic activity and expression of signature RPE markers. 70 nm PLLA ENMs were successfully implanted into the subretinal space of RCS-rdy+p+/LAV rats, also commonly know as rdy rats. At week 4, in the absence of immunosuppressants, implanted PLLA ENMs were surrounded by a significantly low number of activated microglial cells, compared to week 1, indicating no adverse long-term immune response. In conclusion, we successfully designed and tested ENMs emulating the RPE cell supporting layers of the BM, and found 70 nm PLLA ENMs to be best suited as scaffolds for fabricating retinal constructs. Statement of significance Age related macular degeneration (AMD) is a leading cause of vision loss in the developed world, with an increasing number of people suffering from blindness or severe visual impairment. Transplantation of retinal pigment epithelium (RPE) cells supported on a synthetic, biomimetic-like Bruch’s membrane (BM) is considered a promising treatment. However, the synthetic scaffolds used do not mimic the microenvironment of the RPE cell supporting layers, required for the development of a functional RPE monolayer. This study indicated that porous, laminin coated, 70 nm PLLA ENMs supported functional RPE monolayers, exhibiting 3D polygonal-cobblestone morphology, apical microvilli, basal infoldings, high transepithelial resistance (TER), phagocytic activity and expression of signature RPE markers. These findings indicate the potential clinical use of porous, laminin coated, 70 nm PLLA ENMs in fabricating retinal constructs aimed at treating dry AMD.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.032
       
  • A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant
           combined with rhbFGF in a rat limb ischemia model
    • Authors: Hanmei Bao; Feng Lv; Tianjun Liu
      Abstract: Publication date: Available online 23 September 2017
      Source:Acta Biomaterialia
      Author(s): Hanmei Bao, Feng Lv, Tianjun Liu
      Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4 weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and α-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p<0.05, p<0.01 and p<0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1±2.9% and 80.7±3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia. Statement of Significance Magnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site-specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.033
       
  • Quantitative multiphoton microscopy of murine urinary bladder morphology
           during in situ uniaxial loading
    • Authors: Jack Hornsby; Donna M Daly; David Grundy; Fangzhou Cheng; Anne M Robertson; Paul N Watton; Mark S Thompson
      Abstract: Publication date: Available online 22 September 2017
      Source:Acta Biomaterialia
      Author(s): Jack Hornsby, Donna M Daly, David Grundy, Fangzhou Cheng, Anne M Robertson, Paul N Watton, Mark S Thompson
      Urodynamic tests are the gold standard for the diagnosis of bladder dysfunction, and the mechanical compliance of the bladder is an important parameter in these tests. The bladder wall has a layered structure, differentially affected by pathology, so knowledge of the contribution and role of these layers and their constituents to overall bladder compliance will enhance interpretation of these clinical tests. In this study we document the functional morphology of the detrusor and lamina propria of the murine bladder wall using a custom in-situ tensile loading system under multiphoton microscopy (MPM) observation in unloaded state and under incremental uniaxial stretch. Features in the stress-stretch curves of bladder samples were then directly related to corresponding MPM images. Collagen organisation across wall depth was quantified using image analysis techniques. The hypothesis that the lamina propria deformed at low strain by unfolding of the rugae and rearranging collagen fibrils was confirmed. A novel ‘pocket’ feature in the detrusor was observed along with extensive rearrangement of fibrils in two families at different depths, providing higher stiffness at high stretches in the detrusor. The very different deformations of detrusor and lamina propria were accommodated by the highly coiled structure of collagen in the lamina propria. Imaging and mechanical studies presented here allow gross mechanical response to be attributed to specific components of the bladder wall and further, may be used to investigate the impact of microstructural changes due to pathology or aging, and how they impair tissue functionality. Statement of significance This article reports the first in-situ multiphoton microscopy observations of microstructural deformation under uniaxial tensile loading of ex vivo bladder. We describe collagen rearrangement through the tissue thickness and relate this directly to the stress-stretch behaviour. We confirm for the first time the unfolding of rugae and realignment of fibrils in the lamina propria during extension and the rapid stiffening as two fibril families in the detrusor are engaged. This technique provides new insight into microstructure function and will enhance understanding of the impact of changes due to pathology or aging.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.029
       
  • In vitro and in vivo study of the application of volvox spheres to
           co-culture vehicles in liver tissue engineering
    • Authors: Siou Han Chang; Han Hsiang Huang; Pei Leun Kang; Yu Chian Wu; Ming-Huang Chang; Shyh Ming Kuo
      Abstract: Publication date: Available online 21 September 2017
      Source:Acta Biomaterialia
      Author(s): Siou Han Chang, Han Hsiang Huang, Pei Leun Kang, Yu Chian Wu, Ming-Huang Chang, Shyh Ming Kuo
      Volvox sphere is a biomimetic concept of a natural Volvox, wherein a large outer sphere contains smaller inner spheres, which can encapsulate cells and provide a double-layer three-dimensional environment for culturing cells. This study simultaneously encapsulated rat mesenchymal stem cells (MSCs) and AML12 hepatocytes in volvox spheres and extensively evaluated the effects of various culturing modes on cell functions and fates. The results showed that compared with a static flask culture, MSCs encapsulated in volvox spheres differentiated into hepatocyte-like cells with a 2-fold increase in albumin (ALB) expression and a 2.5-fold increase in cytokeratin 18 expression in a dynamic bioreactor. Moreover, the restorative effects of volvox spheres encapsulating cells on retrorsine-exposed CCl4-induced liver injuries in rats were evaluated. The data presented significant reductions in AST and ALT levels after the implantation of volvox spheres encapsulating both MSCs and AML12 hepatocytes in vivo. In contrast to the negative control group, histopathological analysis demonstrated liver repair and formation of the new liver tissue in groups implanted with volvox spheres containing cells. These results demonstrate that liver cells implanted with volvox spheres encapsulating both MSCs and AML12 hepatocytes promote liver repair and liver tissue regeneration in liver failure caused by necrotizing agents such as retrorsine and CCl4. Hence, volvox spheres encapsulating MSCs and liver cells can be a promising and clinically effective therapy for liver injury. Statement of Significance In this study, we have utilized used a Vvolvox sphere, which is a unique design to thatmimics the natural vVolvox,that consists of a large outer-sphere that contains smaller inner-spheres, which provide a three-dimensional environment to culture cells. The purpose of this study is to co-culture mesenchymal stem cells(MSCs) and AML12 liver cells in Vvolvox spheres and to evaluate the two different culture methods, dynamic bioreactor and static culture flask,on the cultured cells.AndalsoIn addition, we aimed to evaluate the restorative effects of volvoxspheres encapsulated withingMSCs and/or AML12 liver cellscellsonratswith the retrorsine-exposed CCl4-induced liver injuriesrats. The results showed that MSCs encapsulated in volvoxspheres differentiated into hepatocyte-like cells with a 2-fold increase in albumin expression and a 2.5-fold increasein cytokeratin 18 expression ina dynamic bioreactor. Moreover, thedatapresented significant reductions in AST and ALT levels after the implantationofvolvox spheres encapsulateding with both MSCs and AML12 hepatocytes in vivo. In contrast to the negative control group, histopathological analysis demonstratedliver repair and formation of the new liver tissue in groups implanted with volvox spheres containing cells. These results demonstrate that liver cells implanted withvolvox spheres encapsulated withing both MSCs and AML12 hepatocytes promote liver repair and liver tissue regenerationin liver failure caused by necrotizing agentssuch as retrorsine and CCl4. Hence, volvoxspheresencapsulated with ing MSCs and liver cells can be a promising and clinically effective therapy for liver injury.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.028
       
  • Soft tissue fillers for adipose tissue regeneration: from hydrogel
           development toward clinical applications
    • Authors: I. Van Nieuwenhove; L. Tytgat; M. Ryx; P. Blondeel; F. Stillaert; H. Thienpont; H. Ottevaere; P. Dubruel; S. Van Vlierberghe
      Abstract: Publication date: Available online 20 September 2017
      Source:Acta Biomaterialia
      Author(s): I. Van Nieuwenhove, L. Tytgat, M. Ryx, P. Blondeel, F. Stillaert, H. Thienpont, H. Ottevaere, P. Dubruel, S. Van Vlierberghe
      There is a clear and urgent clinical need to develop soft tissue fillers that outperform the materials currently used for adipose tissue reconstruction. Recently, extensive research has been performed within this field of adipose tissue engineering as the commercially available products and the currently existing techniques are concomitant with several disadvantages. Commercial products are highly expensive and associated with an imposing need for repeated injections. Lipofilling or free fat transfer has an unpredictable outcome with respect to cell survivalandpotential resorption of the fat grafts. Therefore, researchers arepredominantly investigating two challenging adipose tissue engineering strategies: in situ injectable materials and porous 3D printed scaffolds.The present work provides an overview of current research encompassing synthetic, biopolymer-based, and extracellular matrix-derived materials, with a clear focus on emerging fabrication technologies and developments realized throughout the last decade. Moreover, clinical relevance of the most promising materials will be discussed, together with potential concerns associated with their application in the clinic.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.026
       
  • Silk scaffolds in bone tissue engineering: an overview
    • Authors: Promita Bhattacharjee; Banani Kundu; Deboki Naskar; Hae-Won Kim; Tapas K Maiti; Debasis Bhattacharya; Subhas C Kundu
      Abstract: Publication date: Available online 20 September 2017
      Source:Acta Biomaterialia
      Author(s): Promita Bhattacharjee, Banani Kundu, Deboki Naskar, Hae-Won Kim, Tapas K Maiti, Debasis Bhattacharya, Subhas C Kundu
      Bone tissue plays multiple roles in our day-to-day functionality. The frequency of accidental bone damage and disorder is increasing worldwide. Moreover, as the world population continues to grow, the percentage of the elderly population continues to grow, which results in an increased number of bone degenerative diseases. This increased elderly population pushes the need for artificial bone implants that specifically employ biocompatible materials. A vast body of literature is available on the use of silk in bone tissue engineering. The current work presents an overview of this literature from a materials and fabrication perspective. As silk is an easy-to-process biopolymer, this allows silk-based biomaterials to be molded into diverse forms and architectures, which further affects the degradability. This makes silk-based scaffolds suitable for treating a variety of bone reconstruction and regeneration objectives. Silk surfaces offer active sites that aid the mineralization and/or bonding of bioactive molecules that facilitate bone regeneration. Silk has also been blended with a variety of polymers and minerals to enhance its advantageous properties or introduce new ones. Several successful works, both in vitro and in vivo, have been reported using silk-based scaffolds to regenerate bone tissues or other parts of the skeletal system such as cartilage and ligament. A growing trend is observed toward the use of mineralized and nanofibrous scaffolds along with the development of technology that allows to control scaffold architecture, its biodegradability, and the sustained releasing property of scaffolds. Further development of silk-based scaffolds for bone tissue engineering, taking them up to and beyond the stage of human trials, is hoped to be achieved in the near future through a crossdisciplinary coalition of tissue engineers, material scientists, and manufacturing engineers. Statement of Significance The state-of-art of silk biomaterials in bone tissue engineering, covering their wide applications as cell scaffolding matrices to micro-nano carriers for delivering bone growth factors and therapeutic molecules to diseased or damaged site to facilitate bone regeneration, is emphasized here. The review rationalizes that the choice of silk protein as a biomaterial is not only because of its natural polymeric nature, mechanical robustness, flexibility, and wide range of cell compatibility but also because of its ability to template the growth of hydroxyapatite, the chief inorganic component of bone mineral matrix, resulting in improved osteointegration. The discussion extends to the role of inorganic ions such as Si and Ca as a matrix components in combination with silk to influence bone regrowth. The effect of ions or growth factor-loaded vehicle incorporation into regenerative matrix nanotopography is also included.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.027
       
  • A deep learning approach to estimate chemically-treated collagenous tissue
           nonlinear anisotropic stress-strain responses from microscopy images
    • Authors: Liang Liang; Minliang Liu; Wei Sun
      Abstract: Publication date: Available online 20 September 2017
      Source:Acta Biomaterialia
      Author(s): Liang Liang, Minliang Liu, Wei Sun
      Biological collagenous tissues comprised of networks of collagen fibers are suitable for a broad spectrum of medical applications owing to their attractive mechanical properties. In this study, we developed a noninvasive approach to estimate collagenous tissue elastic properties directly from microscopy images using Machine Learning (ML) techniques. Glutaraldehyde-treated bovine pericardium (GLBP) tissue, widely used in the fabrication of bioprosthetic heart valves and vascular patches, was chosen to develop a representative application. A Deep Learning model was designed and trained to process second harmonic generation (SHG) images of collagen networks in GLBP tissue samples, and directly predict the tissue elastic mechanical properties. The trained model is capable of identifying the overall tissue stiffness with a classification accuracy of 84%, and predicting the nonlinear anisotropic stress-strain curves with average regression errors of 0.021 and 0.031. Thus, this study demonstrates the feasibility and great potential of using the Deep Learning approach for fast and noninvasive assessment of collagenous tissue elastic properties from microstructural images. Statement of Significance In this study, we developed, to our best knowledge, the first Deep Learning-based approach to estimate the elastic properties of collagenous tissues directly from noninvasive second harmonic generation images. The success of this study holds promise for the use of Machine Learning techniques to noninvasively and efficiently estimate the mechanical properties of many structure-based biological materials, and it also enables many potential applications such as serving as a quality control tool to select tissue for the manufacturing of medical devices (e.g. bioprosthetic heart valves).
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.025
       
  • Biodegradable and adjustable sol-gel glass based hybrid scaffolds from
           multi-armed oligomeric building blocks
    • Authors: Christian Kascholke; Stephan Hendrikx; Tobias Flath; Dzmitry Kuzmenka; Hans-Martin Dörfler; Dirk Schumann; Mathias Gressenbuch; F. Peter Schulze; Michaela Schulz-Siegmund; Michael C. Hacker
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Christian Kascholke, Stephan Hendrikx, Tobias Flath, Dzmitry Kuzmenka, Hans-Martin Dörfler, Dirk Schumann, Mathias Gressenbuch, F. Peter Schulze, Michaela Schulz-Siegmund, Michael C. Hacker
      Biodegradability is a crucial characteristic to improve the clinical potential of sol-gel-derived glass materials. To this end, a set of degradable organic/inorganic class II hybrids from a tetraethoxysilane(TEOS)-derived silica sol and oligovalent cross-linker oligomers containing oligo(D,L-lactide) domains was developed and characterized. A series of 18 oligomers (Mn: 1100-3200 Da) with different degrees of ethoxylation and varying length of oligoester units was established and chemical composition was determined. Applicability of an established indirect rapid prototyping method enabled fabrication of overall 85 different hybrid scaffold formulations from 3-isocyanatopropyltriethoxysilane-functionalized macromers. In vitro degradation was analyzed over 12 months and a continuous linear weight loss (0.2-0.5 wt%/d) combined with only moderate material swelling was detected which was controlled by oligo(lactide) content and matrix hydrophilicity. Compressive strength (2-30 MPa) and compressive modulus (44-716 MPa) were determined and total content, oligo(ethylene oxide) content, oligo(lactide) content and molecular weight of the oligomeric cross-linkers as well as material porosity were identified as the main factors determining hybrid mechanics. Cytocompatibility was assessed by cell culture experiments with human adipose tissue-derived stem cells (hASC). Cell migration into the entire scaffold pore network was indicated and continuous proliferation over 14 days was found. ALP activity linearly increased over 2 weeks indicating osteogenic differentiation. The presented glass-based hybrid concept with precisely adjustable material properties holds promise for regenerative purposes. Statement of Significance Adaption of degradation kinetics toward physiological relevance is still an unmet challenge of (bio-)glass engineering. We therefore present a glass-derived hybrid material with adjustable degradation. A flexible design concept based on degradable multi-armed oligomers was combined with an established indirect rapid prototyping method to produce a systematic set of porous sol-gel-derived class II hybrid scaffolds. Mechanical properties in the range of cancellous bone were narrowly controlled by hybrid composition. The oligoester introduction resulted in significantly increased compressive moduli. Cytocompatible hybrids degraded in physiologically relevant time frames and a promising linear and controllable weight loss profile was found. To our knowledge, our degradation study represents the most extensive long-term investigation of sol-gel-derived class II hybrids. Due to the broad adjustability of material properties, our concept offers potential for engineering of biodegradable hybrid materials for versatile applications.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.024
       
  • Mechanical characterization of structurally porous biomaterials built via
           additive manufacturing: experiments, predictive models, and design maps
           for load-bearing bone replacement implants
    • Authors: D. Melancon; Z.S. Bagheri; R.B. Johnston; L. Liu; M. Tanzer; D. Pasini
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): D. Melancon, Z.S. Bagheri, R.B. Johnston, L. Liu, M. Tanzer, D. Pasini
      Porous biomaterials can be additively manufactured with micro-architecture tailored to satisfy the stringent mechano-biological requirements imposed by bone replacement implants. In a previous investigation, we introduced structurally porous biomaterials, featuring strength five times stronger than commercially available porous materials, and confirmed their bone ingrowth capability in an in-vivo canine model. While encouraging, the manufactured biomaterials showed geometric mismatches between their internal porous architecture and that of its as-designed counterpart, as well as discrepancies between predicted and tested mechanical properties, issues not fully elucidated. In this work, we propose a systematic approach integrating computed tomography, mechanical testing, and statistical analysis of geometric imperfections to generate statistical based numerical models of high-strength additively manufactured porous biomaterials. The method is used to develop morphology and mechanical maps that illustrate the role played by pore size, porosity, strut thickness, and topology on the relations governing their elastic modulus and compressive yield strength. Overall, there are mismatches between the mechanical properties of ideal-geometry models and as-manufactured porous biomaterials with average errors of 49% and 41% respectively for compressive elastic modulus and yield strength. The proposed methodology gives more accurate predictions for the compressive stiffness and the compressive strength properties with a reduction of the average error to 11% and 7.6%. The implications of the results and the methodology here introduced are discussed in the relevant biomechanical and clinical context, with insight that highlights promises and limitations of additively manufactured porous biomaterials for load-bearing bone replacement implants. Statement of significance In this work, we perform mechanical characterization of load-bearing porous biomaterials for bone replacement over their entire design space. Results capture the shift in geometry and mechanical properties between as-designed and as-manufactured biomaterials induced by additive manufacturing. Characterization of this shift is crucial to ensure appropriate manufacturing of bone replacement implants that enable biological fixation through bone ingrowth as well as mechanical property harmonization with the native bone tissue. In addition, we propose a method to include manufacturing imperfections in the numerical models that can reduce the discrepancy between predicted and tested properties. The results give insight into the use of structurally porous biomaterials for the design and additive fabrication of load-bearing implants for bone replacement.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.013
       
  • Polyurethane foam scaffold as in vitro model for breast cancer bone
           metastasis
    • Authors: Valentina Angeloni; Nicola Contessi; Cinzia De Marco; Serena Bertoldi; Maria Cristina Tanzi; Maria Grazia Daidone; Silvia Farè
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Valentina Angeloni, Nicola Contessi, Cinzia De Marco, Serena Bertoldi, Maria Cristina Tanzi, Maria Grazia Daidone, Silvia Farè
      Breast cancer (BC) represents the most incident cancer case in women (29%), with high mortality rate. Bone metastasis occurs in 20–50% cases and, despite advances in BC research, the interactions between tumor cells and the metastatic microenvironment are still poorly understood. In vitro 3D models gained great interest in cancer research, thanks to the reproducibility, the 3D spatial cues and associated low costs, compared to in vivo and 2D in vitro models. In this study, we investigated the suitability of a poly-ether-urethane (PU) foam as 3D in vitro model to study the interactions between BC tumor-initiating cells and the bone microenvironment. PU foam open porosity (>70%) appeared suitable to mimic trabecular bone structure. The PU foam showed good mechanical properties under cyclic compression (E=69–109kPa), even if lower than human trabecular bone. The scaffold supported osteoblast SAOS-2 cell line proliferation, with no cytotoxic effects. Human adipose derived stem cells (ADSC) were cultured and differentiated into osteoblast lineage on the PU foam, as shown by alizarin red staining and RT-PCR, thus offering a bone biomimetic microenvironment to the further co-culture with BC derived tumor-initiating cells (MCFS). Tumor aggregates were observed after three weeks of co-culture by e-cadherin staining and SEM; modification in CaP distribution was identified by SEM-EDX and associated to the presence of tumor cells. In conclusion, we demonstrated the suitability of the PU foam to reproduce a bone biomimetic microenvironment, useful for the co-culture of human osteoblasts/BC tumor-initiating cells and to investigate their interaction. Statement of significance 3D in vitro models represent an outstanding alternative in the study of tumor metastases development, compared to traditional 2D in vitro cultures, which oversimplify the 3D tissue microenvironment, and in vivo studies, affected by low reproducibility and ethical issues. Several scaffold-based 3D in vitro models have been proposed to recapitulate the development of metastases in different body sites but, still, the crucial challenge is to correctly mimic the tissue to be modelled in terms of physical, mechanical and biological properties. Here, we prove the suitability of a porous polyurethane foam, synthesized using an appropriate formulaton, in mimicking the bone tissue microenvironment and in reproducing the metastatic colonization derived from human breast cancer, particularly evidencing the devastating effects on the bone extracellular matrix caused by metastatic spreading.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.017
       
  • Azopolymer photopatterning for directional control of angiogenesis
    • Authors: Chiara Fedele; Maria De Gregorio; Paolo A. Netti; Silvia Cavalli; Chiara Attanasio
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Chiara Fedele, Maria De Gregorio, Paolo A. Netti, Silvia Cavalli, Chiara Attanasio
      Understanding cellular behavior in response to microenvironmental stimuli is central to tissue engineering. An increasing number of reports emphasize the high sensitivity of cells to the physical characteristics of the surrounding milieu and in particular, topographical cues. In this work, we investigated the influence of dynamic topographic signal presentation on sprout formation and the possibility to obtain a space–time control over sprouting directionality without growth factors, in order to investigate the contribution of just topography in the angiogenic process. To test our hypothesis, we employed a 3D angiogenesis assay based on the use of spheroids derived from human umbilical vein endothelial cells (HUVECs). We then modulated the in situ presentation of topographical cues during early-stage angiogenesis through real-time photopatterning of an azobenzene-containing polymer, poly (Disperse Red 1 methacrylate) (pDR1m). Pattern inscription on the polymer surface was made using the focused laser of a confocal microscope. We demonstrate that during early-stage angiogenesis, sprouts followed the pattern direction, while spheroid cores acquired a polarized shape. These findings confirmed that sprout directionality was influenced by the photo-inscribed pattern, probably through contact guidance of leader cells, thus validating the proposed platform as a valuable tool for understanding complex processes involved in cell-topography interactions in multicellular systems. Statement of Significance The complex relationship between endothelial cells and the surrounding environment that leads to formation of a newly formed vascular network during tissue repair is currently unknown. We have developed an innovative in vitro platform to study these mechanisms in a space and time controlled fashion simulating what happens during regeneration. In particular, we combine a “smart” surface, namely a polymer film, with a three-dimensional living cell aggregate. The polymer is activated by light through which we can design a path to guide cells toward the formation of a new vessel. Our work lies at the intersection of stimuli-responsive biointerfaces and cell biology and may be particularly inspiring for those interested in designing biomaterial surface related to angiogenesis.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.022
       
  • Three-dimensional nano-architected scaffolds with tunable stiffness for
           efficient bone tissue growth
    • Authors: Alessandro Maggi; Hanqing Li; Julia R. Greer
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Alessandro Maggi, Hanqing Li, Julia R. Greer
      The precise mechanisms that lead to orthopedic implant failure are not well understood; it is believed that the micromechanical environment at the bone-implant interface regulates structural stability of an implant. In this work, we seek to understand how the 3D mechanical environment of an implant affects bone formation during early osteointegration. We employed two-photon lithography (TPL) direct laser writing to fabricate 3-dimensional rigid polymer scaffolds with tetrakaidecahedral periodic geometry, herewith referred to as nanolattices, whose strut dimensions were on the same order as osteoblasts’ focal adhesions (∼2μm) and pore sizes on the order of cell size, ∼10μm. Some of these nanolattices were subsequently coated with thin conformal layers of Ti or W, and a final outer layer of 18nm-thick TiO2 was deposited on all samples to ensure biocompatibility. Nanomechanical experiments on each type of nanolattice revealed the range of stiffnesses of 0.7–100MPa. Osteoblast-like cells (SAOS-2) were seeded on each nanolattice, and their mechanosensitve response was explored by tracking mineral secretions and intracellular f-actin and vinculin concentrations after 2, 8 and 12days of cell culture in mineralization media. Experiments revealed that the most compliant nanolattices had ∼20% more intracellular f-actin and ∼40% more Ca and P secreted onto them than the stiffer nanolattices, where such cellular response was virtually indistinguishable. We constructed a simple phenomenological model that appears to capture the observed relation between scaffold stiffness and f-actin concentration. This model predicts a range of optimal scaffold stiffnesses for maximum f-actin concentration, which appears to be directly correlated with osteoblast-driven mineral deposition. This work suggests that three-dimensional scaffolds with titania-coated surfaces may provide an optimal microenvironment for cell growth when their stiffness is similar to that of cartilage (∼0.5–3MPa). These findings help provide a greater understanding of osteoblast mechanosensitivity and may have profound implications in developing more effective and safer bone prostheses. Statement of Significance Creating prostheses that lead to optimal bone remodeling has been a challenge for more than two decades because of a lack of thorough knowledge of cell behavior in three-dimensional (3D) environments. Literature has shown that 2D substrate stiffness plays a significant role in determining cell behavior, however, limitations in fabrication techniques and difficulties in characterizing cell-scaffold interactions have limited our understanding of how 3D scaffolds’ stiffness affects cell response. The present study shows that scaffold structural stiffness affects osteoblasts cellular response. Specifically this work shows that the cells grown on the most compliant nanolattices with a stiffness of 0.7MPa expressed ∼20% higher concentration of intracellular f-actin and secreted ∼40% more Ca and P compared with all other nanolattices. This suggests that bone scaffolds with a stiffness close to that of cartilage may serve as optimal 3D scaffolds for new synthetic bone graft materials.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.007
       
  • Chitosan-Doxycycline hydrogel: an MMP inhibitor/sclerosing embolizing
           agent as a new approach to endoleak prevention and treatment after
           endovascular aneurysm repair
    • Authors: Fatemeh Zehtabi; Pompilia Ispas-Szabo; Djahida Djerir; Lojan Sivakumaran; Borhane Annabi; Gilles Soulez; Mircea Alexandru Mateescu; Sophie Lerouge
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Fatemeh Zehtabi, Pompilia Ispas-Szabo, Djahida Djerir, Lojan Sivakumaran, Borhane Annabi, Gilles Soulez, Mircea Alexandru Mateescu, Sophie Lerouge
      The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)—a sclerosant and MMP inhibitor— was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. Statement of Significance An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade. Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration. This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.021
       
  • Discerning the composition of penetratin for safe penetration from cornea
           to retina
    • Authors: Kuan Jiang; Xin Gao; Qing Shen; Changyou Zhan; Yanyu Zhang; Cao Xie; Gang Wei; Weiyue Lu
      Abstract: Publication date: Available online 18 September 2017
      Source:Acta Biomaterialia
      Author(s): Kuan Jiang, Xin Gao, Qing Shen, Changyou Zhan, Yanyu Zhang, Cao Xie, Gang Wei, Weiyue Lu
      Delivery of biomacromolecules into the eye is greatly hindered by several protective barriers. The cell-penetrating peptide, penetratin, has been found to be an effective absorption enhancer for noninvasive intraocular gene delivery. To discern the composition of penetratin for safe penetration from cornea to retina, we designed a series of penetratin derivatives by varying the hydrophobicity and evaluated their potency for retina-targeted delivery. The hydrophilic amino acids of penetratin, excluding the conserved basic amino acid residues, were respectively replaced with tryptophan. Secondary structure of the resultant derivatives was analyzed by computer simulation and circular dichroism, exhibiting that the hydrophobic derivatives had a propensity to form high content of helix and entered corneal and conjunctival cells more easily than did penetratin. As expected, the hydrophobic derivatives showed improved permeability in excised rabbit cornea and sclera, and kept intact after penetration. When instilled topically in the conjunctival sac of mice eyes, the hydrophobic derivatives distributed safely and rapidly into both cornea and retina, with increased amount and prolonged retention time in comparison to penetratin. In conclusion, we demonstrated that the ocular permeability of penetratin derivatives closely correlated with their hydrophobicity, and introducing hydrophobic amino acids in penetratin was a feasible approach to develop more powerful ocular absorption enhancers. Statement of Significance Due to the defensive barriers of the eye, efficient and safe absorption enhancers are indispensable for noninvasive delivery of exogenous biomacromolecules to the posterior segment. In this manuscript, we designed a series of penetratin derivatives and validated they had significantly improved penetration ability from cornea to retina than wild-type penetratin, without increasing toxicity. More importantly, we provided a sequence of solid evidences that the ocular permeability of penetratin derivatives closely correlated with their hydrophobicity, and introducing hydrophobic amino acids in penetratin was a feasible approach to develop more powerful ocular absorption enhancers. We also demonstrated that the penetratin derivatives permeated through cornea and sclera with intact structure, and might enter the eye by non-corneal pathway.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.023
       
  • Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated
           SiO2@LDH for anti-neuroblastoma therapy
    • Authors: Rongrong Zhu; Zhaoqi Wang; Peng Liang; Xiaolie He; Xizhen Zhuang; Ruiqi Huang; Mei Wang; Qigang Wang; Yechang Qian; Shilong Wang
      Abstract: Publication date: Available online 17 September 2017
      Source:Acta Biomaterialia
      Author(s): Rongrong Zhu, Zhaoqi Wang, Peng Liang, Xiaolie He, Xizhen Zhuang, Ruiqi Huang, Mei Wang, Qigang Wang, Yechang Qian, Shilong Wang
      Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and is highly expressed in carcinoma, which make it an important target for tumor targeting therapy. Neuroblastoma is the main cause for cancer-related death in children. Like most solid tumors, it is also accompanied with the overexpression of VEGF. Doxorubicin Hydrochloride (DOX), a typical chemotherapeutic agent, exhibits efficient anticancer activities for various cancers. However, DOX, without targeting ability, usually causes severe damage to normal tissues. To overcome the shortages, we designed a novel nano-composite, which is Bevacizumab (Bev) modified SiO2@LDH nanoparticles (SiO2@LDH-Bev), loading with DOX to achieve targeting ability and curative efficiency. SiO2@LDH-DOX and SiO2@LDH-Bev-DOX nanoparticles were synthesized and the physicochemical properties were characterized by TEM detection, Zeta potential analysis, FTIR, Raman and XPS analysis. Then in vitro and in vivo anti-neuroblastoma efficiency, targeting ability and mechanisms of anti-carcinoma and anti-angiogenesis of SiO2@LDH-Bev-DOX were explored. Our results indicated that we obtained the core-shell structure SiO2@LDH-Bev with an average diameter of 253±10nm and the amount of conjugated Bev was 4.59±0.38μg/mg SiO2@LDH-Bev. SiO2@LDH-Bev-DOX could improve the cellular uptake and the targeting effect of DOX to brain and tumor, enhance the anti-neuroblastoma and anti-angiogenesis efficiency both in vitro and in vivo, and alleviate side effects of DOX sharply, especially hepatic injury. In addition, we also demonstrated that angiogenesis inhibitory effect was mediated by DOX and VEGF triggered signal pathways, including PI3K/Akt, Raf/MEK/ERK, and adhesion related pathways. In summary, SiO2@LDH-Bev could be a potential VEGF targeting nanocarrier applied in VEGF positive cancer therapy. Statement of Significance This paper explored that a novel core-shell structure nanomaterial SiO2@LDH and modified SiO2@LDH with Bevacizumab (Bev) to form a new tumor vasculature targeting nanocarrier SiO2@LDH-Bev as vector of DOX, which was not reported before. The results indicated that SiO2@LDH-Bev could improve the VEGF targeting ability, anti-neuroblastoma and anti-angiogenesis efficiency of DOX. At the same time, SiO2@LDH-Bev-DOX could erase the cardiac toxicity and hepatic injury coming from DOX. Tube formation showed SiO2@LDH-Bev-DOX had the strongest effect on inhibiting angiogenesis among all the four formulations. SiO2@LDH-Bev-DOX could downregulate expression of p-VEGFR and inhibit activation of the Raf/MEK/ERK, p38MAPK, PI3K/Akt and FAK signaling pathways to achieve the goal of anti-angiogenesis. This work provides a novel system for the safe and efficient use of Bev and DOX on Neuroblastoma and explores the mechanism of the function of nano carrier in cancer therapy both in vitro and in vivo.
      Graphical abstract image

      PubDate: 2017-09-23T18:05:19Z
      DOI: 10.1016/j.actbio.2017.09.009
       
 
 
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: 54.156.69.204
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016