for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3185 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 3185 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 25, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 100, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 427, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 292, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 6, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 179, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 16, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 11, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 28, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 49, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 62, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 20, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 24, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 19, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 12, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 25, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 17)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 413, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 36, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 51, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 363, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 468, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 44, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 57, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 62, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 45, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 11)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 13, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 48)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 233, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 30, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 20, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 199, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 206, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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

Similar Journals
Journal Cover
Acta Biomaterialia
Journal Prestige (SJR): 1.967
Citation Impact (citeScore): 7
Number of Followers: 28  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3185 journals]
  • Crevice Corrosion – A Newly Observed Mechanism of Degradation in
           Biomedical Magnesium
    • Abstract: Publication date: Available online 13 June 2019Source: Acta BiomaterialiaAuthor(s): Hongliu Wu, Chengjian Zhang, Tengfei Lou, Bowei Chen, Ruibang Yi, Wenhui Wang, Ruopeng Zhang, Minchao Zuo, Haidong Xu, Pei Han, Shaoxiang Zhang, Jiahua Ni, Xiaonong ZhangCrevice-induced corrosion is not desirable to occur in metallic magnesium (Mg) during many industrial applications. However, orthopedic implants made of Mg alloys have been demonstrated to degrade faster between the joining surface of bone plates and screws after implantation, suggesting the crevice corrosion may occur in the physiological environment. In this paper, a resin device is designed to parallel high purity magnesium (HP-Mg) plates with closely spaced slits. After a standard corrosion test in the phosphate-buffered saline (PBS) solution, the paralleled HP-Mg samples embedded in the custom-made resin device corrode faster than those without the resin device. The corrosion morphology of Mg with the resin device exhibits features of crevice corrosion with many deep holes and river-like texture. Moreover, implantation of the bone plate and screws in vivo demonstrates similar corrosion morphology as that of the in vitro test, suggesting the occurrence of crevice-enhanced corrosion in the bone–bone plate interface, as well as the contact area between the bone plate and the screws.Statement of significanceUnderstanding corrosion behavior of Mg and Mg alloys after implantation is one of the main challenges for developing desirable biodegradable Mg alloys or effective methods to adjust the corrosion rate of Mg-based implants. In this paper, we attempted to figure out the corrosion behaviors of HP-Mg at the joining surface between HP-Mg plates or HP-Mg screws and bone tissues after implantation. We designed an in vitro setup to mimic crevice environment of in vivo joining surface and found the existed crevices on the HP-Mg would significantly accelerate the corrosion rate and change the corrosion morphology of HP-Mg plates. The in vivo implantation also showed similar corrosion morphology caused by crevice corrosion appeared at the joining surface between HP-Mg plates or HP-Mg screws and bone tissues. Then, we proposed a new crevice corrosion explanation of Mg-based alloys. Our finding can help us broaden our cognition to the corrosion behavior of Mg and Mg alloys orthopedic implants.Graphical abstractGraphical abstract for this article
       
  • Acta Biomaterialia Outstanding Reviewers in 2018
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s):
       
  • In vivo study of the efficacy, biosafety, and degradation of a zinc alloy
           osteosynthesis system
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Xiang Wang, Xiaoxi Shao, Taiqiang Dai, Fangfang Xu, Jack G. Zhou, Gongqi Qu, Lei Tian, Bin Liu, Yanpu Liu In this study, a comprehensive analysis of a novel zinc alloy osteosynthesis system in a canine mandibular fracture model is presented. The efficacy of the system was compared for PLLA (poly-l-lactic acid) and titanium materials using X-ray radiography, micro-CT tomography, undecalcified bone histomorphometry, and a three-point bending test. Histology, blood normal, blood biochemical, and serum zinc concentration tests were also performed to assess the biosafety of the zinc alloy osteosynthesis system. The degradability of the zinc alloy was evaluated using a micro-CT and scanning electron microscope during the 24-week post operation period. The results showed that zinc alloy possesses good mechanical properties that support fracture healing. Its uniform and slow corrosion leads to adequate degradation behavior in 24 weeks. Additionally, the zinc alloy proved to be biocompatible, indicating that this novel osteosynthesis system is safe for use in the body. The results of the study demonstrate that this zinc alloy-based osteosynthesis system is a promising candidate for a new generation of osteosynthesis systems, with further improvements required in the future.Graphical abstractGraphical abstract for this article
       
  • Cisplatin-loaded polymeric complex micelles with a modulated
           drug/copolymer ratio for improved in vivo performance
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Qiuyue Chen, Lifeng Luo, Yingyan Xue, Jian Han, Yi Liu, Yu Zhang, Tian Yin, LiHui Wang, Dongmei Cun, Jingxin Gou, Haibing He, Xing Tang This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 were 0.20, 0.61 and 0.38 PEG/nm2, respectively. CDDP-PM1-3 and CDDP-PM1-6 had similar sustained release behavior, while CDDP-PM1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM1-1 to CDDP-PM1-6, the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff.Statement of SignificanceCancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot.Graphical abstractGraphical abstract for this article
       
  • A collagen scaffold loaded with human umbilical cord-derived mesenchymal
           stem cells facilitates endometrial regeneration and restores fertility
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Liaobing Xin, Xiaona Lin, Yibin Pan, Xiaowen Zheng, Libing Shi, Yanling Zhang, Lie Ma, Changyou Gao, Songying Zhang In women of reproductive age, severe injuries to the endometrium are often accompanied by endometrial scar formation or intrauterine adhesions (IUAs), which can result in infertility or miscarriage. Although many approaches have been used to treat severe IUAs, high recurrence rates and endometrial thinning have limited therapeutic efficiency. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrial regeneration. The CS/UC-MSCs promoted human endometrial stromal cell proliferation and inhibited apoptosis in vitro through paracrine effects. In a model of endometrial damage, transplantation with the CS/UC-MSCs maintained normal luminal structure, promoted endometrial regeneration and collagen remodeling, induced intrinsic endometrial cell proliferation and epithelium recovery, and enhanced the expression of estrogen receptor α and progesterone receptor. An improved ability of the regenerated endometrium to receive embryos was confirmed. Together, our results indicate that the CS/UC-MSCs promoted endometrial structural reconstruction and functional recovery. Topical administration of the CS/UC-MSCs after trans-cervical resection of adhesions might prevent re-adhesion, promote endometrium regeneration and improve pregnancy outcomes for patients with severe IUAs.Statement of SignificanceIntrauterine adhesions due to severe endometrium injuries happen frequently in clinic and become one of the crucial reasons for women’s infertility or miscarriage. Therefore, how to regenerate the damaged endometrium is a big challenge. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrium regeneration. Herein, UC-MSCs, known for low immunogenicity and high proliferative potential, exhibit promising potential for endometrium regeneration; and collagen scaffolds provide suitable physical support. It was proved that transplantation with CS/UC-MSCs promoted endometrial regeneration and fertility restoration. It suggested that topical administration of CS/UC-MSCs in uterus could be a promising strategy for patients suffering severe intrauterine adhesion and infertility.Graphical abstractGraphical abstract for this article
       
  • Nitric oxide-releasing vascular grafts: A therapeutic strategy to promote
           angiogenic activity and endothelium regeneration
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Fatemeh Kabirian, Peiman Brouki Milan, Ali Zamanian, Ruth Heying, Masoud Mozafari Small-diameter vascular grafts (SDVGs) are associated with a high incidence of failure due to infection and obstruction. Although several vascular grafts are commercially available, specific anatomical differences of defect sites require patient-based design and fabrication. Design and fabrication of such custom-tailored grafts are possible with 3d-printing technology. The aim of this study is to develop 3d-printed SDVGs with a nitric oxide (NO)-releasing coating to improve the success rate of implantation. The SDVGs were printed from polylactic acid and coated with blending of 10 wt% S-nitroso-N-acetyl-D-penicillamine into the polymeric substrate consisting of poly (ethylene glycol) and polycaprolactone. Our results show that NO is released in the physiological range (0.5–4 × 10−10 mol·cm−2·min−1) for 14 days and NO-releasing coating showed significant antibacterial potential against Gram-positive and Gram-negative strains. It was shown that both NO-releasing and control grafts are biocompatible in-vitro and in-vivo. Interestingly, the NO-releasing SDVGs dramatically enhanced ECs proliferation and significantly enhanced ECs migration in-vitro compared to control grafts. In addition, the NO-releasing SDVGs showed angiogenic potential in-vivo which can further prove the results of our in-vitro study. These findings are expected to facilitate tissue regeneration and integration of custom-made vascular implants with enhanced clinical success.Statement of significanceA series of 3d-printed small-diameter vascular grafts (SDVGs,
       
  • 4D printing and stimuli-responsive materials in biomedical aspects
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Yuan Siang Lui, Wan Ting Sow, Lay Poh Tan, Yunlong Wu, Yuekun Lai, Huaqiong Li Three-dimensional (3D) printing has revolutionized the world manufacturing production. In biomedical applications, however, 3D printed constructs fell short of expectations mainly due to their inability to adequately mimic the dynamic human tissues. To date, most of the 3D printed biomedical structures are largely static and inanimate as they lack the time-dependant dimension. To adequately address the dynamic healing and regeneration process of human tissues, 4D printing emerges as an important development where “time” is incorporated into the conventional concept of 3D printing as the fourth dimension. As such, additive manufacturing (AM) evolves from 3D to 4D printing and in the process putting stimulus-responsive materials in the limelight. In this review, the state-of-the-art efforts in integrating the time-dependent behaviour of stimulus-responsive materials in 4D printing will be discussed. In addition, current literatures on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials will be the major focus in this review. Lastly, potential usage of 4D printing in biomedical applications will also be discussed, followed by technical considerations as well as outlook for future discoveries.Statement of SignificanceIn this Review, we have demonstrated the significance of 4D printing in biomedical applications, in which “time” has been incorporated into the conventional concept of 3D printing as the 4th dimension. As such, 4D printing differentiates and evolves from 3D printing using stimulus-responsive materials which can actively respond to external stimuli and more sophisticated “hardware”-printer which can achieve multi-printing via mathematical-predicted designs that are programmed to consider the transformation of 3D constructs over time. The emphasize will be on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials, followed by technical considerations as well as outlook for future discoveries.Graphical abstractGraphical abstract for this article
       
  • Differential outcomes of venous and arterial tissue engineered vascular
           grafts highlight the importance of coupling long-term implantation studies
           with computational modeling
    • Abstract: Publication date: Available online 12 June 2019Source: Acta BiomaterialiaAuthor(s): Cameron A. Best, Jason M. Szafron, Kevin A. Rocco, Jacob Zbinden, Ethan W. Dean, Mark W. Maxfield, Hirotsugu Kurobe, Shuhei Tara, Paul S. Bagi, Brooks V. Udelsman, Ramak Khosravi, Tai Yi, Toshiharu Shinoka, Jay D. Humphrey, Christopher K. Breuer Electrospinning is commonly used to generate polymeric scaffolds for tissue engineering. Using this approach, we developed a small-diameter tissue engineered vascular graft (TEVG) composed of poly-ε-caprolactone-co-L-lactic acid (PCLA) fibers and longitudinally assessed its performance within both the venous and arterial circulations of immunodeficient (SCID/bg) mice. Based on in vitro analysis demonstrating complete loss of graft strength by 12 weeks, we evaluated neovessel formation in vivo over 6-, 12- and 24-week periods. Mid-term observations indicated excellent physiologic graft function, characterized by 100% patency and excellent luminal matching with adjoining native vessel in both the venous and arterial circulations. An active and robust remodeling process was characterized by a confluent endothelial cell monolayer, macrophage infiltrate, and extracellular matrix deposition and remodeling. Long-term follow-up of venous TEVGs at 24 weeks revealed viable neovessel formation beyond graft degradation when implanted in this high flow, low-pressure environment. Arterial TEVGs experienced catastrophic graft failure due to aneurysmal dilatation and rupture after 14 weeks. Scaffold parameters such as porosity, fiber diameter, and degradation rate informed a previously described computational model of vascular growth and remodeling, and simulations predicted the gross differential performance of the venous and arterial TEVGs over the 24-week time course. Taken together, these results highlight the requirement for in vivo implantation studies to extend past the critical time period of polymer degradation, the importance of differential neotissue deposition relative to the mechanical (pressure) environment, and further support the utility of predictive modeling in the design, use, and evaluation of TEVGs in vivo.Statement of SignificanceHerein, we apply a biodegradable electrospun vascular graft to the arterial and venous circulations of the mouse and follow recipients beyond the point of polymer degradation. While venous implants formed viable neovessels, arterial grafts experienced catastrophic rupture due to aneurysmal dilation. We then inform a previously developed computational model of tissue engineered vascular graft growth and remodeling with parameters specific to the electrospun scaffolds utilized in this study. Remarkably, model simulations predict the differential performance of the venous and arterial constructs over 24 weeks. We conclude that computational simulations should inform the rational selection of scaffold parameters to fabricate tissue engineered vascular grafts that must be followed in vivo over time courses extending beyond polymer degradation.Graphical abstractGraphical abstract for this article
       
  • In-air Production of 3D Co-culture Tumor Spheroid Hydrogels for Expedited
           Drug Screening
    • Abstract: Publication date: Available online 12 June 2019Source: Acta BiomaterialiaAuthor(s): Jéssica Antunes, Vítor M. Gaspar, Luís Ferreira, Maria Monteiro, Rui Henrique, Carmen Jerónimo, João F. Mano Three-dimensional (3D) in vitro tumor spheroids are becoming popular as pre-clinical platforms for testing the performance of existing drugs or for discovery of innovative anti-cancer therapeutics. This focus is correlated with in vitro 3D tumor models ability to mimic the multicellular compact structure and spatial architecture of human solid tumors. However, these microphysiological systems generally lack the pre-existence of tumor-ECM, a critical aspect that can affect the overall therapeutic performance and the decision of advancing candidate drugs to later stages of the pipeline. Aiming to face this drawback and mimic tumors-ECM, herein we rapidly fabricated in-air hyaluronan-methacrylate (HA-MA) and gelatin-methacrylate (GelMA) photocrosslinkable 3D spheroid microgels by using superhydrophobic surfaces. These platforms were used for establishing heterotypic 3D co-culture models of prostate cancer cells (PC-3) and human osteoblasts (hOB) to mimic prostate cancer-to-bone metastasis cellular heterogeneity and the tumor-ECM microenvironment. 3D microgel microtumors morphology, size and cell number were easily controlled via digital droplet generation on polystyrene superhydrophobic surfaces and under solvent-free conditions when compared to microfluidics or electrospray. Co-culture 3D microgels formed by 2.5%HA-MA-5%GelMA and 5%HA-MA-5%GelMA ratios showed the highest calcium deposition after 14 days of culture, evidencing osteoblasts viability and the establishment of functional mineralization in the 3D hydrogel matrix. Cisplatin cytotoxicity evaluation showed that 3D microgels are more resistant to platin chemotherapeutics than single or co-culture 3D multicellular spheroid counterparts. Overall, our findings indicate that solvent-free, in-air produced 3D microgel microenvironments are cost-effective and robust tumor mimicking platforms for in vitro high-throughput screening of therapeutics targeted to prostate-to-bone metastasis microenvironments.Statement of Significance:The generation of robust microphysiological systems that recapitulate the complexity of the metastatic prostate-to-bone tumor microenvironment is crucial for pre-clinical evaluation of new therapeutics that can eradicate these secondary tumors. In this study, we employed superhydrophobic (SH) surfaces to rapidly fabricate photocrosslinkable hyaluronan-methacrylate/gelatin-methacrylate 3D spheroid microgels for prostate cancer cells and human osteoblasts co-culture models that simultaneously mimic the cellular and ECM tumor components. The use of SH platforms overcomes the issues of standard in-liquid microgel production technologies by providing a robust control over 3D microgels size/morphology and cell-cell co-encapsulation numbers, while avoiding the use of oil-based microgel droplets generation. Overall, SH surfaces allowed a solvent-free, cost-effective, reproducible and adaptable fabrication of heterotypic 3D spherical microgels for high throughput drug screening.Graphical abstractGraphical abstract for this article
       
  • RGD-containing elastin like polypeptide improves islet transplantation
           outcomes in diabetic mice
    • Abstract: Publication date: Available online 12 June 2019Source: Acta BiomaterialiaAuthor(s): Kyeong-Min Lee, Jung-Hee Kim, Eun-Sook Choi, Eunjoo Kim, Seong-Kyoon Choi, Won Bae Jeon Successful islet transplantation critically depends on the isolation of healthy islets. However, the islet isolation procedure itself contributes to islet death due to the destruction of intra- and peri-islet extracellular matrices (ECMs) during digestion. We investigated whether an RGD-containing elastin-like polypeptide (REP) could function as a self-assembling matrix to replenish ECMs and protects islets from cell death. Immediately following isolation, islets were coated with REP coacervate particles via isothermal adsorption of an REP solution followed by thermal gelation. REP-coated islets displayed increased viability and insulin secretory capacity pretransplant culture compared to untreated islets. Co-transplantation of REP-treated islets and REP beneath the renal sub-capsule in streptozoticin-induced diabetic mice restored normoglycemia and serum insulin levels. Mice that received co-transplants maintained normoglycemia for a longer period of time than those receiving untreated islets without REP. Moreover, co-transplantation sites exhibited enhanced β-cell proliferation and vascularization. Thus, the REP-based coacervation strategy improve the survival, function and therapeutic potential of transplanted islets.Statement of Significance1). An artificial matrix polypeptide comprised of thermoresponsive elastin-like peptides and integrin-stimulatory RGD ligands (REP) to reconstitute damaged or lost matrices.2). Through body temperature-induced coacervation, REP reconstitutes intra-islet environment and enhances islet viability and insulin secretion by activating the pro-survival and insulin signaling pathways.3). REP-coated islets were transplanted together with the matrix polypeptide under the kidney sub-capsule of mice, it develops a new peri-insular environment, which protects the islet grafts from immune rejection thus extending islet longevity.4). Our data suggest that in situ self-assembly of biomimetic islet environments become a new platform allowing for improved islet transplantation at extrahepatic sites.Graphical abstractGraphical abstract for this article
       
  • Development of a collagen-like peptide polymer via end-to-end disulfide
           cross-linking and its application as a biomaterial
    • Abstract: Publication date: Available online 11 June 2019Source: Acta BiomaterialiaAuthor(s): Shinichiro F. Ichise, Shungo Takeuchi, Shigehisa Aoki, Kazuki C. Kuroda, Hiroshi Nose, Ryo Masuda, Takaki Koide Collagen is the most abundant protein in the animal kingdom and has a unique triple-helical structure. It not only provides mechanical strength to tissues, but also performs specific biological functions as a multifaceted signaling molecule. Animal-derived collagen is therefore widely used as a biocompatible material in vitro and in vivo. In this study, we developed a novel peptide-based material that mimicked both the polymeric properties and a selected biological function of native collagen. This material was prepared by end-to-end multiple disulfide cross-linking of chemically synthesized triple-helical peptides. The peptide polymer showed a gel-forming property, and receptor-specific cell binding was observed in vitro by incorporating a peptide harboring an integrin α2β1-binding sequence. Furthermore, cell signaling activity and biodegradability were tunable according to the polymer contents. The results demonstrated the potential of this material as a designer collagen.Statement of SignificanceCollagen is a useful biomaterial with the gel-forming property. It also exhibits various biological activities through the interaction of specific amino acid sequences displayed on the triple helix with functional biomacromolecules. Here we report a novel synthetic material, artificial collagen, by end-to-end cross-linking of chemically synthesized collagen-like triple-helical peptides. The material allows independent regulation of polymer properties, i.e. gel stiffness, and sequence-specific bioactivities by altering peptide compositions. This material can also be variously shaped, for example, thin films with high transparency. In addition, it has low inflamatogenic properties and tunable biodegradability in vivo.Graphical abstractGraphical abstract for this article
       
  • An Electrospun Fiber-Covered Stent with Programmable Dual Drug Release for
           Endothelialization Acceleration and Lumen Stenosis Prevention
    • Abstract: Publication date: Available online 10 June 2019Source: Acta BiomaterialiaAuthor(s): Yiran Zhang, Jienan Wang, Junyuan Xiao, Tonglei Fang, Nan Hu, Minghua Li, Lianfu Deng, Yingsheng Cheng, Yueqi Zhu, Wenguo Cui Aneurysmal subarachnoid hemorrhage (SAH) causes high rates of mortality and morbidity. A covered stent is an effective endovascular treatment for complicated aneurysms intractable to endovascular coiling and surgical clipping. However, in-stent restenosis and delayed endothelialization are the main challenges contributing to its safety. In this study, we designed a biofunctional stent covered with dual drug-loaded electrospun fibers to achieve programmed vascular endothelial growth factor (VEGF) and paclitaxel (PTX) release for the early promotion of stent endothelialization and long-term inhibition of stenosis caused by smooth muscle hyperplasia. By encapsulating PTX-loaded mesoporous silica nanoparticles (MSNs) within electrospun polylactic acid (PLA) fibers, the release period of PTX was effectively extended. Furthermore, VEGF was conjugated onto the surface of the membrane by reacting with polydopamine (PDA) for quick release. The in vitro drug release profile revealed the sustained release of PTX, which persisted for 63 days without early burst release, while up to 87.05% of VEGF was rapidly released within 3 days. After 6 days of incubation, cell experiments demonstrated that the dual drug-loaded scaffold effectively prompted endothelial cell proliferation (488% vs. 386% in the control group, P=0.001) and inhibited the proliferation of smooth muscle cells (SMCs) using the 21-day extracts (155% vs. 303% in the control group, P=0.039). Animal studies showed that compared to bare stents, the drug-loaded covered stents improved the immediate- and mid-term complete aneurysm occlusion rates (P
       
  • The role of magnesium ions in bone regeneration involves the canonical Wnt
           signaling pathway
    • Abstract: Publication date: Available online 8 June 2019Source: Acta BiomaterialiaAuthor(s): Chu-Chih Hung, Amy Chaya, Kai Liu, Konstantinos Verdelis, Charles Sfeir Magnesium (Mg)-based implants have become of interest to both academia and the medical industry. The attraction largely is due to Mg’s biodegradability and ability to enhance bone healing and formation. However, the underlying mechanism of how Mg regulates osteogenesis is still unclear. Based on our previous in vivo and molecular signaling work demonstrating the osteogenic effect of Mg, the current study aims to extend this work at the molecular level especially that we also observed and quantified mineral deposits in the bone marrow space in a rabbit ulna fracture model with Mg plates and screws. Histological analysis and quantitative results of micro-CT showed mineralized deposition and a significant increase in bone volume at 8 weeks and 16 weeks post-operative. These in vivo results led us to focus on studying the effect of Mg2+ on human bone marrow stromal cells (hBMSCs). The data presented in this manuscript demonstrate the activation of the canonical Wnt signaling pathway in hBMSCs when treated with 10 mM Mg2+. With additional Mg2+ present, the protein expression of active β-catenin was significantly increased to a level similar to that of the positive control. Immunocytochemistry and the increased expression of LEF1 and Dkk1, downstream target genes that are controlled directly by active β-catenin, demonstrated the protein translocation and the activation of transcription. Taken together, these data suggest that Mg2+ induces an osteogenic effect in the bone marrow space by activating the canonical Wnt signaling pathway, which in turn causes BMSCs to differentiate toward the osteoblast lineage.Graphical abstractGraphical abstract for this article
       
  • Magnesium matrix nanocomposites for orthopedic applications: a review from
           mechanical, corrosion, and biological perspectives
    • Abstract: Publication date: Available online 7 June 2019Source: Acta BiomaterialiaAuthor(s): Mohammad Shahin, Khurram Munir, Cuie Wen, Yuncang Li Magnesium (Mg) and some of its alloys have attracted extensive interests for biomedical applications as they exhibit biodegradability and low elastic modulus that is closer to natural bones than the currently used metallic implant materials such as titanium (Ti) and its alloys, stainless steels, and cobalt-chromium (Co-Cr) alloys. However, the rapid degradation of Mg alloys and loss of their mechanical integrity before sufficient bone healing impede their clinical application. Our literature review shows that magnesium matrix nanocomposites (MMNCs) reinforced with nanoparticles possess enhanced strength, high corrosion resistance, and good biocompatibility. This article provides a detailed analysis of the effects of nanoparticle reinforcements on the mechanical properties, corrosion behavior, and biocompatibility of MMNCs as promising biodegradable implant materials. The governing equations to quantitatively predict the mechanical properties and underlying synergistic strengthening mechanisms in MMNCs are elucidated. The potential, recent advances, challenges and future research directions in relation to nanoparticles reinforced MMNCs are highlighted.Statement of significanceCritically reviewing magnesium metal matrix nanocomposites (MMNCs) for the biomedical application.Clear definitions of strengthening mechanisms using reinforcement particle in the magnesium matrix, as there were controversial in governing equations of strengthening parameters.Providing better understanding of the effect of particle size, volume fraction, interfacial bonding, and uniform dispersion of reinforcement particles on MMNCs.Graphical abstractGraphical abstract for this article
       
  • Emerging themes and unifying concepts underlying cell behavior regulation
           by the pericellular space
    • Abstract: Publication date: Available online 6 June 2019Source: Acta BiomaterialiaAuthor(s): Kiersten E. Scott, Kevin Rychel, Sural Ranamukhaarachchi, Padmini Rangamani, Stephanie I. Fraley Cells reside in a complex three-dimensional (3D) microenvironment where physical, chemical, and architectural features of the pericellular space regulate important cellular functions like migration, differentiation, and morphogenesis. A major goal of tissue engineering is to identify which properties of the pericellular space orchestrate these emergent cell behaviors and how. In this review, we highlight recent studies at the interface of biomaterials and single cell biophysics that are lending deeper insight towards this goal. Advanced methods have enabled the decoupling of architectural and mechanical features of the microenvironment, revealing multiple mechanisms of adhesion and mechanosensing modulation by biomaterials. Such studies are revealing important roles for pericellular space degradability, hydration, and adhesion competition in cell shape, volume, and differentiation regulation.Statement of significanceCell fate and function are closely regulated by the local extracellular microenvironment. Advanced methods at the interface of single cell biophysics and biomaterials have shed new light on regulators of cell-pericellular space interactions by decoupling more features of the complex pericellular milieu than ever before. These findings lend deeper mechanistic insight into how biomaterials can be designed to fine-tune outcomes like differentiation, migration, and collective morphogenesis.Graphical abstractGraphical abstract for this article
       
  • Intracameral Injection of a Chemically Cross-Linked Hydrogel to Study
           Chronic Neurodegeneration in Glaucoma
    • Abstract: Publication date: Available online 6 June 2019Source: Acta BiomaterialiaAuthor(s): Kevin C. Chan, Yu Yu, Shuk Han Ng, Heather K. Mak, Yolanda W.Y. Yip, Yolandi van der Merwe, Tianmin Ren, Jasmine S.Y. Yung, Sayantan Biswas, Xu Cao, Ying Chau, Christopher K.S. Leung Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinylsulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14±3 and 24±3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse, confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies.Statement of SignificanceA new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinylsulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.Graphical abstractGraphical abstract for this article
       
  • Response to Letter to Editor “Comment on ‘Tuning the bioactivity of
           bone morphogenetic protein-2 with surface immobilization strategies’ by
           Chen et al.”
    • Abstract: Publication date: Available online 6 June 2019Source: Acta BiomaterialiaAuthor(s): May Griffith
       
  • Comment on “Short peptide analogs as alternatives to collagen in
           pro-regenerative corneal implants” by Jangamreddy JR et al
    • Abstract: Publication date: Available online 6 June 2019Source: Acta BiomaterialiaAuthor(s): Jaywant Phopase
       
  • Endogenous Viable Cells in Lyopreserved Amnion Retain Differentiation
           Potential and Anti-fibrotic Activity In Vitro
    • Abstract: Publication date: Available online 6 June 2019Source: Acta BiomaterialiaAuthor(s): Yong Mao, Tyler Hoffman, Sandeep Dhall, Amit Singal, Malathi Sathyamoorthy, Alla Danilkovitch, Joachim Kohn Human amniotic membrane (AM) has intrinsic anti-inflammatory, anti-fibrotic and antimicrobial properties. Tissue preservation methods have helped to overcome the short shelf life of fresh AM allowing “on demand” use of AM grafts. Cryopreserved AM that retains all native tissue components, including viable cells, has clinical benefits in treating chronic wounds. However, cryopreservation requires ultra-low temperature storage, limiting the use of cryopreserved products. To overcome this limitation, a new lyopreservation method has been developed for ambient storage of living tissues. The goal of this study was to investigate the viability and functionality of AM cells following lyopreservation. Fresh AM and devitalized lyopreserved AM (DLAM) served as positive and negative controls, respectively. Using live/dead staining, we confirmed the presence of living cells in viable lyopreserved AM (VLAM) and showed that these cells persisted up to 21 days in culture medium. The functionality of cells in VLAM was assessed by their differentiation potential and anti-fibrotic activity in vitro. With osteogenic induction, cells in VLAM deposited calcium within the membrane, a marker of osteogenic cells, in a time-dependent manner. The migration of human lung fibrotic fibroblasts in a scratch wound assay was reduced significantly in the presence of VLAM-derived conditioned medium. Quantitative PCR analyses indicated that VLAM reduced the expression of pro-fibrotic factors such as type I collagen and increased the expression of anti-fibrotic factors such as hepatocyte growth factor and anti-fibrotic microRNA in fibrotic fibroblasts. Taken together, these results demonstrate that endogenous cells in VLAM remain viable and functional post-lyophilization.Statement of SignificanceThis study, for the first time, provides direct evidence showing that tissue viability and functional cells can be preserved by lyophilization. Similar to fresh amniotic membrane (AM), viable lyopreserved AM (VLAM) retains viable cells for extended periods of time. More importantly, these cells are functional and maintain their osteogenic differentiation potential and anti-fibrotic activity. Our results confirmed that the novel lyophilization method preserves tissue viability.Graphical abstractGraphical abstract for this article
       
  • Improving our understanding of metal implant failures: Multiscale chemical
           imaging of exogenous metals in ex-vivo biological tissues
    • Abstract: Publication date: Available online 5 June 2019Source: Acta BiomaterialiaAuthor(s): Alexander P. Morrell, Hayley Floyd, J. Frederick W. Mosselmans, Liam M. Grover, Hiram Castillo-Michel, Edward Davis, Julia E. Parker, Richard A. Martin, Owen Addison Biological exposures to micro- and nano-scale exogenous metal particles generated as a consequence of in-service degradation of orthopaedic prosthetics can result in severe adverse tissues reactions. However, individual reactions are highly variable and are not easily predicted, due to in part a lack of understanding of the speciation of the metal-stimuli which dictates cellular interactions and toxicity. Investigating the chemistry of implant derived metallic particles in biological tissue samples is complicated by small feature sizes, low concentrations and often a heterogeneous speciation and distribution. These challenges were addressed by developing a multi-scale two-dimensional X-ray absorption spectroscopic (XAS) mapping approach to discriminate sub-micron changes in particulate chemistry within ex-vivo tissues associated with failed CoCrMo total hip replacements (THRs). As a result, in the context of THRs, we demonstrate much greater variation in Cr chemistry within tissues compared with previous reports. Cr compounds including phosphate, hydroxide, oxide, metal and organic complexes were observed and correlated with Co and Mo distributions. This variability may help explain the lack of agreement between biological responses observed in experimental exposure models and clinical outcomes. The multi-scale 2D XAS mapping approach presents an essential tool in discriminating the chemistry in dilute biological systems where speciation heterogeneity is expected.SignificanceMetal implants are routinely used in healthcare but may fail following degradation in the body. Although specific implants can be identified as ‘high-risk’, our analysis of failures is limited by a lack of understanding of the chemistry of implant metals within the peri-prosthetic milieu. A new approach to identify the speciation and variability in speciation at sub-micron resolution, of dilute exogenous metals within biological tissues is reported; applied to understanding the failure of metallic (CoCrMo) total-hip-replacements widely used in orthopedic surgery. Much greater variation in Cr chemistry was observed compared with previous reports and included phosphate, hydroxide, oxide, metal and organic complexes. This variability may explain lack of agreement between biological responses observed in experimental exposure models and clinical outcomes.Graphical abstractGraphical abstract for this article
       
  • Delivery of Bupivacaine from UHMWPE and its implications for managing pain
           after joint arthroplasty
    • Abstract: Publication date: Available online 5 June 2019Source: Acta BiomaterialiaAuthor(s): Scott C. Grindy, Dmitry Gil, Jeremy V. Suhardi, Orhun K. Muratoglu, Hany Bedair, Ebru Oral Total joint replacement is a widely used and successful surgical approach. Approximately 7 million US adults are currently living with a hip or knee replacement. However, the surgical procedures for total joint replacement are associated with significant postoperative pain, and current strategies do not adequately address this pain, which leads to patient dissatisfaction, reduced mobility, and increased risk of opioid addiction. We hypothesized that the ultra-high-molecular-weight polyethylene (UHMWPE)-bearing surfaces used in total joint prosthetics could provide sustained release of the local anesthetic bupivacaine, to provide relief from joint pain for an extended period of time after surgery. In this paper, we describe the production of bupivacaine-loaded UHMWPE (BPE) and measure the in vitro bupivacaine release kinetics of BPE. We found that bupivacaine could be released from BPE at clinically relevant rates for up to several days and that BPE possesses antibacterial effects. Therefore, bupivacaine-loaded UHMWPE is a promising material for joint replacement prostheses, and future studies will evaluate its safety and efficacy in in vivo models.Statement of SignificanceTotal joint replacement is associated with significant pain and risk of infection. In our paper, we introduce bupivacaine-loaded ultra-high molecular weight polyethylene (BPE) which releases bupivacaine, a pain-treating drug, at levels comparable to currently-used doses. Additionally, BPE inhibits growth of infection-causing bacteria. Therefore, BPE may be able to reduce both post-surgical pain and risk of infection, treating two of the most prominent complications associated with total joint replacement. To our knowledge, this is the first development of a material that can address both complications, and devices incorporating BPE would represent a significant advance in joint arthroplasty prosthetics. More generally, the incorporation of therapeutic agents into ultra-high molecular weight polyethylene could impact many orthopedic procedures due its ubiquity.Graphical abstractGraphical abstract for this article
       
  • Biodegradable atrial septal defect occluder: A current review
    • Abstract: Publication date: Available online 31 May 2019Source: Acta BiomaterialiaAuthor(s): Daokun Shi, Yahong Kang, Guoyi Zhang, Chenguang Gao, Wei Lu, Hua Zou, Hongyan Jiang Atrial septal defect (ASD) is a common structural congenital heart disease. With the development of interventional closure devices and transcatheter techniques, interventional closure therapy has become the most well-accepted therapeutic alternative worldwide, as it offers a number of advantages over conventional therapies such as improved safety, easier operation, lower complication rates and invasiveness, and shorter anesthetic time and hospitalizations. During the past decades, various types of occluders based on nondegradable shape memory alloys have been used in clinical applications. Considering that the permanent existence of foreign nondegradable materials in vivo can cause many potential complications in the long term, the research and development of biodegradable occluders has emerged as a crucial issue for interventional treatment of ASD. This review aims to summarize partially or fully biodegradable occlusion devices currently reported in the literature from the aspects of design, construction, and evaluation of animal experiments. Furthermore, a comparison is made on the advantages and disadvantages of the materials used in biodegradable ASD occlusion devices, followed by an analysis of the problems and limitations of the occlusion devices. Finally, several strategies are proposed for future development of biodegradable cardiac septal defect occlusion devices.Statement of SignificanceAlthough occlusion devices based on nondegradable alloys have been widely used in clinical applications and saved numerous patients, biodegradable occlusion devices may offer some advantages such as fewer complications, acceptable biocompatibility, and particularly temporary existence, thereby leaving “native” tissue behind, which will certainly become the development trend in the long term. This review summarizes almost all partially or fully biodegradable occlusion devices currently reported in the literature from the aspects of design, construction, and evaluation of animal experiments. Furthermore, a comparison is made on the advantages and disadvantages of the materials used in biodegradable ASD occlusion devices, followed by an analysis of the problems and limitations of the occlusion devices. Finally, several strategies are proposed for future development of biodegradable cardiac septal defect occlusion devices.Graphical abstractGraphical abstract for this article
       
  • Corrosion resistance and antibacterial activity of zinc-loaded
           montmorillonite coatings on biodegradable magnesium alloy AZ31
    • Abstract: Publication date: Available online 31 May 2019Source: Acta BiomaterialiaAuthor(s): Yu-Hong Zou, Wang Jian, Lan-Yue Cui, Rong-Chang Zeng, Qing-Zhao Wang, Qiu-Xia Han, Jun Qiu, Xiao-Bo Chen, Dong-Chu Chen, Shao-Kang Guan, Yu-Feng Zheng A Zinc-loaded montmorillonite (Zn-MMT) coating was hydrothermally prepared using Zn2+ ion intercalated sodium montmorillonite (Na-MMT) upon magnesium (Mg) alloy AZ31 as bone repairing materials. Biodegradation rate of the Mg-based materials was studied via potentiodynamic polarization curves, electrochemical impedance spectroscopy (EIS) and hydrogen evolution tests. Results revealed that both Na-MMT and Zn-MMT coatings exhibited better corrosion resistance in Dulbecco's modified eagle medium (DMEM) + 10% calf serum (CS) than bare Mg alloy AZ31 counterparts. Hemolysis results demonstrated that hemocompatibility of the Na-MMT and Zn-MMT coatings were 5%, and lower than that of uncoated Mg alloy AZ31 pieces. In vitro MTT tests and live-dead stain of osteoblast cells (MC3T3-E1) indicated a significant improvement in cytocompatibility of both Na-MMT and Zn-MMT coatings. Antibacterial properties of two representative bacterial strains associated with device-related infection, i.e. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), were employed to explore the antibacterial behavior of the coatings. The measured inhibitory zone and bacterial growth rate confirmed that Zn-MMT coatings exhibited higher suppression toward both E. coli and S. aureus than that of Na-MMT coatings. The investigation on antibacterial mechanism through scanning electron microscopy (SEM) and lactate dehydrogenase (LDH) release assay manifested that Zn-MMT coating led to severe breakage of bacterial membrane of E. coli and S. aureus, which resulted in a release of cytoplasmic materials from the bacterial cells. In addition, the good inhibition of Zn-MMT coatings against E. coli and S. aureus might be attributed to the slow but sustainable release of Zn2+ ions (up to 144 h) from the coatings into the culture media. This study provides a novel coating strategy for manufacturing biodegradable Mg alloys with good corrosion resistance, biocompatibility and antibacterial activity for future orthopedic applications.Statement of SignificanceThe significance of the current work is to develop a corrosion-resistant and antibacterial Zn-MMT coating on magnesium alloy AZ31 through a hydrothermal method. The Zn-MMT coating on magnesium alloy AZ31 shows better corrosion resistance, biocompatibility and excellent antibacterial ability than magnesium alloy AZ31. This study provides a novel coating on Mg alloys for future orthopedic applications.Graphical abstractGraphical abstract for this article
       
  • scCO2 foamed composite scaffolds incorporating bioactive lipids promote
           vascularized bone regeneration via Hif-1α upregulation and enhanced type
           H vessel formation
    • Abstract: Publication date: Available online 31 May 2019Source: Acta BiomaterialiaAuthor(s): Shuang Li, Chaobo Song, Shengbing Yang, Weijun Yu, Weiqi Zhang, Guohua Zhang, Zhenhao Xi, Eryi Lu Bone tissue engineering has substantial potential for the treatment of massive bone defects; however, efficient vascularization coupled with bone regeneration still remains a challenge in this field. In the current study, supercritical carbon dioxide (scCO2) foaming technique was adopted to fabricate mesoporous bioactive glasses (MBGs) particle-poly (lactic-co-glycolic acid) (PLGA) composite scaffolds with appropriate mechanical and degradation properties as well as in vitro bioactivity. The MBG-PLGA scaffolds incorporating the bioactive lipid FTY720 (designated as FTY/MBG-PLGA) exhibited simultaneously sustained release of the bioactive lipid and ions. In addition to providing a favorable microenvironment for cellular adhesion and proliferation, FTY/MBG-PLGA scaffolds significantly facilitated the in vitro osteogenic differentiation of rBMSCs and also markedly stimulated the upregulation of Hif-1α expression via the activation of the Erk1/2 pathway, which mediated the osteogenic and pro-angiogenic effects on rBMSCs. Furthermore, FTY/MBG-PLGA extracts induced superior in vitro angiogenic performance of HUVECs. In vivo evaluation of critical-sized rat calvarial bone defects indicated that FTY/MBG-PLGA scaffolds potently promoted vascularized bone regeneration. Notably, the significantly enhanced formation of type H vessels (CD31hiEmcnhi neo-vessels) was observed in newly formed bone tissue in FTY/MBG-PLGA group, strongly suggesting that FTY720 and therapeutic ions released from the scaffolds synergistically induced more type H vessel formation, which indicated the coupling of angiogenesis and osteogenesis to achieve efficiently vascularized bone regeneration. Overall, the results indicated that the foamed porous MBG-PLGA scaffolds incorporating bioactive lipids achieved desirable vascularization-coupled bone formation and could be a promising strategy for bone regenerative medicine.Statement of Significance:Efficacious coupling of vascularization and bone formation is critical for the restoration of large bone defects. A novel technique was used to fabricate composite scaffolds incorporating bioactive lipids which possessed synergistic cues of bioactive lipids and therapeutic ions to potently promote bone regeneration as well as vascularization. The underlying molecular mechanism for the osteogenic and pro-angiogenic effects of the composite scaffolds was unveiled. Interestingly, the scaffolds were further found to enhance the formation of type H capillaries within the bone healing microenvironment to couple angiogenesis to osteogenesis to achieve satisfying vascularized bone regeneration. These findings provide a novel strategy to develop efficiently vascularized engineering constructs to treat massive bone defects.Graphical abstractGraphical abstract for this article
       
  • Planar AFM macro-probes to study the biomechanical properties of large
           cells and 3D cell spheroids
    • Abstract: Publication date: Available online 30 May 2019Source: Acta BiomaterialiaAuthor(s): Laura Andolfi, Silvio L.M. Greco, Domenico Tierno, Roberto Chignola, Monica Martinelli, Elena Giolo, Stefania Luppi, Ines Delfino, Michele Zanetti, Alice Battistella, Giovanna Baldini, Giuseppe Ricci, Marco Lazzarino The ability to measure mechanical response of cells under applied load is essential for developing more accurate models of cell mechanics and mechanotransduction. Living cells have been mechanically investigated by several approaches. Among them, atomic force microscopy (AFM) is widely used thanks to its high versatility and sensitivity. In the case of large cells or 3D multicellular aggregates, standard AFM probes may not be appropriate to investigate the mechanical properties of the whole biological system. Owing to their size, standard AFM probes can compress only a single somatic cell or part of it. To fill this gap, we have designed and fabricated planar AFM macro-probes compatible with commercial AFM instruments. The probes are constituted of a large flat compression plate, connected to the chip by two flexible arms, whose mechanical characteristics are tuned for specific biological applications. As proof of concept, we have used the macro-probes to measure the viscoelasticity of large spherical biological systems, which have a diameter above 100 μm: human oocytes and 3D cell spheroids. Compression experiments are combined with visual inspection, using a side-view configuration imaging, which allows us to monitor the sample morphology during the compression and to correlate it with the viscoelastic parameters. Our measurements provide a quantitative estimate of the relaxation times of such biological systems, which are discussed in relation to data present in literature. The broad applicability of the AFM macro-probes can be relevant to study the biomechanical features in any biological process involving large soft materials.Statement of significanceThe understanding of the role of physical factors in defining cell and tissue functions requires to develop new methods or improve the existing ones to accurately measure the biomechanical properties. AFM is a sensitive and versatile tool to measure the mechanical features from single proteins to single cells. When cells or cell aggregates exceed few tens of microns, AFM suffers from limitations. On these biological systems the control of the contact area and the application of a precise uniform compression becomes crucial. A modification of the standard cantilevers fabrication allowed us obtaining AFM macro-probes, having large planar contact area and spring constant suitable for biological investigations. They were demonstrated valuable to characterize the mechanical properties of large hierarchical biological systems.Graphical abstractGraphical abstract for this article
       
  • Contribution of Nascent Cohesive Fiber-Fiber Interactions to the
           Non-Linear Elasticity of Fibrin Networks under Tensile Load
    • Abstract: Publication date: Available online 30 May 2019Source: Acta BiomaterialiaAuthor(s): Samuel Britton, Oleg Kim, Francesco Pancaldi, Zhiliang Xu, Rustem I. Litvinov, John W. Weisel, Mark Alber Fibrin is a viscoelastic proteinaceous polymer that determines the deformability and integrity of blood clots and fibrin-based biomaterials in response to biomechanical forces. Here, a previously unnoticed structural mechanism of fibrin clots' mechanical response to external tensile loads is tested using high-resolution confocal microscopy and recently developed three-dimensional computational model. This mechanism, underlying local strain-stiffening of individual fibers as well as global stiffening of the entire network, is based on previously neglected nascent cohesive pairwise interactions between individual fibers (crisscrossing) in fibrin networks formed under tensile load. Existence of fiber-fiber crisscrossings of reoriented fibers was confirmed using 3D imaging of experimentally obtained stretched fibrin clots. The computational model enabled us to study structural details and quantify mechanical effects of the fiber-fiber cohesive crisscrossing during stretching of fibrin gels at various spatial scales. The contribution of the fiber-fiber cohesive contacts to the elasticity of stretched fibrin networks was characterized by changes in individual fiber stiffness, the length, width, and alignment of fibers, as well as connectivity and density of the entire network. The results show that the nascent cohesive crisscrossing of fibers in stretched fibrin networks comprise an underappreciated important structural mechanism underlying the mechanical response of fibrin to (patho)physiological stresses that determine the course and outcomes of thrombotic and hemostatic disorders, such as heart attack and ischemic stroke.Statement of SignificanceFibrin is a viscoelastic proteinaceous polymer that determines the deformability and integrity of blood clots and fibrin-based biomaterials in response to biomechanical forces. In this paper, a novel structural mechanism of fibrin clots’ mechanical response to external tensile loads is tested using high-resolution confocal microscopy and newly developed computational model. This mechanism, underlying local strain-stiffening of individual fibers as well as global stiffening of the entire network, is based on previously neglected nascent cohesive pairwise interactions between individual fibers (crisscrossing) in fibrin networks formed under tensile load. Cohesive crisscrossing is an important structural mechanism that influences the mechanical response of blood clots and which can determine the outcomes of blood coagulation disorders, such as heart attacks and strokes.Graphical abstractGraphical abstract for this article
       
  • Mechanisms of pore formation in hydrogel scaffolds textured by
           freeze-drying
    • Abstract: Publication date: Available online 30 May 2019Source: Acta BiomaterialiaAuthor(s): Jérôme Grenier, Hervé Duval, Fabrice Barou, Pin Lv, Bertrand David, Didier Letourneur Whereas freeze-drying is a widely used method to produce porous hydrogel scaffolds, the mechanisms of pore formation involved in this process remained poorly characterized. To explore this, we focused on a cross-linked polysaccharide-based hydrogel developed for bone tissue engineering. Scaffolds were first swollen in 0.025% NaCl then freeze-dried at low cooling rate, i.e. - 0.1 °C min-1, and finally swollen in solvents of increasing ionic strength. We found that scaffold’s porous structure is strongly conditioned by the nucleation of ice. Electron cryo-microscopy of frozen scaffolds demonstrates that each pore results from the growth of one to a few ice grains. Most crystals were formed by secondary nucleation since very few nucleating sites were initially present in each scaffold (0.1 nuclei cm-3 °C-1). The polymer chains are rejected in the intergranular space and form a macro-network. Its characteristic length scale coincides with the ice grain size (160 μm) and is several orders of magnitude greater than the mesh size (90 nm) of the cross-linked network. After sublimation, the ice grains are replaced by macro-pores of 280 μm mean size and the resulting dry structure is highly porous, i.e. 93%, as measured by high-resolution X-ray tomography. In the swollen state, the scaffold mean pore size decreases in solvent of increasing ionic strength (120 µm in 0.025% NaCl and 54 µm in DBPS) but the porosity remains the same, i.e. 29% regardless of the solvent. Finally, cell seeding of dried scaffolds demonstrates that the pores are adequately interconnected to allow homogenous cell distribution.Statement of significanceThe fabrication of hydrogel scaffolds is an important research area in tissue engineering. Hydrogels are textured to provide a 3D-framework that is favorable for cell proliferation and/or differentiation. Optimum hydrogel pore size depends on its biological application. Producing porous hydrogels is commonly achieved through freeze-drying. However, the mechanisms of pore formation remain to be fully understood. We carefully analyzed scaffolds of a cross-linked polysaccharide-based hydrogel developed for bone tissue engineering, using state-of-the-art microscopic techniques. Our experimental results evidenced the shaping of hydrogel during the freezing step, through a specific ice-templating mechanism. These findings will guide the strategies for controlling the porous structure of hydrogel scaffolds.Graphical abstractGraphical abstract for this article
       
  • Bio-engineering a tissue flap utilizing a porous scaffold incorporating a
           human induced pluripotent stem cell-derived endothelial cell capillary
           network connected to a vascular pedicle
    • Abstract: Publication date: Available online 30 May 2019Source: Acta BiomaterialiaAuthor(s): Anne M. Kong, Kiryu K. Yap, Shiang Y. Lim, Diego Marre, Alice Pébay, Yi-wen Gerrand, Jarmon Lees, Jason A. Palmer, Wayne A. Morrison, Geraldine M Mitchell Tissue flaps are used to cover large/poorly healing wounds, but involve complex surgery and donor site morbidity. In this study a tissue flap is assembled using the mammalian body as a bioreactor to functionally connect an artery and vein to a human capillary network assembled from induced pluripotent stem cell-derived endothelial cells (hiPSC ECs). In vitro: Porous NovoSorb™ scaffolds (3 mm x1.35 mm) were seeded with 200,000 iPSC ECs±100,000 human vascular smooth muscle cells (hvSMC), and cultured for 1-3 days, with capillaries formed by 24 hours which were CD31+, VE-Cadherin+, EphB4+, VEGFR2+ and Ki67+, whilst hvSMCs (calponin+) attached abluminally. In vivo: In SCID mice, bi-lateral epigastric vascular pedicles were isolated in a silicone chamber for a 3 week ‘delay period’ for pedicle capillary sprouting, then reopened, and two hiPSC EC±hvSMCs seeded scaffolds transplanted over the pedicle. The chamber was either resealed (Group 1), or removed and surrounding tissue secured around the pedicle+scaffolds (Group 2), for 1 or 2 weeks. Human capillaries survived in vivo and were CD31+, VE-Cadherin+ and VEGFR2+. Human vSMCs remained attached, and host mesenchymal cells also attached abluminally. Systemically injected FITC-dextran present in human capillary lumens indicated inosculation to host capillaries. Human iPSC EC capillary morphometric parameters at one week in vivo were equal to or higher than the same parameters measured in human abdominal skin. This ‘proof of concept’ study has demonstrated that bio-engineering an autologous human tissue flap based on hiPSC EC could minimize the use of donor flaps and has potential applications for complex wound coverage.Statement of SignificanceTissue flaps, used for surgical reconstruction of wounds, require complex surgery, often associated with morbidity. Bio-engineering a simpler alternative, we assembled a human induced pluripotent stem cell derived endothelial cell (hiPSC ECs) capillary network in a porous scaffold in vitro, which when transplanted over a mouse vascular pedicle in vivo formed a functional tissue flap with mouse blood flow in the human capillaries. Therefore it is feasible to form an autologous tissue flap derived from a hiPSC EC capillary network assembled in vitro, and functionally connect to a vascular pedicle in vivo that could be utilized in complex wound repair for chronic or acute wounds.Graphical abstractGraphical abstract for this article
       
  • Microporous annealed particle hydrogel stiffness, void space size, and
           adhesion properties impact cell proliferation, cell spreading, and gene
           transfer
    • Abstract: Publication date: Available online 30 May 2019Source: Acta BiomaterialiaAuthor(s): Norman F. Truong, Evan Kurt, Nairi Tahmizyan, Sasha Cai Lesher-Pérez, Mabel Chen, Nicole J. Darling, Weixian Xi, Tatiana Segura Designing scaffolds for polyplex-mediated therapeutic gene delivery has a number of applications in regenerative medicine, such as for tissue repair after wounding or disease. Microporous annealed particle (MAP) hydrogels are an emerging class of porous biomaterials, formed by annealing microgel particles to one another in situ to form a porous bulk scaffold. MAP gels have previously been shown to support and enhance proliferative and regenerative behaviors both in vitro and in vivo. Therefore, coupling gene delivery with MAP hydrogels presents a promising approach for therapy development. To optimize MAP hydrogels for gene delivery, we studied the effects of particle size and stiffness as well as adhesion potential on cell surface area and proliferation and then correlated this information with the ability of cells to become transfected while seeded in these scaffolds. We find that the void space size as well as the presentation of integrin ligands influence transfection efficiency. This work demonstrates the importance of considering MAP material properties for guiding cell spreading, proliferation, and gene transfer.Statement of significanceMicroporous annealed particle (MAP) hydrogels are an emerging class of porous biomaterials, formed by annealing spherical microgels together in situ, creating a porous scaffold from voids between the packed beads. Here we investigated the effects of MAP physical and adhesion properties on cell spreading, proliferation, and gene transfer in fibroblasts. Particle size and void space influenced spreading and proliferation, with larger particles improving transfection. MAP stiffness was also important, with stiffer scaffolds increasing proliferation, spreading, and transfection, contrasting studies in nonporous hydrogels that showed an inverse response. Last, RGD ligand concentration and presentation modulated spreading similar to non-MAP hydrogels. These findings reveal relationships between MAP properties and cell processes, suggesting how MAP can be tuned to improve future design approaches.Graphical abstractGraphical abstract for this article
       
  • Recent advances in polymer-based drug delivery systems for local
           anesthetics
    • Abstract: Publication date: Available online 29 May 2019Source: Acta BiomaterialiaAuthor(s): Bo Wang, Shuo Wang, Qi Zhang, Yixuan Deng, Xiang Li, Liangyu Peng, Xianghao Zuo, Meihua Piao, Xin Kuang, Shihou Sheng, Yingjie Yu Local anesthetics, which cause temporary loss of pain by inhibiting the transmission of nerve impulses, have been widely used in clinical practice. However, neurotoxicity and short half-lives have significantly limited their clinical applications. To overcome those barriers, numerous drug delivery systems (DDS) have been designed to encapsulate local anesthetic agents, so that large doses can be released slowly and provide analgesia over a prolonged period. So far, multiple classes of local anesthetic carriers have been investigated, with some of them already on the market. Among those, polymer-based delivery platforms are the most extensively explored, especially in the form of polymeric nanoparticle carriers. This review gives a specific focus on the most commonly used natural and synthetic polymers for local anesthetics delivery, owing to their excellent biocompatibility, biodegradability and versatility. State-of-the-art studies concerning such polymer delivery systems have been discussed in depth. We also highlight the impact of those delivery platforms as well as some key challenges that need to be overcome for their broader clinical applications.Statement of significanceCurrently, local anesthetics have been widely used in clinically practices to prevent transmission of nerve impulses. However, the applications of anesthetics are greatly limited due to their neurotoxicity and short half-lives. Moreover, it is difficult to maintain frequent administrations which can cause poor compliance and serious consequences. Numerous drug delivery systems have been developed to solve those issues. In this review, we highlight the recent advances in polymer-based drug delivery systems for local anesthetics. The advantages as well as shortcoming for different types of polymer-based drug delivery systems are summarized in this paper. In the end, we also give prospects for future development of polymer drug delivery systems for anesthetics.Graphical abstractGraphical abstract for this article
       
  • Bioactive Tri/dicalcium Silicate Cements for Treatment of Pulpal and
           Periapical Tissues
    • Abstract: Publication date: Available online 27 May 2019Source: Acta BiomaterialiaAuthor(s): Carolyn M. Primus, Franklin R. Tay, Li-na Niu Over 2500 articles and 200 reviews have been published on the bioactive tri/dicalcium silicate dental materials. The indications have expanded since their introduction in the 1990s from endodontic restorative and pulpal treatments to endodontic sealing and obturation. Bioactive ceramics, based on tri/dicalcium silicate cements, are now an indispensable part of the contemporary dental armamentarium for specialists including endodontists, pediatric dentists, oral surgeons andfor general dentists. This review emphasizes research on how these materials have conformed to international standards for dental materials ranging from biocompatibility (ISO 7405) to conformance as root canal sealers (ISO 6876). Potential future developments of alternative hydraulic materials were included. This review provides accurate materials science information on these important materials.Statement of significanceThe broadening indications and the proliferation of tri/dicalcium silicate-based products make this relatively new dental material important for all dentists and biomaterials scientists. Presenting the variations in compositions, properties, indications and clinical performance enable clinicians to choose the material most suitable for their cases. Researchers may expand their bioactive investigations to further validate and improve materials and outcomes.Graphical abstractGraphical abstract for this article
       
  • In vitro aged, hiPSC-origin engineered heart tissue models with
           age-dependent functional deterioration to study myocardial infarction
    • Abstract: Publication date: Available online 27 May 2019Source: Acta BiomaterialiaAuthor(s): Aylin Acun, Trung Dung Nguyen, Pinar Zorlutuna Deaths attributed to ischemic heart disease increased by 41.7% from 1990 to 2013. This is primarily due to an increase in the aged population, however, research on cardiovascular disease (CVD) has been overlooking aging, a well-documented contributor to CVD. The use of young animals is heavily preferred due to lower costs and ready availability, despite the prominent differences between young and aged heart structure and function. Here we present the first human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (iCM)-based, in vitro aged myocardial tissue model as an alternative research platform. Within 4 months, iCMs go through accelerated senescence and show cellular characteristics of aging. Furthermore, the model tissues fabricated using aged iCMs, with stiffness resembling that of aged human heart, show functional and pharmacological deterioration specific to aged myocardium. Our novel tissue model with age-appropriate physiology and pathology presents a promising new platform for investigating CVD or other age-related diseases.Statement of significanceIn vitro and in vivo models of cardiovascular disease are aimed to provide crucial insight on the pathology and treatment of these diseases. However, the contribution of age-dependent cardiovascular changes is greatly underestimated through the use of young animals and premature cardiomyocytes. Here, we developed in vitro aged cardiac tissue models that mimic the aged heart tissue microenvironment and cellular phenotype and present the first evidence that age-appropriate in vitro disease models can be developed to gain more physiologically-relevant insight on development, progression, and amelioration of cardiovascular diseases.Graphical abstractGraphical abstract for this article
       
  • In vitro degradation behavior of Mg wire/poly(lactic acid) composite rods
           prepared by hot pressing and hot drawing
    • Abstract: Publication date: Available online 27 May 2019Source: Acta BiomaterialiaAuthor(s): Hong Cai, Jiao Meng, Xuan Li, Feng Xue, Chenglin Chu, Chao Guo, Jing Bai In this study, we prepared Mg wire/poly(lactic acid) composite rods by hot pressing (HP) and hot drawing (HD) processes, which show desirable application potential as a biodegradable implant in orthopedics. The influences of the volume content of Mg wires and processing steps on the degradation behavior of composite rods as well as the mutual influence between Mg and poly(lactic acid) (PLA) during degradation were investigated. During degradation, the improved interface bonding between Mg and PLA by micro-arc oxidation can effectively inhibit the diffusion of the medium from the ends to the central part, supported by XR-CT results, which show the degradation cracks in PLA initiated and propagated along the radial direction of the rod rather than the axial direction. When compared with the hot pressed rod, the three passes hot drawn rod had lower degradation rate and better strength retention during long-time immersion. This is ascribed to the higher crystallinity of the PLA matrix by HD. For both hot pressed and hot drawn rods, more Mg content of the wires will result in an increase in the degradation rate of PLA due to alkaline catalytic hydrolysis. Therefore, we can not only predict the degradation period by the present degradation mathematical model but also further control degradation rate by adjusting processing steps and wire volume content. This will be helpful for future material design and indication selection.Statement of significanceWe investigated the influence of interface microstructure, self-reinforced PLA matrix, and wire volume content on the degradation behavior and clarified the differences in the degradation mechanism of composite rods. The 3D morphology of cracks in composite rods enlightened us a clear understanding about the emergence and evolution of cracks, which revealed the reason for the failure of composite rods. The degradation model can be used to predict the degradation period and provide valuable information for their future application.Graphical abstractGraphical abstract for this article
       
  • Feasible and pure P2O5-CaO nanoglasses: an in-depth NMR study of synthesis
           for the modulation of the bioactive ion release
    • Abstract: Publication date: Available online 26 May 2019Source: Acta BiomaterialiaAuthor(s): Joan Marti-Munoz, Elena Xuriguera, John W. Layton, Josep A. Planell, Stephen E. Rankin, Elisabeth Engel, Oscar Castano The use of bioactive glasses (e.g. silicates, phosphates, borates) has demonstrated to be an effective therapy for the restoration of bone fractures, wound healing and vascularization. Their partial dissolution towards the surrounding tissue has shown to trigger positive bioactive responses, without the necessity of using growth factors or cell therapy, which reduces money-costs, side effects and increases their translation to the clinics. However, bioactive glasses often need from stabilizers (e.g. SiO44-, Ti4+, Co2+, etc.) that are not highly abundant in the body and which metabolization is not fully understood. In this study, we were focused on synthesizing pure calcium phosphate glasses without the presences of such stabilizers. We combined a mixture of ethyphosphate and calcium 2-methoxyethoxide to synthesize nanoparticles with different compositions and degradability. Synthesis was followed by an in-depth nuclear magnetic resonance characterization, complemented with other techniques that helped us to correlate the chemical structure of the glasses with their physiochemical properties and reaction mechanism. After synthesis, the organically modified xerogel (i.e. calcium monoethylphosphate) was treated at 200 or 350 °C and its solubility was maintained and controlled due to the elimination of organics, increase of phosphate-calcium interactions and phosphate polycondensation. To the best of our knowledge, we are reporting the first sol-gel synthesis of binary (P2O5-CaO) calcium phosphate glass nanoparticles in terms of continuous poycondensated phosphate chains structure without the addition of extra ions. The main goal is to straightforward the synthesis, to get a safer metabolization and to modulate the bioactive ion release. Additionally, we shed light on the chemical structure, reaction mechanism and properties of calcium phosphate glasses with high calcium contents, which nowadays are poorly understood.Statement of significanceThe use of bioactive inorganic materials (i.e. bioactive ceramics, glass-ceramics and glasses) for biomedical applications is attractive due to their good integration with the host tissue without the necessity of adding exogenous cells or growth factors. In particular, degradable calcium phosphate glasses are completely resorbable, avoiding the retention in the body of the highly stable silica network of silicate glasses, and inducing a more controllable degradability than bioactive ceramics. However, most calcium phosphate glasses include the presence of stabilizers (e.g. Ti4+, Na+, Co2+), which metabolization is not fully understood and complicates their synthesis. The development of binary calcium phosphate glasses with controlled degradability reduces these limitations, offering a simple and completely metabolizable material with higher transfer to the clinics.Graphical abstractGraphical abstract for this article
       
  • Magnetron sputtered freestanding MgAg films with ultra-low corrosion rate
    • Abstract: Publication date: Available online 26 May 2019Source: Acta BiomaterialiaAuthor(s): L.K. Jessen, C. Zamponi, R. Willumeit-Römer, E. Quandt Magnesium based alloys are of great interest for temporary medical applications. In order to tailor the corrosion rate, Mg is often alloyed with other elements for the envisaged application as a biodegradable medical implant. In this study 10 µm thick freestanding MgAg thin film samples with varied Ag concentrations (nominal 2 - 10 wt%) are presented. These films could have the potential as scaffolds, e.g. in neurological applications. The films are fabricated by a combination of UV lithography, sacrificial layer technique and magnetron sputtering, where the latter allows the fabrication of supersaturated metastable alloys. After removing the sacrificial layer, the released freestanding thin film samples are investigated. The corrosion properties are determined using potentiodynamic polarization measurements in Hankś balanced salt solution. The microstructure investigations are done by X-ray diffraction and scanning transmission electron microscopy. The results obtained show that it is possible using magnetron sputtering to achieve supersaturated materials with up to 6 wt% Ag which show a significant decrease in the corrosion rate compared to pure Mg by a factor of approximately three (0.04 ± 0.01 mm/yr compared to 0.12± 0.02 mm/yr).Statement of significanceIn this study magnetron sputtered freestanding MgAg films with a Ag concentration of 2-10 wt% were investigated in terms of corrosion properties and microstructure. The 10 µm thick films were produced by a combination of UV lithography and magnetron sputtering, the latter allows the fabrication of supersaturated alloys. It was possible to fabricate single phase materials up to 6 wt% Ag, which showed a decrease in the corrosion rate by the factor of 2.9 compared to pure Mg. For materials with 10 wt% it was not possible to obtain single phase materials, in this case the corrosion rate was increased by a factor of 19.6 compared to pure Mg due to the formation of galvanic cells.Graphical abstractGraphical abstract for this article
       
  • Doxorubicin and Adjudin co-loaded pH-sensitive nanoparticles for the
           treatment of drug-resistant cancer
    • Abstract: Publication date: Available online 26 May 2019Source: Acta BiomaterialiaAuthor(s): Qiong Wang, Chenming Zou, Lingying Wang, Xueqin Gao, Jindan Wu, Songwei Tan, Gang Wu Multi-drug resistance (MDR) of tumor is a major cause of chemotherapy failure. In this study, a pH-sensitive graft copolymer, poly(β-amino ester)-g-β-cyclodextrin (PBAE-g-β-CD), was synthesized via Michael addition polymerization and was employed to co-deliver doxorubicin (DOX), a chemotherapy agent, and adjudin (ADD), a mitochondrial inhibitor, in the form of dual-drug co-loaded nanoparticles (NPs). Specifically, DOX was conjugated to 1-adamantaneacetic acid (Aa) to generate a prodrug that was subsequently encapsulated in the cavity of cyclodextrin via host-guest interactions. In addition, ADD was encapsulated by poly(β-aminoester) (PBAE). The introduction of the Aa-d-α-tocopheryl polyethylene glycolsuccinate (TPGS) conjugate enhanced the biocompatibility and serum stability of the resulting NPs. The NPs can realize precise ratiometric control of drugs being loaded, increase cellular uptake of the drugs, induce mitochondrial dysfunction and augment tumor treatment efficiency by inducing apoptosis. Western blot and polymerase chain reaction analyses showed that inhibition of P-glycoprotein and X-linked inhibitor of apoptosis protein expression may underlie inhibition of tumor resistance mediated by NPs. The MCF-7/ADR xenograft tumor model also revealed that in comparison with DOX, the NPs exhibited satisfactory performance in promoting apoptosis of tumor cells and achieved high therapeutic outcomes for MDR tumors.Statement of SignificanceCombination chemotherapy is an effective way to overcome MDR of tumor. However, one of the major obstacles for successful combination chemotherapy is the co-loading, co-delivery and controlled release of two different drugs, whose chemo-physical properties may be totally different. In this study, a pH-sensitive NP system was designed to realize the co-loading and precise ratiometric control of DOX and ADD, and the programmed drug release. That is, ADD release was triggered by low pH in endo/lysosome after endocytosis and then DOX was hydrolyzed to achieve a sustained release in tumor cells. Therefore, the NPs exhibited an effectively growth inhibition against MDR cells both in vitro and in vivo via the synergistic effect of ADD and DOX, which provided a promising strategy for treatment of MDR cancer.Graphical abstractGraphical abstract for this article
       
  • Local delivery of FK506 to injured peripheral nerve enhances axon
           regeneration after surgical nerve repair in rats
    • Abstract: Publication date: Available online 26 May 2019Source: Acta BiomaterialiaAuthor(s): Kasra Tajdaran, Katelyn Chan, Molly S. Shoichet, Tessa Gordon, Gregory H. Borschel Administration of FK506, an FDA approved immunosuppressant, has been shown to enhance nerve regeneration following peripheral nerve injuries. However, the severe side effects of the systemically delivered FK506 has prevented clinicians from the routine use of the drug. In this study, we analyzed the effectiveness of our fibrin gel-based FK506 delivery system to promote axon regeneration in a rat peripheral nerve transection and immediate surgical repair model. In addition, biodistribution of FK506 from the local delivery system to the surrounding tissues was analyzed in vivo. Rats in the negative control groups either did not receive any delivery system treatment or received fibrin gel with empty microspheres. The experimental groups included rats treated with fibrin gel loaded with solubilized, particulate, and poly(lactic-co-glycolic) acid microspheres-encapsulated FK506. Rats in experimental groups receiving FK506 microspheres and the particulate FK506 regenerated the highest number of motor and sensory neurons. Histomorphometric analysis also demonstrated greater numbers of myelinated axons following particulate FK506 and FK506 microspheres treatment compared to the negative control groups. In biodistribution studies, FK506 was found at the nerve repair site, the sciatic nerve, and spinal cord, with little to no drug detection in other vital organs. Hence, the local application of FK506 via our delivery systems enhanced axon regeneration whilst avoiding the toxicity of systemic FK506. This local delivery strategy represents a new opportunity for clinicians to use for cases of peripheral nerve injuries.Statement of SignificanceThis work for the first time investigated the influence of locally administered FK506 to the site of nerve injury and immediate repair directly on the number of motor and sensory neurons that regenerated their axons. Furthermore, using the immediate nerve repair model, we obtained valuable information about the biodistribution of FK506 within the nervous system following its release from the delivery system implanted at the site of nerve injury and repair. The strategy of local FK506 delivery holds a great promise in the clinical translation, as the localized delivery circumvents the main limitation of the systemic delivery of FK506, that of immunosuppression and toxicity.Graphical abstractGraphical abstract for this article
       
  • Additive manufacturing of photo-crosslinked gelatin scaffolds for adipose
           tissue engineering
    • Abstract: Publication date: Available online 25 May 2019Source: Acta BiomaterialiaAuthor(s): Liesbeth Tytgat, Lana Van Damme, Jasper Van Hoorick, Heidi Declercq, Hugo Thienpont, Heidi Ottevaere, Phillip Blondeel, Peter Dubruel, Sandra Van Vlierberghe There exists a clear clinical need for adipose tissue reconstruction strategies to repair soft tissue defects which outperform the currently available approaches. In this respect, additive manufacturing has shown to be a promising alternative for the development of larger constructs able to support adipose tissue engineering. In the present work, a thiol-ene photo-click crosslinkable gelatin hydrogel was developed which allowed extrusion-based additive manufacturing into porous scaffolds. To this end, norbornene-functionalized gelatin (Gel-NB) was combined with thiolated gelatin (Gel-SH). The application of a macromolecular gelatin-based thiolated crosslinker holds several advantages over conventional crosslinkers including cell-interactivity, less chance at phase separation between scaffold material and crosslinker and the formation of a more homogeneous network. Throughout the paper, these photo-click scaffolds were benchmarked to the conventional methacrylamide-modified gelatin (Gel-MA). The results indicated that stable scaffolds could be realized which were further characterized physico-chemically by performing swelling, mechanical and in vitro biodegradability assays. Furthermore, the seeded adipose tissue-derived stem cells (ASCs) remained viable (> 90%) up to 14 days and were able to proliferate. In addition, the cells could be differentiated into the adipogenic lineage on the photo-click crosslinked scaffolds, thereby performing better than the cells supported by the frequently reported Gel-MA scaffolds. As a result, the developed photo-click crosslinked scaffolds can be considered a promising candidate towards adipose tissue engineering and a valuable alternative for the omnipresent Gel-MA.Statement of significanceThe field of adipose tissue engineering has emerged as a promising strategy to repair soft tissue defects. Herein, Gel-NB/Gel-SH gelatin-based hydrogel scaffolds were produced using extrusion-based additive manufacturing. Using a cell-interactive, thiolated gelatin crosslinker, a homogeneous network was formed and the risk of phase separation between norbornene-modified gelatin and macromolecular crosslinkers was reduced. UV-induced crosslinking of these materials is based on step-growth polymerization which requires less free radicals to enable polymerization. Our results demonstrated the potential of the developed scaffolds, due to their favourable physico-chemical characteristics as well as their adipogenic differentiation potential when benchmarked to Gel-MA scaffolds. Hence, the hydrogels could be of great interest towards future development of adipose tissue constructs and tissue engineering in general.Graphical abstractGraphical abstract for this article
       
  • Laser additive manufacturing of biodegradable magnesium alloy WE43: a
           detailed microstructure analysis
    • Abstract: Publication date: Available online 25 May 2019Source: Acta BiomaterialiaAuthor(s): Florian Bär, Leopold Berger, Lucas Jauer, Güven Kurtuldu, Robin Schäublin, Johannes H. Schleifenbaum, Jörg F. Löffler WE43, a magnesium alloy containing yttrium and neodymium as main alloying elements, has become a well-established bioresorbable implant material. Implants made of WE43 are often fabricated by powder extrusion and subsequent machining, but for more complex geometries laser powder bed fusion (LPBF) appears to be a promising alternative. However, the extremely high cooling rates and subsequent heat treatment after solidification of the melt pool involved in this process induce a drastic change in microstructure, which governs mechanical properties and degradation behaviour in a way that is still unclear. In this study we investigated the changes in the microstructure of WE43 induced by LPBF in comparison to that of cast WE43. We did this mainly by electron microscopy imaging, and chemical mapping based on energy-dispersive X-ray spectroscopy in conjunction with electron diffraction for the identification of the various phases. We identified different types of microstructure: an equiaxed grain zone in the center of the laser-induced melt pool, and a lamellar zone and a partially melted zone at its border. The lamellar zone presents dendritic lamellae lying on the Mg basal plane and separated by aligned Nd-rich nanometric intermetallic phases. They appear as globular particles made of Mg3Nd and as platelets made of Mg41Nd5 occurring on Mg prismatic planes. Yttrium is found in solid solution and in oxide particles stemming from the powder particles’ shell. Due to the heat influence on the lamellar zone during subsequent laser passes, a strong texture developed in the bulk material after substantial grain growth.Statement of SignificanceAdditively manufactured magnesium alloys have the potential of comprising a major breakthrough in bone-reconstruction surgery by serving as biodegradable porous scaffold material. This study is the first to report in detail on the microstructure development of the established magnesium alloy WE43 fabricated by the additive manufacturing process of Laser Powder Bed Fusion (LPBF). It presents unique microstructural features which originate from the laser-melting process. An in situ transmission electron microscopy heating experiment further demonstrates the development of two distinct intermetallic phases for additively manufactured WE43 alloys. While one forms already during solidification, the other precipitates due to the ongoing heat treatment during LPBF processing.Graphical abstractGraphical abstract for this article
       
  • Translational Mechanobiology: Designing Synthetic Hydrogel Matrices for
           Improved In Vitro Models and Cell-Based Therapies
    • Abstract: Publication date: Available online 24 May 2019Source: Acta BiomaterialiaAuthor(s): Nathaniel Huebsch Synthetic hydrogels have ideal physiochemical properties to serve as reductionist mimics of the extracellular matrix (ECM) for studies on cellular mechanosensing. These studies range from basic observation of correlations between ECM mechanics and cell fate changes to molecular dissection of the underlying mechanisms. Despite intensive work on hydrogels to study mechanobiology, many fundamental questions regarding mechanosensing remain unanswered. In this review, I first discuss historical motivation for studying cellular mechanobiology, and challenges impeding this effort. I next overview recent efforts to engineer hydrogel properties to study cellular mechanosensing. Finally, I focus on in vitro modeling and cell-based therapies as applications of hydrogels that will exploit our ability to create micro-environments with physiologically relevant elasticity and viscoelasticity to control cell biology. These translational applications will not only use our current understanding of mechanobiology but will also bring new tools to study the fundamental problem of how cells sense their mechanical environment.Statement of significanceHydrogels are an important tool for understanding how our cells can sense their mechanical environment, and to exploit that understanding in regenerative medicine. In the current review, I discuss historical work linking mechanics to cell behavior in vitro, and highlight the role hydrogels played in allowing us to understand how cells monitor mechanical cues. I then highlight potential translational applications of hydrogels with mechanical properties similar to those of the tissues where cells normally reside in our bodies, and discuss how these types of studies can provide clues to help us enhance our understanding of mechanosensing.Graphical abstractGraphical abstract for this article
       
  • A sintered graphene/titania material as a synthetic keratoprosthesis skirt
           for end-stage corneal disorders
    • Abstract: Publication date: Available online 24 May 2019Source: Acta BiomaterialiaAuthor(s): Zhong Li, Tze-Wei Goh, Gary Hin-Fai Yam, Brianna C. Thompson, Huanlong Hu, Melina Setiawan, Wen Sun, Andri K. Riau, Donald T. Tan, Khiam Aik Khor, Jodhbir S. Mehta An artificial cornea or keratoprosthesis requires high mechanical strength, good biocompatibility, and sufficient wear and corrosion resistance to withstand the hostile environment. We report a reduced graphene oxide-reinforced titania-based composite for this application. Graphene oxide nanoparticles (GO) and liquid crystalline graphene oxide (LCGO) were the graphene precursors and mixed with titanium dioxide (TiO2) powder. The composites reinforced with reduced GO or LCGO were produced through spark plasma sintering (SPS). The mechanical properties (Young’s modulus and hardness), wear behaviour and corrosion resistance were studied using nanoindentation, anoidic polarization, long-term corrosion assay in artificial tear fluid and tribology assay in corroboration with atomic force microscopy and scanning electron microscopy. Biocompatibility was assessed by human corneal stromal cell attachment, survival and proliferation, and DNA damages. Sintered composites were implanted into rabbit corneas to assess for in vivo stability and host tissue responses. We showed that reduced graphene/TiO2 hybrids were safe and biocompatible. In particular, the 1% reduced LCGO/TiO2 (1rLCGO/TiO2) composite was mechanically strong, chemically stable, and showed better wear and corrosion resistance than pure titania and other combinations of graphene-reinforced titania. Hence the 1rLCGO/ TiO2 bioceramics can be a potential skirt biomaterial for keratoprosthesis to treat end-stage corneal blindness.Statement of SignificanceThe osteo-odonto-keratoprosthesis (OOKP) is an artificial cornea procedure used to restore vision in end-stage corneal diseases, however it is contraindicated in young subjects, patients with advanced imflammatory diseases and posterior segment complications. Hence, there is a need of an improved keratoprosthesis skirt material with high mechanical and chemical stability, wear resistance and tissue integration ability. Our study characterized a reduced graphene oxide-reinforced titania-based biomaterial, which demonstrated strong mechanical strength, wear and corrosion resistance, and was safe and biocompatible to human corneal stromal cells. In vivo implantation to rabbit corneas did not cause any immune and inflammation outcomes. In conclusion, this invention is a potential keratoprosthesis skirt biomaterial to withstand the hostile environment in treating end-stage corneal blindness.Graphical abstractGraphical abstract for this article
       
  • Degradable antimicrobial polycarbonates with unexpected activity and
           selectivity for treating multidrug-resistant Klebsiella pneumoniae lung
           infection in mice
    • Abstract: Publication date: Available online 24 May 2019Source: Acta BiomaterialiaAuthor(s): Chuan Yang, Weiyang Lou, Guansheng Zhong, Ashlynn Lee, Jiayu Leong, Willy Chin, Bisha Ding, Chang Bao, Jeremy P.K. Tan, Qinqin Pu, Shujun Gao, Liang Xu, Li Yang Hsu, Min Wu, James L. Hedrick, Weimin Fan, Yi Yan Yang Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections around the world, with attendant high rates of morbidity and mortality. Progressive reduction in potency of antibiotics capable of treating MDR K. pneumoniae infections – including lung infection - as a consequence of escalating drug resistance provides the motivation to develop drug candidates targeting MDR K. pneumoniae. We recently reported degradable broad-spectrum antimicrobial guanidinium-functionalized polycarbonates with unique antimicrobial mechanism – membrane translocation followed by precipitation of cytosolic materials. These polymers exhibited high potency against bacteria with negligible toxicity. The polymer with ethyl spacer between the quanidinium group and the polymer backbone (pEt_20) showed excellent in vivo efficacy for treating MDR K. pneumoniae-caused peritonitis in mice. In this study, the structures of the polymers were optimized for the treatment of MDR Klebsiella pneumoniae lung infection. Specifically, in vitro antimicrobial activity and selectivity of guanidinium-functionalized polycarbonates containing the same number of guanidinium groups but of a shorter chain length and a structural analogue containing a thiouronium moiety as the pendent cationic group were evaluated. The polymers with optimal compositions and varying hydrophobicity were assessed against 25 clinically isolated K. pneumonia strains for antimicrobial activity and killing kinetics. The results showed that the polymers killed the bacteria more efficiently than clinically used antibiotics, and repeated use of the polymers did not cause drug resistance in K. pneumonia. Particularly, the polymer with butyl spacer (pBut_20) self-assembled into micelles at high concentrations, where the hydrophobic component was shielded in the micellar core, preventing interacting with mammalian cells. A subtle change in the hydrophobicity increased the antimicrobial activity while reducing in vivo toxicity. The in vivo efficacy studies showed that pBut_20 alleviated K. pneumonia lung infection without inducing damage to major organs. Taken together, pBut_20 is promising for treating MDR Klebsiella pneumoniae lung infection in vivo.Statement of SignificanceMultidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections, with attendant high rates of morbidity and mortality. The progressive reduction in antibiotics capable of treating MDR K. pneumoniae infections – including lung infection - as a consequence of escalating drug resistance rates provides the motivation to develop drug candidates. In this study, we report a degradable guanidinium-functionalized polycarbonate with unexpected antimicrobial activity and selectivity towards MDR Klebsiella pneumoniae. A subtle change in polymer hydrophobicity increases antimicrobial activity while reducing in vivo toxicity due to self-assembly at high concentrations. The polymer with optimal composition alleviates Klebsiella pneumonia lung infection without inducing damage to major organs. The polymer is promising for treating MDR Klebsiella pneumoniae lung infection in vivo.Graphical abstractGraphical abstract for this article
       
  • Toll-like receptor-targeted particles: a paradigm to manipulate the tumor
           microenvironment for cancer immunotherapy
    • Abstract: Publication date: Available online 24 May 2019Source: Acta BiomaterialiaAuthor(s): Tuan Hiep Tran, Thi Thu Phuong Tran, Duy Hieu Truong, Hanh Thuy Nguyen, Tung Thanh Pham, Chul Soon Yong, Jong Oh Kim The expression of Toll-like receptors (TLRs) on antigen presenting cells, especially dendritic cells, offers several sensitive mediators to trigger an adaptive immune response, which potentially can be exploited to detect and eliminate pathogenic objects. Consequently, numerous agonists that target TLRs are being used clinically either alone or in combination with other therapies to strengthen the immune system in the battle against cancer. This review summarizes the roles of TLRs in tumor biology, and focuses on relevant TLR-dependent antitumor pathways and the conjugation of TLR agonists as adjuvants to nano- and micro-particles for boosting responses leading to cancer suppression and eradication.Statement of significanceToll-like receptors (TLRs), which express on antigen presenting cells, such as dendritic cells and macrophages, play an important role in sensing pathogenic agents and inducing adaptive immunity. As a result, several TLR agonists have been investigating as therapeutic agents individually or in combination with other treatment modalities for cancer treatment through boosting the immune system. This review aims to focus on the roles of TLRs in cancer and TLR-dependent antitumor pathways as well as the use of different nano- or micro-particles bearing TLR agonists for tumor inhibition and elimination.Graphical abstractGraphical abstract for this article
       
  • Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug
           delivery
    • Abstract: Publication date: Available online 24 May 2019Source: Acta BiomaterialiaAuthor(s): Sagar Rayamajhi, Tuyen Duong Thanh Nguyen, Ramesh Marasini, Santosh Aryal Extracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the form of smaller (30-200 nm) and larger (micron size) particles. While all of these vesicles are called as EVs, the smaller size are normally called as exosomes. Small EVs (sEVs) have now been explored as a potential candidate in therapeutics delivery owing to their endogenous functionality, intrinsic targeting property, and ability to cooperate with a host defense mechanism. Considering these potentials, we hypothesize that immune cell-derived sEVs can mimic immune cell to target cancer. However, different sEVs isolation technique reported poor yield and loss of functional properties. To solve this problem, herein we hybridized sEVs with synthetic liposome to engineer vesicles with size less than 200 nm to mimic the size of exosome and named as hybrid exosome (HE). To achieve this goal, sEVs from mouse macrophage was hybridized with synthetic liposome to engineer HE. The fluorescence-based experiment confirmed the successful hybridization process yielding HE with the size of 177±21 nm. Major protein analysis from Blot techniques reveals the presence of EV marker proteins CD81, CD63, and CD9. Differential cellular interaction of HE was observed when treated with normal and cancerous cells thereby supporting our hypothesis. Moreover, a water-soluble doxorubicin was loaded in HE. Drug-loaded HE showed enhanced toxicity against cancer cells and pH-sensitive drug release in acidic condition, benefiting drug delivery to acidic cancer environment. These results suggest that the engineered HE would be an exciting platform for tumor-targeted drug delivery.Statement of SignificanceExtracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the human body. These vesicles can efficiently deliver their parental biomolecules to the recipient cells and assist in intracellular communication without a direct cell-to-cell contact. Moreover, they have the ability to perform some of the molecular task similar to that of its parent cells. For example, exosome derived from immune cells can seek for diseased and/or inflammatory cells by reading the cell surface proteins. However, different EVs isolation techniques reported poor yield and loss of functional properties. Therefore, to overcome this limitation, we herein propose to re-engineer immuno-exosome with a synthetic liposome as a refined biomimetic nanostructure for the delivery of doxorubicin (clinical drug) for breast cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Bioinspirational Understanding of Flexural Performance in Hedgehog Spines
    • Abstract: Publication date: Available online 23 May 2019Source: Acta BiomaterialiaAuthor(s): Christopher J. Drol, Emily B. Kennedy, Bor-Kai Hsiung, Nathan B. Swift, Kwek-Tze Tan In this research, the flexural performance of hedgehog spines is investigated in four ways. First, x-ray micro-computed tomography (μCT) is employed to analyze the complex internal architecture of hedgehog spines. μCT images reveal distinct structural morphology, characterized by longitudinal stringers and transverse central plates, which enhance flexural performance. Second, computer-aided design (CAD) is utilized to create and produce different three-dimensional (3D) computational models that gradually approach resemblance to hedgehog spines. Various levels of models are constructed by including and excluding key internal features of hedgehog spines, resulting in the formation of model levels from the simplest to the most realistic form. Third, finite element analysis (FEA) is exploited to simulate flexural behavior of hedgehog spines undergoing three-point bending. FEA results aim to identify and elucidate how internal structural features affect flexural stiffness and bending stress contours. Fourth, flexural analytical modeling is performed to calculate flexural shear flow and twist angle during transverse loading. The effects of the number of hedgehog outer cells, the spine wall thickness ratio and radius ratio are theoretically investigated to predict the shear stress and twist angle of the hedgehog spine structure. Results demonstrate that longitudinal stringers of the hedgehog spine significantly increase the overall flexural stiffness, while the transverse central plates provide support and rigidity to prevent spines from buckling and collapsing. Interestingly, the 3D model level that most realistically resembles the actual hedgehog spine is evidenced to have the highest specific bending stiffness, demonstrating nature’s most efficient design. The findings of this study may be useful for developing hedgehog-inspired lightweight, high-stiffness, impact-tolerant structures.Statement of SignificanceThis research has given much needed insight on the inner morphology of hedgehog spines and the structure-property relationship to the spine’s flexural performance. X-ray μCT images reveal inner structural morphology, characterized by longitudinal stringers and transverse plates. Finite element analysis shows that longitudinal stringers significantly increase flexural stiffness, while the transverse plates provide support and rigidity to prevent buckling. The model that resembles the actual hedgehog spine is evidenced to have the highest specific bending stiffness, demonstrating nature’s most efficient design. Analytical model studies influence on cell number, spine geometrical ratios, and further confirms nature’s perfect design with lowest flexural shear flow and twist angle during transverse loading. This work paths future design for hedgehog-inspired lightweight, high-stiffness, impact-tolerant structures.Graphical abstractGraphical abstract for this article
       
  • Nanofiber-based Matrices for Rotator Cuff Regenerative Engineering
    • Abstract: Publication date: Available online 23 May 2019Source: Acta BiomaterialiaAuthor(s): Nikoo Saveh-Shemshaki, Lakshmi S.Nair, Cato T. Laurencin The rotator cuff consists of a cuff of soft tissue responsible for rotating the shoulder. Rotator cuff tendon tears are responsible for a significant source of disability and pain in the adult population. Most rotator cuff tendon tears occur at the bone-tendon interface. Tear size, patient age, fatty infiltration of muscle, have a major influence on the rate of retear after surgical repair. The high incidence of retears (up to 94% in some studies) after surgery makes rotator cuff injuries a critical musculoskeletal problem to address. The limitations of current treatments motivate regenerative engineering approaches for rotator cuff regeneration. Various fiber-based matrices are currently being investigated due to their structural similarity with native tendons and their ability to promote regeneration. This review will discuss the current approaches for rotator cuff regeneration, recent advances in fabrication and enhancement of nanofiber-based matrices and the development and use of complex nano/microstructures for rotator cuff regeneration.Statement of significantRegeneration paradigms for musculoskeletal tissues involving the rotator cuff of the shoulder have received great interest. Novel technologies based on nanomaterials have emerged as possible robust solutions for rotator cuff injury and treatment due to structure/property relationships. The aim of the review submitted is to comprehensively describe and evaluate the development and use of nano-based material technologies for applications to rotator cuff tendon healing and regeneration.Graphical abstractGraphical abstract for this article
       
  • An integrated cell printing system for the construction of heterogeneous
           tissue models
    • Abstract: Publication date: Available online 23 May 2019Source: Acta BiomaterialiaAuthor(s): Tian-kun Liu, Yuan Pang, Zhen-zhen Zhou, Rui Yao, Wei Sun A new three-dimensional (3D) cell printing system was developed and investigated to organize multiple cells/biomaterials with a control precision within 100 μm. This system can be used for the in vitro construction of heterogeneous tissue models. The proposed printing system was achieved by the integration of extrusion printing and alternating viscous and inertial force jetting (AVIFJ) techniques using dual-nozzle switching. In this technique, hydrogels containing high cell densities were extruded using extrusion printing, while droplets containing single cells were precisely manipulated using AVIFJ. The droplets that contained single cells were at the scale of pico-liters and could be accurately positioned at the micron scale. Stable hydrogel structures with adjustable diameters were also printed, with cell viabilities exceeding 90% after printing. A heterogeneous tumor model that contained spheroids and human umbilical vein endothelial cells (HUVECs) was then constructed using the established integrated cell printing system in a stepwise or simultaneous fashion. HUVEC-loaded droplets were observed to locate around the preformed tumor spheroids as designed. Cells and spheroids in the model maintained high cell viability and sustained growth throughout the culture period. The ELISA results of albumin production also proved that the spheroids maintained increased cellular function during the culture. These results demonstrated the feasibility of this integrated 3D printing system for the engineering of in vitro heterogeneous tissue models for future biological and pathological studies.Statement of SignificanceTo addressing the challenge of multi-scale printing in the construction of heterogeneous tissue models, a new 3D cell printing system was developed to organize cells/biomaterials of a control precision within 100 μm. AVIFJ was integrated with extrusion printing, thereby achieving the construction of cell interactions between single cells and spheroids, the manipulation of single cells in a 3D microenvironment with high accuracy, and the real-time on-demand printing. The printed heterogeneous tumor model maintained cell viability, sustained cell growth, and increased cell function during 7 days of culture. We believed that this work would benefit the production of functional artificial tissues, enabling the construction of more biomimetic cell arrangements and microenvironment to support cell functions.Graphical abstractGraphical abstract for this article
       
  • Engineering the Vasculature for Islet Transplantation
    • Abstract: Publication date: Available online 23 May 2019Source: Acta BiomaterialiaAuthor(s): Daniel T. Bowers, Wei Song, Long-Hai Wang, Minglin Ma The microvasculature in the pancreatic islet is highly specialized for glucose sensing and insulin secretion. Although pancreatic islet transplantation is a potentially life-changing treatment for patients with insulin-dependent diabetes, a lack of blood perfusion reduces viability and function of newly transplanted tissues. Functional vasculature around an implant is not only necessary for the supply of oxygen and nutrients but also required for rapid insulin release kinetics and removal of metabolic waste. Inadequate vascularization is particularly a challenge in islet encapsulation. Selectively permeable membranes increase the barrier to diffusion and often elicit a foreign body reaction including a fibrotic capsule that is not well vascularized. Therefore, approaches that aid in the rapid formation of a mature and robust vasculature in close proximity to the transplanted cells are crucial for successful islet transplantation or other cellular therapies. In this paper, we review various strategies to engineer vasculature for islet transplantation. We consider properties of materials (both synthetic and naturally derived), prevascularization, local release of proangiogenic factors, and co-transplantation of vascular cells that have all been harnessed to increase vasculature. We then discuss the various other challenges in engineering mature, long-term functional and clinically viable vasculature as well as some emerging technologies developed to address them. The benefits of physiological glucose control for patients and the healthcare system demand vigorous pursuit of solutions to cell transplant challenges.Statement of SignificanceInsulin-dependent diabetes affects more than 1.25 million people in the United States alone. Pancreatic islets secrete insulin and other endocrine hormones that control glucose to normal levels. During preparation for transplantation, the specialized islet blood vessel supply is lost. Furthermore, in the case of cell encapsulation, cells are protected within a device, further limiting delivery of nutrients and absorption of hormones. To overcome these issues, this review considers methods to rapidly vascularize sites and implants through material properties, pre-vascularization, delivery of growth factors, or co-transplantation of vessel supporting cells. Other challenges and emerging technologies are also discussed. Proper vascular growth is a significant component of successful islet transplantation, a treatment that can provide life-changing benefits to patients.Graphical abstractGraphical abstract for this article
       
  • Formation of Stable Strontium-Rich Amorphous Calcium Phosphate: Possible
           Effects on Bone Mineral
    • Abstract: Publication date: Available online 22 May 2019Source: Acta BiomaterialiaAuthor(s): Camila B. Tovani, Alexandre Gloter, Thierry Azaïs, Mohamed Selmane, Ana P. Ramos, Nadine Nassif Bone, tooth enamel, and dentin accumulate Sr2+, a natural trace element in the human body. Sr2+ comes from dietary and environmental sources and is thought to play a key role in osteoporosis treatments. However, the underlying impacts of Sr2+on bone mineralization remain unclear and the use of synthetic apatites (which are structurally different from bone mineral) and non-physiological conditions have led to contradictory results. Here, we report on the formation of a new Sr2+-rich and stable amorphous calcium phosphate phase, Sr(ACP). Relying on a bioinspired pathway, a series of Sr2+ substituted hydroxyapatite (HA) that combines the major bone mineral features is depicted as model to investigate how this phase forms and Sr2+ affects bone. In addition, by means of a comprehensive investigation the biomineralization pathway of Sr2+ bearing HA is described showing that not more than 10 at% of Sr2+, i.e. the physiological limit incorporated in bone, can be incorporated into HA without phase segregation. A combination of 31P and 1H solid state NMR, energy electron loss spectromicroscopy, transmission electron microscopy, electron diffraction, and Raman spectroscopy shows that Sr2+ introduces disorder in the HA culminating with the unexpected Sr(ACP), which co-exists with the HA under physiological conditions. These results suggest that heterogeneous Sr2+ distribution in bone is associated with regions of low structural organization. Going further, such observations give clues from the physicochemical standpoint to understand the defects in bone formation induced by high Sr2+ doses.Statement of significanceUnderstanding the role played by Sr2+ has a relevant impact in physiological biomineralization and provides insights for its use as osteoporosis treatments. Previous studies inspired by the bone remodelling pathway led to the formation of biomimetic HA in terms of composition, structures and properties in water. Herein, by investigating different atomic percentage of Sr2+ related to Ca2+ in the synthesis, we demonstrate that 10% of Sr2+ is the critical loads into the biomimetic HA phase; percent being the limited amount incorporated into bone. Unexpectedly, using higher amount leads to the formation of a stable Sr2+-rich amorphous calcium phosphate phase that may high-dose related pathologies. Our results provide further understanding of the different ways Sr2+ impacts bone.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Anti-infective efficacy, cytocompatibility and
           biocompatibility of a 3D-printed osteoconductive composite scaffold
           functionalized with quaternized chitosan” [Acta Biomater. 46 (2016)
           112–128]
    • Abstract: Publication date: Available online 21 May 2019Source: Acta BiomaterialiaAuthor(s): Ying Yang, Shengbing Yang, Yugang Wang, Zhifeng Yu, Haiyong Ao, Hongbo Zhang, Ling Qin, Olivier Guillaume, David Eglin, R. Geoff Richards, Tingting Tang
       
  • Targeted delivery of ibrutinib to tumor-associated macrophages by sialic
           acid-stearic acid conjugate modified nanocomplexes for cancer
           immunotherapy
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): Qiujun Qiu, Cong Li, Yanzhi Song, Tao Shi, Xiang Luo, Hongxia Zhang, Ling Hu, Xinyang Yan, Huangliang Zheng, Mengyang Liu, Mingqi Liu, Min Liu, Shuaishuai Yang, Xinrong Liu, Guoliang Chen, Yihui Deng Ibrutinib (IBR), an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)–stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy.Statement of SignificanceIbrutinib (IBR), an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)–stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokines release, reducing angiogenesis, and suppressing tumor growth. These results implied that SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.Graphical abstractGraphical abstract for this article
       
  • 3D printing of hydrogel scaffolds for future application in photothermal
           therapy of breast cancer and tissue repair
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): Yongxiang Luo, Xiaoyue Wei, Yilin Wan, Xin Lin, Zhiyong Wang, Peng Huang Surgical removal remains the main clinical approach to treat breast cancer, although risks including high local recurrence of cancer and loss of breast tissues are the threats for the survival and quality of life of patients after surgery. In this study, bifunctional scaffold based on dopamine-modified alginate and polydopamine (PDA) was fabricated using 3D printing with an aim to treat breast cancer and fill the cavity, thereby achieving tissue repair. The as-prepared alginate-polydopamine (Alg-PDA) scaffold exhibited favorable photothermal effect both in vitro and in vivo upon 808 nm laser irradiation. Further, the Alg-PDA scaffold showed great flexibility and similar modulus with normal breast tissues and facilitated the adhesion and proliferation of normal breast epithelial cells. Moreover, the in vivo performance of the Alg-PDA scaffold could be tracked by magnetic resonance and photoacoustic dual-modality imaging. The scaffold that was fabricated using simple and biocompatible materials with individual-designed structure and macropores, as well as outstanding photothermal effect and enhanced cell proliferation ability, might be a potential option for breast cancer treatment and tissue repair after surgery.Statement of SignificanceIn this study, a three-dimensional porous scaffold was developed using 3D printing for the treatment of local recurrence of breast cancer and the following tissue repair after surgery. In this approach, easily available materials (dopamine-modified alginate and PDA) with excellent biocompatibility were selected and prepared as printing inks. The fabricated scaffold showed effective photothermal effects for cancer therapy, as well as matched mechanical properties with breast tissues. Furthermore, the scaffold supported attachment and proliferation of normal breast cells, which indicates its potential ability for adipose tissue repair. Together, the 3D-printed scaffold might be a promising option for the treatment of locally recurrent breast cancer cells and the following tissue repair after surgery.Graphical abstractGraphical abstract for this article
       
  • The degradation and performance of electrospun supramolecular vascular
           scaffolds examined upon in vitro enzymatic exposure
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): E.E. van Haaften, R. Duijvelshoff, B.D. Ippel, S.H.M. Söntjens, M.H.C.J. van Houtem, H.M. Janssen, A.I.P.M. Smits, N.A. Kurniawan, P.Y.W. Dankers, C.V.C. Bouten To maintain functionality during in situ vascular regeneration, the rate of implant degradation should be closely balanced by neo-tissue formation. It is unknown, however, how the implant’s functionality is affected by the degradation of the polymers it is composed of. We therefore examined the macro- and microscopic features as well as the mechanical performance of vascular scaffolds upon in vitro enzymatic degradation. Three candidate biomaterials with supramolecularly interacting bis-urea (BU) hard blocks (‘slow-degrading’ polycarbonate-BU (PC-BU), ‘intermediate-degrading’ polycarbonate-ester-BU (PC(e)-BU), and ‘fast-degrading’ polycaprolactone-ester-BU (PCL-BU)) were synthesized and electrospun into microporous scaffolds. These materials possess a sequence-controlled macromolecular structure, so their susceptibility to degradation is tunable by controlling the nature of the polymer backbone. The scaffolds were incubated in lipase and monitored for changes in physical, chemical, and mechanical properties. Remarkably, comparing PC-BU to PC(e)-BU, we observed that small changes in macromolecular structure led to significant differences in degradation kinetics. All three scaffold types degraded via surface erosion, which was accompanied by fiber swelling for PC-BU scaffolds, and some bulk degradation and a collapsing network for PCL-BU scaffolds. For the PC-BU and PC(e)-BU scaffolds this resulted in retention of mechanical properties, whereas for the PCL-BU scaffolds this resulted in stiffening. Our in vitro study demonstrates that vascular scaffolds, electrospun from sequence-controlled supramolecular materials with varying ester contents, not only display different susceptibilities to degradation, but also degrade via different mechanisms.Statement of SignificanceOne of the key elements to successfully engineer vascular tissues in situ, is to balance the rate of implant degradation and neo-tissue formation. Due to their tunable properties, supramolecular polymers can be customized into attractive biomaterials for vascular tissue engineering. Here, we have exploited this tunability and prepared a set of polymers with different susceptibility to degradation. The polymers, which were electrospun into microporous scaffolds, displayed not only different susceptibilities to degradation, but also obeyed different degradation mechanisms. This study illustrates how the class of supramolecular polymers continues to represent a promising group of materials for tissue engineering approaches.Graphical abstractGraphical abstract for this article
       
  • Construction of vascularized tissue-engineered bone with
           polylysine-modified coral hydroxyapatite and a double cell-sheet complex
           to repair a large radius bone defect in rabbits
    • Abstract: Publication date: June 2019Source: Acta Biomaterialia, Volume 91Author(s): Hualin Zhang, Yueli Zhou, Na Yu, Hairong Ma, Kairong Wang, Jinsong Liu, Wen Zhang, Zhuoyan Cai, Yalan He In this study, the potential of vascularized tissue-engineered bone constructed by a double cell-sheet (DCS) complex and polylysine (PLL)-modified coralline hydroxyapatite (CHA) to repair large radius bone defects was investigated in rabbits. Firstly, the DCS complex was obtained after rabbit adipose-derived mesenchymal stem cell (ADSC) culture was induced. Secondly, PLL-CHA composite scaffolds with different concentrations of PLL were prepared by the soaking and vacuum freeze-drying methods, and then the scaffolds were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, compression performance testing and cytocompatibility evaluation. Thirdly, DCS-PLL-CHA vascularized tissue-engineered bone was constructed in vitro and transplanted into a large radius bone defect model in rabbits. Finally, the potential of the DCS-PLL-CHA vascularized tissue-engineered bone to repair the large bone defect was evaluated through general observations, laser speckle imaging, scanning electron microscopy (SEM), histological staining, radiography observations and RT-PCR. The in vitro experimental results showed that the DCS complex provided a very large cell reserve, which carried a large number of osteoblasts and vascular endothelial cells that were induced in vitro. When the DCS complex was combined with the PLL-CHA scaffold in vitro, the effects of PLL on cell adhesion, proliferation and differentiation led to a situation similar to the chemotaxis of the body, making the combined complex more conducive to graft cellularization than the DCS complex alone. The in vivo experiments showed blood supply on the surface of the callus in each group, and the amount of blood perfusion on the surface of the defect area was almost equal among the groups. At 12 weeks, the surface of the DCS-PLL-CHA group was completely wrapped by bone tissue and osteoids, the cortical bone image was basically continuous, and the medullary cavity was mainly perforated. A large amount of well-arranged lamellar bone was formed, a small amount of undegraded CHA exhibited a linear pattern, and a large amount of bone filling could be seen in the pores. At 12 weeks, the expression levels of BGLAP, SPP1 and VEGF were similar in each group, but PECAM1 expression was higher in the DCS-PLL-CHA group than in the autogenous bone group and CHA group. The results showed that PLL could effectively promote the adhesion, proliferation and differentiation of ADSCs and that DCS-PLL-CHA vascularized tissue-engineered bone has potential for bone regeneration and bone reconstruction and can be used to repair large bone defects.Statement of Significance1. PLL-CHA composite scaffolds with different concentrations of PLL were prepared by the soaking and vacuum freeze-drying methods.2. The vascularized tissue-engineered bone was constructed by the double cell sheet (DCS) complex combined with PLL-CHA scaffolds.3. The DCS-PLL-CHA vascularized tissue-engineered bone has potential for bone regeneration and bone reconstruction and can be used to repair large bone defects.Graphical abstractGraphical abstract for this article
       
  • Thermally triggered injectable chitosan/silk fibroin/bioactive glass
           nanoparticle hydrogels for in-situ bone formation in rat calvarial bone
           defects
    • Abstract: Publication date: June 2019Source: Acta Biomaterialia, Volume 91Author(s): Jingjing Wu, Kai Zheng, Xuetao Huang, Jiaoyan Liu, Haoming Liu, Aldo. R. Boccaccini, Ying Wan, Xiaodong Guo, Zengwu Shao Copper-containing bioactive glass nanoparticles (Cu-BG NPs) with designed compositions and sizes were synthesized and incorporated into chitosan (CH)/silk fibroin (SF)/glycerophosphate (GP) composites to prepare injectable hydrogels for cell-free bone repair. The resulting Cu-BG/CH/SF/GP gels were found to exhibit well-defined injectability and to undergo rapid gelation at physiological temperature and pH. They were highly porous and showed the ability to administer Si, Ca and Cu ions at their respective safe doses in a sustained and controlled manner. In vitro studies revealed that the gels supported the growth of seeded MC3T3-E1 and human umbilical vein endothelial cells, and effectively induced them toward osteogenesis and angiogenesis, respectively. In vivo bone repair based on a critical-size rat calvarial bone defect model demonstrated that the optimal Cu-BG/CH/SF/GP gel was able to fully restore the bone defect with formation of vascularized bone tissue and mineralized collagen deposition during a treatment period of 8 weeks without utilization of any cells and/or growth factors. The results suggest that the presently developed Cu-BG/CH/SF/GP composite hydrogels have great potential and translation ability for bone regeneration owing to their thermo-sensitive properties, cell-free bioactivity, and cost-effectiveness.Statement of SignificanceHydrogels loaded with cells and/or growth factors exhibit potential in bone repair. However, they have been facing obstacles related to the clinic translation. Here, a novel type of hydrogel system consisting of copper-containing bioactive glass nanoparticles and chitosan/silk fibroin composite was developed. These gels showed injectability and thermally triggered in situ gelation properties and were able to administer the release of ions at safe but effective doses in a controlled manner while inducing the seeded cells toward osteogenesis and angiogenesis. The optimal gel showed the ability to fully repair critical-size rat calvarial bone defects without involving time consuming cell processing and/or the use of expensive growth factors, confirming that this novel hydrogel system has great potential for translation to the clinic.Graphical abstractGraphical abstract for this article
       
  • Low-Toxicity Transferrin-Guided Polymersomal Doxorubicin for Potent
           Chemotherapy of Orthotopic Hepatocellular Carcinoma in Vivo
    • Abstract: Publication date: Available online 15 May 2019Source: Acta BiomaterialiaAuthor(s): Yaohua Wei, Xiaolei Gu, Liang Cheng, Fenghua Meng, Gert Storm, Zhiyuan Zhong Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies. The current chemotherapy with typically low tumor uptake and high toxicity reveals a poor anti-HCC efficacy. Here, we report transferrin-guided polycarbonate-based polymersomal doxorubicin (Tf-Ps-Dox) as a low-toxic and potent nanotherapeutic agent for effective treatment of liver tumor using a transferrin receptor (TfR)-positive human liver tumor SMMC-7721 model. Tf-Ps-Dox was facilely fabricated with small size of ca. 75 nm and varying Tf densities from 2.2% to 7.0%, by postmodification of maleimide-functionalized Ps-Dox (Dox loading content of 10.6 wt.%) with thiolated transferrin. MTT assays showed that Tf-Ps-Dox had an optimal Tf surface density of 3.9%. The cellular uptake, intracellular Dox level, and anticancer efficacy of Tf-Ps-Dox to SMMC-7721 cells were inhibited by supplementing free transferrin, which supports that Tf-Ps-Dox is endocytosed through TfR. Interestingly, Tf-Ps-Dox exhibited a high accumulation of 8.5%ID/g (percent injected dose per gram of tissue) in subcutaneous SMMC-7721 tumors, which was 2- and 3-fold higher than that of nontargeted Ps-Dox and clinically used liposomal Dox formulation (Lipo-Dox), respectively. The median survival times of mice bearing orthotopic SMMC-7721 tumors increased from 82, 88 to 96 days when treated with Tf-Ps-Dox at Dox doses from 8, 12 to 16 mg/kg, which was significantly longer than that of Ps-Dox at 8 mg/kg (58 days) and Lipo-Dox at 4 mg/kg (48 days) or PBS (36 days). Notably, unlike Lipo-Dox, no body weight loss and damage to major organs could be discerned for all Tf-Ps-Dox groups, indicating that Tf-Ps-Dox caused low systemic toxicity. This transferrin-dressed polymersomal doxorubicin provides a potent and low-toxic treatment modality for human hepatocellular carcinoma.Statement of SignificanceHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Vast work has focused on developing HCC-targeted nanotherapeutics. However, none of the nanotherapeutics has advanced to clinics, partly because the ligands used have not been validated in patients. Transferrin (Tf) is a natural ligand for transferrin receptor (TfR) that is overexpressed on cancerous cells, and it is currently under clinical trials (MBP-426 and CALAA-01) for the treatment of solid tumors. We designed Tf-functionalized polymersomal doxorubicin (Tf-Ps-Dox) for targeted therapy of orthotopic SMMC-7721 tumor in nude mice. Tf-Ps-Dox showed potent anti-HCC efficacy and significantly improved survival time with low toxicity as compared with nontargeted Ps-Dox and clinical liposomal Dox (Lipo-Dox). Hence, Tf-Ps-Dox is very appealing for targeted treatment of HCC.Graphical abstractGraphical abstract for this article
       
  • Polymer-Integrated Amnion Scaffold Significantly Improves Cleft Palate
           Repair
    • Abstract: Publication date: Available online 15 May 2019Source: Acta BiomaterialiaAuthor(s): Wuwei Li, Yuqian Fu, Bin Jiang, Aaron Y. Lo, Guillermo A. Ameer, Cleon Barnett, Bo Wang Cleft palate is a common oral and craniomaxillofacial birth defect. As the ideal surgery time is shortly after birth, clinical treatments should result in minimal disruption of the skeleton to allow tissue growth in children. A tissue-engineered graft was created in this study for cleft palate repair by integrating poly(1,8-octamethylene-citrate) (POC) with a decellularized amnion membrane (DAM-POC) to incorporate the advantages of both the synthetic polymer and the native tissue. The success of POC incorporation was confirmed by laser-induced breakdown spectroscopy and fluorescence detection. The DAM-POC scaffold showed a certain level of structure collapse and lower stiffness but better resistance to enzyme digestion than the native amnion and DAM scaffold. The DAM-POC scaffold is cell compatible when seeded with mesenchymal stem cells, as evidenced by adequate cell viability and improved alkaline phosphatase (ALP) activity and calcium deposit. A large palate defect was first surgically created in a young rat model and then repaired with the DAM-POC scaffold. Eight weeks postsurgery, histological study and CT scans showed nearly complete healing of both soft and hard tissues. In conclusion, we developed a cell-free, resorbable graft by incorporating and integrating a synthetic polymer with a human DAM. When the DAM-POC scaffold was applied to repair a large palate defect in young rats, it showed adequate biocompatibility as evidenced by its effectiveness in guiding hard and soft tissue regeneration and minimum interference with natural growth and palate development of rats.Statement of SignificanceProper restoration of severe cleft palate remains a major challenge because of insufficient autologous soft tissues to close the open wounds, thereby causing high tension at the surgical junction, secondary palatal fistulas, wound contraction, scar tissue formation, and facial growth disturbances. In this study, we have developed a tissue-engineered graft through incorporating and integrating a synthetic polymer with the human amnion membrane for cleft palate repair. The significance of this study lies in our ability to develop a cell-free, resorbable graft that can provide a less surgically invasive option to cover the open defect and support palate regeneration and tissue growth. This technique could potentially advance soft and hard tissue regeneration in children with birth craniomaxillofacial defects.Graphical abstractGraphical abstract for this article
       
  • Co-administration of combretastatin A4 nanoparticles and sorafenib for
           systemic therapy of hepatocellular carcinoma
    • Abstract: Publication date: Available online 14 May 2019Source: Acta BiomaterialiaAuthor(s): Yalin Wang, Haiyang Yu, Dawei Zhang, Guanyi Wang, Wantong Song, Yingmin Liu, Sheng Ma, Zhaohui Tang, Ziling Liu, Kazuo Sakurai, Xuesi Chen Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg-1 plus sorafenib 30 mg·kg-1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment.Statement of significanceEffective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.Graphical abstractGraphical abstract for this article
       
  • Acta Journals Editors Transitioning to Joint Appointments
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s):
       
  • Stimulus-Responsive Polymeric Nanogels as Smart Drug Delivery Systems
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s): Sakineh Hajebi, Navid Rabiee, Mojtaba Bagherzadeh, Sepideh Ahmadi, Mohammad Rabiee, Hossein Roghani-Mamaqani, Mohammadreza Tahriri, Lobat Tayebi, Michael R. Hamblin Nanogels are three-dimensional nanoscale networks formed by physically or chemically cross-linking polymers. Nanogels have been explored as drug delivery systems due to their advantageous properties, such as biocompatibility, high stability, tunable particle size, drug loading capacity, and possible modification of the surface for active targeting by attaching ligands that recognize cognate receptors on the target cells or tissues. Nanogels can be designed to be stimulus responsive, and react to internal or external stimuli such as pH, temperature, light and redox, thus resulting in the controlled release of loaded drugs. This “smart” targeting ability prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. This review aims to provide an introduction to nanogels, their preparation methods,and to discuss the design of various stimulus-responsive nanogels that are able to provide controlled drug release in response to particular stimuli.Statement of significanceSmart and stimulus-responsive drug delivery is a rapidly growing area of biomaterial research. The explosive rise in nanotechnology and nanomedicine, has provided a host of nanoparticles and nanovehicles which may bewilder the uninitiated reader. This review will lay out the evidence that polymeric nanogels have an important role to play in the design of innovative drug delivery vehicles that respond to internal and external stimuli such as temperature, pH, redox, and light.Graphical abstractGraphical abstract for this article
       
  • Superhydrophobic hierarchical fiber/bead composite membranes for efficient
           burns treatment
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s): Weichang Li, Qianqian Yu, Hang Yao, Yue Zhu, Paul D. Topham, Kan Yue, Li Ren, Linge Wang One of the current challenges in burn wound care is the development of multifunctional dressings that can protect the wound from bacteria or organisms and promote skin regeneration and tissue reconstitution. To this end, we report the design and fabrication of a composite electrospun membrane, comprised of electrospun polylactide : poly(vinyl pyrrolidone)/polylactide : poly(ethylene glycol) (PLA:PVP/PLA:PEG) core/shell fibers loaded with bioactive agents, as a functionally integrated wound dressing for efficient burns treatment. Different mass ratios of PLA:PVP in the shell were screened to optimize mechanical, physicochemical, and biological properties, in addition to controlled release profiles of loaded antimicrobial peptides (AMPs) from the fibers for desirable antibacterial activity. Fibroblasts were shown to readily adhere and proliferate when cultured on the membrane, indicating good in vitro cytocompatibility. The introduction of PLA beads by electrospraying on one side of the membrane resulted in biomimetic micro-nanostructures similar to those of lotus leaves. This designer structure rendered the composite membranes with superhydrophobic property to inhibit the adhesion/spreading of exogenous bacteria and other microbes. The administration of the resulting composite fibrous membrane on burnt skin in an infected rat model led to faster healing than a conventional product (sterile silicone membrane) and control detailed herein. These composite fibrous membranes loaded with bioactive drugs provide an integrated strategy for promoting burn wound healing and skin regeneration.Statement of SignificanceTo address an urgent need in complex clinical requirements on developing a new generation of wound dressings with integrated functionalities. This article reports research work on a hierarchical fiber/bead composite membranes design, which combines a lotus-leaf-like superhydrophobic surface with drugs preloaded in the core and shell of fibers for effective burn treatment. This demonstrates a balance between simplified preparation processes and increased multifunctionality of the wound dressings. The creation of hierarchically structured surfaces can be readily achieved by electrospinning, and the composite dressings possessed a considerable mechanical strength, effective wound exudate absorption and permeability, good biocompatibility, broad antibacterial ability and promoting wound healing etc. Thus, our work unveils a promising strategy for the development of functionally integrated wound dressings for burn wound care.Graphical abstractGraphical abstract for this article
       
  • Graphene oxide containing self-assembling peptide hybrid hydrogels as a
           potential 3D injectable cell delivery platform for intervertebral disc
           repair applications
    • Abstract: Publication date: Available online 12 May 2019Source: Acta BiomaterialiaAuthor(s): Cosimo Ligorio, Mi Zhou, Jacek K. Wychowaniec, Xinyi Zhu, Cian Bartlam, Aline F. Miller, Aravind Vijayaraghavan, Judith A. Hoyland, Alberto Saiani Cell-based therapies have shown significant promise in tissue engineering with one key challenge being the delivery and retention of cells. As a result, significant efforts have been made in the past decade to design injectable biomaterials to host and deliver cells at injury sites. Intervertebral disc (IVD) degeneration, a major cause of back pain, is a particularly relevant example where a minimally-invasive cellular therapy could bring significant benefits specifically at the early stages of the disease, when a cell-driven process starts in the gelatinous core of the IVD, the nucleus pulposus (NP).In this present study we explore the use of graphene oxide (GO) as nano-filler for the reinforcement of FEFKFEFK (β-sheet forming self-assembling peptide) hydrogels. Our results confirm the presence of strong interactions between FEFKFEFK and GO flakes with the peptide coating and forming short thin fibrils on the surface of the flakes. These strong interactions were found to affect the bulk properties of hybrid hydrogels. At pH 4 electrostatic interactions between the peptide fibres and the peptide-coated GO flakes are thought to govern the final bulk properties of the hydrogels while at pH 7, after conditioning with cell culture media, electrostatic interactions are removed leaving the hydrophobic interactions to govern hydrogel final properties. The GO-F820 hybrid hydrogel, with mechanical properties similar to the NP, was shown to promote high cell viability and retained cell metabolic activity in 3D over the 7 days of culture and therefore shown to harbour significant potential as an injectable hydrogel scaffold for the in-vivo delivery of NP cells.Statement of significanceShort self-assembling peptide hydrogels (SAPHs) have attracted significant interest in recent years as they can mimic the natural extra-cellular matrix, holding significant promise for the ab-initio design of cells’ microenvironments. Recently the design of hybrid hydrogels for biomedical applications has been explored through the incorporation of specific nanofillers.In this study we exploited graphene oxide (GO) as nanofiller to design hybrid injectable 3Dscaffolds for the delivery of nucleus pulposus cells (NPCs) for intervertebral disc regeneration. Our work clearly shows the presence of strong interactions between peptide and GO, mimicking the mechanical properties of the NP tissue and promoting high cell viability and metabolic activity. These hybrid hydrogels therefore harbour significant potential as injectable scaffolds for the in-vivo delivery of NPCs.Graphical abstractGraphical abstract for this article
       
  • A Rapid Biofabrication Technique for Self-Assembled Collagen-based
           Multicellular and Heterogeneous 3D Tissue Constructs
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Alireza Shahin-Shamsabadi, P. Ravi Selvaganapathy Although monolayer cell culture models are considered as gold standard for in vitro modeling of pathophysiological events, they cannot reconstruct in vivo like gradient of gases and nutrients and lack proper cell-cell and cell-matrix interactions. Spherical cellular aggregates, otherwise known as multicellular spheroids, are widely used as three-dimensional in vitro models to mimic natural in vivo cellular microenvironment for applications such as drug screening. Although very useful, the previously established techniques are limited to low cell numbers, their processes are usually slow, and sometimes show limitations in terms of the cell type that can be used. Here, a versatile technique based on rapid self-assembly of cells and extracellular matrix material in different shapes using microfabricated molds is introduced to form multicellular tissue constructs. The self-assembly process takes less than 6 hrs and produces a mechanically robust tissue construct that could be handled easily. We demonstrate that a variety of shapes including spherical, cuboidal, dumbbell- and cross-like shapes could be fabricated using this approach. Interestingly, the structures formed with non-spherical shapes were able to retain that shape even after removal from the molds and during long term cell culture. This versatile approach is applicable to a variety of cell types (breast cancer cell lines MCF-7, MDA-MB-321, Hs-578T; osteosarcoma cell line SaOS-2; endothelial cell line HUVEC) as well as a range of cell numbers (104-106). Furthermore, we also show that the constructs could be spatially patterned to position various cell types in a precisely controlled way. Such heterogeneous constructs that are formed provide physiologically relevant cell densities, 3D structure as well as close positioning of multiple types of cells that are not possible using other fabrication approaches. This fabrication approach will find significant applications in developing 3D cell culture models for drug discovery as well as tissue grafts for implantation.Statement of significanceIn this manuscript we describe a method for rapid formation of tissue constructs (6 hrs as opposed to several days for current state of art methods). We also identify the essential factors needed for such a rapid consolidation into a construct. We demonstrate the ability to form non-spherical constructs of various shapes that retain their shape over long term as opposed to those formed with current state of art lose their shape during long time cell culture. We also show the ability to form precise heterogeneous constructs consisting of multiple cell types and with well-defined interfaces that are not possible with current state of art methods. This method could be used with a wide variety of cell types and are mechanically robust within 6 hrs to be handled with tweezers. We believe that such multicellular, heterogeneous constructs would be of significant use to biologists and drug discovery researchers investigating mechanisms involved in diseases processes or the effect of drug on them.Graphical abstractGraphical abstract for this article
       
  • Nonlinear elasticity of the lung extracellular microenvironment is
           regulated by macroscale tissue strain
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Ignasi Jorba, Gabriel Beltrán, Bryan Falcones, Béla Suki, Ramon Farré, José Manuel García-Aznar, Daniel Navajas The extracellular matrix (ECM) of the lung provides physical support and key mechanical signals to pulmonary cells. Although lung ECM is continuously subjected to different stretch levels, detailed mechanics of the ECM at the scale of the cell is poorly understood. Here, we developed a new polydimethylsiloxane (PDMS) chip to probe nonlinear mechanics of tissue samples with atomic force microscopy (AFM). Using this chip, we performed AFM measurements in decellularized rat lung slices at controlled stretch levels. The AFM revealed highly nonlinear ECM elasticity with the microscale stiffness increasing with tissue strain. To correlate micro- and macroscale ECM mechanics, we also assessed macromechanics of decellularized rat lung strips under uniaxial tensile testing. The lung strips exhibited exponential macromechanical behavior but with stiffness values one order of magnitude lower than at the microscale. To interpret the relationship between micro- and macromechanical properties, we carried out a finite element (FE) analysis which revealed that the stiffness of the alveolar cell microenvironment is regulated by the global strain of the lung scaffold. The FE modeling also indicates that the scale dependence of stiffness is mainly due to the porous architecture of the lung parenchyma. We conclude that changes in tissue strain during breathing result in marked changes in the ECM stiffness sensed by alveolar cells providing tissue-specific mechanical signals to the cells.Statement of significanceThe micromechanical properties of the extracellular matrix (ECM) are a major determinant of cell behavior. The ECM is exposed to mechanical stretching in the lung and other organs during physiological function. Therefore, a thorough knowledge of the nonlinear micromechanical properties of the ECM at the length scale that cells probe is required to advance our understanding of cell-matrix interplay. We designed a novel PDMS chip to perform atomic force microscopy measurements of ECM micromechanics on decellularized rat lung slices at different macroscopic strain levels. For the first time, our results reveal that the microscale stiffness of lung ECM markedly increases with macroscopic tissue strain. Therefore, changes in tissue strain during breathing result in variations in ECM stiffness providing tissue-specific mechanical signals to lung cells.Graphical abstractGraphical abstract for this article
       
  • Osteogenic and pH Stimuli-responsive Self-healing Coating on Biomedical
           Mg-1Ca Alloy
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Pan Xiong, Zhaojun Jia, Wenhao Zhou, Jianglong Yan, Pei Wang, Wei Yuan, Yangyang Li, Yan Cheng, Zhenpeng Guan, Yufeng Zheng Various coatings have been used to slow down the corrosion rate of biomedical magnesium alloys. However, these coatings usually act only as passive barriers. It is much more desirable to endow such coatings with active, biocorrosion-responsive self-repairing capacity. In the present work, a self-healing coating system (denoted as “silk-PA”) was constructed in the form of a sandwich architecture of fluoride precoating (bottom), silk-phytic acid (PA) coating (middle), and silk fibroin coating (top). Here, PA was loaded in the middle coating as a corrosion inhibitor by harnessing its strong chelating ability toward dissolving Mg2+ and Ca2+ ions. The self-healing property was evaluated by scratch and SVET tests, and the corrosion resistance was evaluated by in vitro immersion and electrochemical measurements. The results showed that the silk-PA manifested intriguing self-healing capacity with pH responsiveness, hence profiting the corrosion resistance of the Mg-1Ca alloy. The biocompatibility and osteogenic activity of the coating system were further evaluated using MC3T3-E1 cells, and it demonstrated favorable responses in multiple cellular behaviors, i.e., adherence, spreading, proliferation, and differentiation. These findings open new opportunities in the study of self-healing coatings for protection against corrosion in biomedical Mg alloys.Statement of significanceIn the present study, a self-healing coating system with pH stimuli-responsiveness as well as osteogenic activity was fabricated on Mg-1Ca alloy by integrating a silk fibroin barrier coating, a silk fibrin/phytic acid composite coating, and a fluoride pre-coating. This coating system demonstrated interesting self-healing ability in comparison to traditional surface modification layers. Furthermore, self-healing ability enhanced corrosion resistance of biomedical magnesium alloys, while effective compositions of the coating system endowed the substrate with osteogenic activity. This work gives some new insights into smart surface modification for biomedical Mg alloys.Graphical abstractGraphical abstract for this article
       
  • Synchrotron tomography of intervertebral disc deformation quantified by
           digital volume correlation reveals microstructural influence on strain
           patterns
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): C.M. Disney, A. Eckersley, J.C. McConnell, H. Geng, A.J. Bodey, J.A Hoyland, P.D. Lee, M.J. Sherratt, B.K. Bay The intervertebral disc (IVD) has a complex and multiscale extracellular matrix structure which provides unique mechanical properties to withstand physiological loading. Low back pain has been linked to degeneration of the disc but reparative treatments are not currently available. Characterising the disc’s 3D microstructure and its response in a physiologically relevant loading environment is required to improve understanding of degeneration and to develop new reparative treatments. In this study, techniques for imaging the native IVD, measuring internal deformation and mapping volumetric strain were applied to an in situ compressed ex vivo rat lumbar spine segment. Synchrotron X-ray micro-tomography (synchrotron CT) was used to resolve IVD structures at microscale resolution. These image data enabled 3D quantification of collagen bundle orientation and measurement of local displacement in the annulus fibrosus between sequential scans using digital volume correlation (DVC). The volumetric strain mapped from synchrotron CT provided a detailed insight into the micromechanics of native IVD tissue. The DVC findings showed that there was no slipping at lamella boundaries, and local strain patterns were of a similar distribution to the previously reported elastic network with some heterogeneous areas and maximum strain direction aligned with bundle orientation, suggesting bundle stretching and sliding. This method has the potential to bridge the gap between measures of macro-mechanical properties and the local 3D micro-mechanical environment experienced by cells. This is the first evaluation of strain at the micro scale level in the intact IVD and provides a quantitative framework for future IVD degeneration mechanics studies and testing of tissue engineered IVD replacements.Statement of SignificanceSynchrotron in-line phase contrast X-ray tomography provided the first visualisation of native intact intervertebral disc microstructural deformation in 3D. For two annulus fibrosus volumes of interest, collagen bundle orientation was quantified and local displacement mapped as strain. Direct evidence of microstructural influence on strain patterns could be seen such as no slipping at lamellae boundaries and maximum strain direction aligned with collagen bundle orientation. Although disc elastic structures were not directly observed, the strain patterns had a similar distribution to the previously reported elastic network. This study presents technical advances and is a basis for future X-ray microscopy, structural quantification and digital volume correlation strain analysis of soft tissue.Graphical abstractGraphical abstract for this article
       
  • Zwitterionic poly-carboxybetaine coating reduces artificial lung
           thrombosis in sheep and rabbits
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Rei Ukita, Kan Wu, Xiaojie Lin, Neil M. Carleton, Noritsugu Naito, Angela Lai, Chi Chi Do-Nguyen, Caitlin T. Demarest, Shaoyi Jiang, Keith E. Cook Current artificial lungs fail in 1-4 weeks due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymerization (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymerized with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N=5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-hours. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-hour rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300s (N≥5). Here, DOPA-pCB reduced fibrin formation (p=0.06) and gross thrombus formation by 59% (p
       
  • Biological Properties of ZnO, SiO2, and Ag2O Ternary Dopant Plasma Sprayed
           Hydroxyapatite Coating for Orthopaedic and Dental Applications
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Ashley A. Vu, Samuel Ford Robertson, Dongxu Ke, Amit Bandyopadhyay, Susmita Bose In this study, we explored a ternary dopant system utilizing 0.25 wt.% ZnO to induce osteogenesis, 0.50 wt.% SiO2 to induce angiogenesis, and 2.0 wt.% Ag2O to provide secondary infection control within a plasma assisted hydroxyapatite coating for orthopaedic or dental applications. The objective of this study was to understand the effects of ZnO, SiO2, and Ag2O dopants on the mechanical and biological properties of hydroxyapatite (HA) coatings on titanium (Ti). Coatings were deposited using a 30 kW plasma spray system equipped with a supersonic nozzle to produce above standard coating bond strengths of 24 ± 2 MPa on Ti6Al4V and 22 ± 1 MPa on commercially pure Ti substrates. Antibacterial properties were revealed in vitro against E. coli and S. aureus. The ternary dopant system was implanted in 18 male Sprague-Dawley rats with timepoints of 5 and 10 weeks. By week 5, ZnSiAg-HA produced 32% bone mineralization of 68% total bone formation compared to only 11% bone mineralization of 55% total bone formation in the undoped coating. This system can be employed for younger patient replacement surgeries and revision surgeries to lower healing time and enhance osseointegration.Statement of significanceTotal hip replacements increased 124% from 2000 to 2010 with an ever-increasing rate due to the rise in average life span and an escalation in surgeries for younger age patients. With all replacement surgeries comes the risk of rejection, poor integration, and infection. This study incorporates biologically relevant metallic oxides of ZnO, SiO2, and Ag2O within a hydroxyapatite coating on titanium deposited using a radio frequency induction plasma spray. A ternary dopant system has not been explored in the current literature and little is known about these particular dopants in vivo meaning ‘within a living organism.’ This proposed system can be employed for younger patient replacement surgeries to lower healing time and enhance osseointegration between implant and host tissue.Graphical abstractGraphical abstract for this article
       
  • Starvation-amplified CO generation for enhanced cancer therapy through
           erythrocyte membrane-biomimetic gas nanofactory
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Yuqian Wang, Zhangya Liu, Hao Wang, Zhengjie Meng, Yonglu Wang, Wenjun Miao, Xueming Li, Hao Ren Carbon monoxide (CO)-based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. However, the main challenges are the in situ-triggered and efficient delivery of CO in tumors, which limit its further clinical application. Herein, we developed an erythrocyte membrane-biomimetic gas nanofactory (MGP@RBC) to amplify the in situ generation of CO for combined energy starvation of cancer cells and gas therapy. This nanofactory was constructed by encapsulating glucose oxidase (GOx) and Mn2(CO)10 (CO-donor) into the biocompatible polymer poly(lactic-co-glycolic acid), obtaining MGP nanoparticles, which are further covered by red blood cell (RBC) membrane. Because of the presence of proteins on RBC membranes, the nanoparticles could effectively avoid immune clearance in macrophages (Raw264.7) and significantly prolong their blood circulation time, thereby achieving higher accumulation at the tumor site. After that, the GOx in GMP@RBC could effectively catalyze the conversion of endogenous glucose to hydrogen peroxide (H2O2) in the presence of oxygen. The concomitant generation of H2O2 could efficiently trigger CO release to cause dysfunction of mitochondria and activate caspase, thereby resulting in apoptosis of the cancer cells. In addition, the depletion of intratumoral glucose could starve tumor cells by shutting down the energy supply. Altogether, the in vitro and in vivo studies of our synthesized biomimetic gas nanofactory exhibited an augmentative synergistic efficacy of CO gas therapy and energy starvation to inhibit tumor growth. It provides an attractive strategy to amplify CO generation for enhanced cancer therapy in an accurate and more efficient manner.Statement of significationCarbon monoxide (CO) based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. In this study, we developed an erythrocyte membranebiomimetic gas nanofactory to amplify the in-situ generation of CO for combined cancer starvation and gas therapy. It is constructed by coating glucose oxidase (GOx) and CO donor-loaded nanoparticles with erythrocyte membrane. Due to the erythrocyte membrane, it can effectively prolong blood circulation time and achieve higher tumor accumulation. After accumulated in tumor, endogenous glucose can be effectively catalyzed to hydrogen peroxide, in-situ ampfied CO release to induce the apoptosis of cancer cells. In addition, depleting glucose can also starve tumor cells by shutting down the energy supply. Overall, our biomimetic gas nanofactory exhibits an augmentative synergistic efficacy of CO gas therapy and starvation to increased tumor inhibition. It provide a novel strategy to deliver CO in an accurate and more efficient manner, promising for combined cancer therapy in future clinical application.Graphical abstractGraphical abstract for this article
       
  • Substrate Stiffness- and Topography-dependent Differentiation of Annulus
           Fibrosus-derived Stem Cells Is Regulated by Yes-associated Protein (YAP)
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Genglei Chu, Zhangqin Yuan, Caihong Zhu, Pinghui Zhou, Huan Wang, Weidong Zhang, Yan Cai, Xuesong Zhu, Huilin Yang, Bin Li Annulus fibrosus (AF) tissue engineering has attracted increasing attention as a promising therapy for degenerative disc disease (DDD). However, regeneration of AF still faces many challenges due to the tremendous complexity of this tissue and lack of in-depth understanding of the structure-function relationship at cellular level within AF is highly required. In light of the fact that AF is composed of various types of cells and has gradient mechanical, topographical and biochemical features along the radial direction. In this study, we aimed to achieve directed differentiation of AF-derived stem cells (AFSCs) by mimicking the mechanical and topographical features of native AF tissue. AFSCs were cultured on four types of electrospun poly(ether carbonate urethane) urea (PECUU) scaffolds with various stiffness and fiber size (soft, small size; stiff, small size; soft, large size and stiff, large size). The results show that with constant fiber size, the expression level of the outer AF (oAF) phenotypic marker genes in AFSCs increased with the scaffold stiffness, while that of inner AF (iAF) phenotypic marker genes showed an opposite trend. When scaffold stiffness was fixed, the expression of oAF phenotypic marker genes in AFSCs increased with fiber size. While the expression of iAF phenotypic marker genes decreased. Such substrate stiffness- and topography- dependent changes of AFSCs was in accordance with the genetic and biochemical distribution of AF tissue from the inner to outer regions. Further, we found that the Yes-associated protein (YAP) was translocated to the nucleus in AFSCs cultured with increasing stiffness and fiber size of scaffolds, yet it remained mostly phosphorylated and cytosolic in cells on soft scaffolds with small fiber size. Inhibition of YAP down-regulated the expression of tendon/ligament-related genes, whereas expression of the cartilage-related genes was upregulated. The results illustrate that matrix stiffness is a potent regulator of AFSC differentiation. Moreover, we reveal that fiber size of scaffolds induced changes in cell adhesions and determined cell shape, spreading area, and extracellular matrix expression. In all, both mechanical property and topography features of scaffolds regulate AFSC differentiation, possibly through a YAP-dependent mechanotransduction mechanism.Graphical abstractMechanistic hypothesis linking the mechanical and topographical variation to AFSC differentiation via YAP activation. YAP mediates cell differentiation in concern with FAs assembly through integrin to maintain the integrity of actin fiber cytoskeleton. This triggers YAP nuclear shuttling. In the nucleus, YAP helps transcribe the tendon/ligament-related genes encoding for proteins participating in AFSC differentiation.Graphical abstract for this article
       
  • Photodynamic PEG-Coated ROS-Sensitive Prodrug Nanoassemblies for
           Core-Shell Synergistic Chemo-Photodynamic Therapy
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Bingjun Sun, Yao Chen, Han Yu, Chen Wang, Xuanbo Zhang, Hanqing Zhao, Qin Chen, Zhonggui He, Cong Luo, Jin Sun The combination of chemotherapy with photodynamic therapy (PDT) holds promising applications in cancer therapy. However, co-encapsulation of chemotherapeutic agents and photosensitizers (PS) into the conventional nanocarriers suffers from inefficient co-loading and aggregation-caused quenching (ACQ) effect of PS trapped in dense carrier materials. Herein, we report a light-activatable photodynamic PEG-coated prodrug nanoplatform for core-shell synergistic chemo-photodynamic therapy. A novel photodynamic polymer is rationally designed and synthesized by conjugating pyropheophorbide a (PPa) to polyethylene glycol 2000 (PEG2k). PPa is used as the hydrophobic and photodynamic moiety of the amphipathic PPa-PEG2k polymer. Then, a core-shell nanoassembly is prepared, with an inner core of a reactive oxygen species (ROS)-responsive oleate prodrug of paclitaxel (PTX) and an outer layer of PPa-PEG2k. PPa-PEG2k serves for both PEGylation and PDT. Instead of being trapped in the inner core, PPa in the outer PPa-PEG2k layer significantly alleviates the ACQ effect. Under laser irradiation, ROS generated by PPa-PEG2k not only is used for PDT but also synergistically promotes PTX release in combination with the endogenous ROS overproduced in tumor cells. The photodynamic PEG-coated nanoassemblies demonstrated synergistic antitumor activity in vivo. Such a unique nanoplatform, with an inner chemotherapeutic core and an outer photodynamic PEG shell, provides a new strategy for synergistic chemo-photodynamic therapy.Statement of significationThe combination of chemotherapy with photodynamic therapy (PDT) holds promising prospects in cancer therapy. However, it remains a tremendous challenge to effectively co-deliver chemotherapeutic drugs and photosensitizers into tumors. Herein, we construct a photodynamic PEGylation-coated prodrug-nanoplatform for high-efficiency synergistic cancer therapy, which is composed of a light-activatable PPa-PEG2k shell and a ROS-responsive paclitaxel (PTX) prodrug core. The PPa-PEG2k-generated ROS not only was used for synergistic PTX release but also synergistically facilitated tumor cell apoptosis in combination with PTX-initiated chemo-cytotoxicity. The light-activatable nanoassemblies exhibited multiple drug delivery advantages including high co-loading efficiency, self-enhanced PTX release, extended circulation time, favorable biodistribution, and potent synergistic anticancer activity. Our findings provide a new strategy for the rational design of advanced nano-DDS for high-efficiency combinational chemo-photodynamic therapy.Graphical abstractGraphical abstract for this article
       
  • Investigating the passive mechanical behaviour of skeletal muscle fibres:
           Micromechanical experiments and Bayesian hierarchical modelling
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Markus Böl, Rahul Iyer, Johannes Dittmann, Mayra Garcés-Schröder, Andreas Dietzel Characterisation of the skeletal muscle’s passive properties is a challenging task since its structure is dominated by a highly complex and hierarchical arrangement of fibrous components at different scales. The present work focuses on the micromechanical characterisation of skeletal muscle fibres, which consist of myofibrils, by realising three different deformation states, namely, axial tension, axial compression, and transversal compression. To the best of the authors’ knowledge, the present study provides a novel comprehensive data set representing of different deformation states. These data allow for a better understanding of muscle fibre load transfer mechanisms and can be used for meaningful modelling approaches. As the present study shows, axial tension and compression experiments reveal a strong tension-compression asymmetry at fibre level. In comparison to the tissue level, this asymmetric behaviour is more pronounced at the fibre scale, elucidating the load transfer mechanism in muscle tissue and aiding in the development of future modelling strategies. Further, a Bayesian hierarchical modelling approach was used to consider the experimental fluctuations in a parameter identification scheme, leading to more comprehensive parameter distributions that reflect the entire observed experimental uncertainty.Statement of significanceThis article examines for the first time the mechanical properties of skeletal muscle fibres under axial tension, axial compression, and transversal compression, leading to a highly comprehensive data set. Moreover, a Bayesian hierarchical modelling concept is presented to identify model parameters in a broad way. The results of the deformation states allow a new and comprehensive understanding of muscle fibres’ load transfer mechanisms; one example is the effect of tension-compression asymmetry. On the one hand, the results of this study contribute to the understanding of muscle mechanics and thus to the muscle’s functional understanding during daily activity. On the other hand, they are relevant in the fields of skeletal muscle multiscale, constitutive modelling.Graphical abstractGraphical abstract for this article
       
  • Transplantation of human meningioma stem cells loaded on a self-assembling
           peptide nanoscaffold containing IKVAV improves traumatic brain injury in
           rats
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Sajad Sahab Negah, Pardis Oliazadeh, Ali Jahanbazi Jahan-Abad, Arezou Eshaghabadi, Fariborz Samini, Sepideh Ghasemi, Amir Asghari, Ali Gorji Traumatic brain injury (TBI) can result in permanent brain function impairment due to the poor regenerative ability of neural tissue. Tissue engineering has appeared as a promising approach to promote nerve regeneration and to ameliorate brain damage. The present study was designed to investigate the effect of transplantation of the human meningioma stem-like cells (hMgSCs) seeded in a promising three-dimensional scaffold (RADA4GGSIKVAV; R-GSIK) on the functional recovery of the brain and neuroinflammatory responses following TBI in rats. After induction of TBI, hMgSCs seeded in R-GSIK was transplanted within the injury site and its effect was compared to several control groups. Application of hMgSCs with R-GSIK improved functional recovery after TBI. A significant higher number of hMgSCs was observed in the brain when transplanted with R-GSIK scaffold compared to the control groups. Application of hMgSCs seeded in R-GSIK significantly decreased the lesion volume, reactive gliosis, and apoptosis at the injury site. Furthermore, treatment with hMgSCs seeded in R-GSIK significantly inhibited the expression of Toll-like receptor 4 and its downstream signaling molecules, including interleukin-1β and tumor necrosis factor. These data revealed the potential for hMgSCs seeded in R-GSIK to improve the functional recovery of the brain after TBI; possibly via amelioration of inflammatory responses.Statement of significanceTissue engineered scaffolds that mimic the natural extracellular matrix of the brain may modulate stem cell fate and contribute to tissue repair following traumatic brain injury (TBI). Among several scaffolds, self-assembly peptide nanofiber scaffolds markedly promotes cellular behaviors, including cell survival and differentiation. We developed a novel three-dimensional scaffold (RADA16GGSIKVAV; R-GSIK). Transplantation of the human meningioma stem-like cells seeded in R-GSIK in an animal model of TBI significantly improved brain functional recovery, possibly via enhancement of stem cell survival as well as reduction of the lesion volume, inflammatory process, and reactive gliosis at the injury site. R-GSIK is a suitable microenvironment for human stem cells and could be a potential biomaterial for the reconstruction of the injured brain after TBI.Graphical abstractGraphical abstract for this article
       
  • Mechanical behavior of ctenoid scales: joint-like structures control the
           deformability of the scales in the flatfish Solea solea
           (Pleuronectiformes)
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Marlene Spinner, Clemens F. Schaber, Shao-Min Chen, Marco Geiger, Stanislav N. Gorb, Hamed Rajabi Ctenoid scales protect the fish body against predators and other environmental impacts. At the same time, they allow for sufficient degree of flexibility to perform species-specific locomotion. The scales of the flatfish Solea solea were chosen to elucidate the specific mechanical behavior and material properties of the ctenoid scales. Using scanning electron microscopy and micro-computed tomography, the three-dimensional asymmetric structures of the stacked mineralized ctenial spines in the posterior field, which is a part of the scales exposed to the environment, were examined in detail. Nanoindentations on the surface of the ctenial spines indicated that the elastic modulus and hardness of these mineralized structures are about 14 GPa and 0.4 GPa, respectively. The spines appeared to be connected to each other by means of joint-like structures containing soft tissues. Bending tests demonstrated that the ctenoid scales have two functional zones: a stiff supporting main body and an anisotropically deformable posterior field. While the stiff plate-like main body provides support for the whole scale, the deformable joint-like structures in the ctenial spines increase the deformability of the posterior field in downward bending. During upward bending, however, the spines prevent complete folding of the posterior field by an interlocking effect.Statement of significanceIn contrast to the continuously mineralized cycloid scales, ctenoid scales combine two conflicting properties: They are hard to protect the body of fish against predators and other environmental impacts, yet flexible enough to allow for sufficient degree of body bendability for locomotion. To understand the structural background underlying this specific biomechanical feature, here we investigated the scales of the flatfish Solea solea. For the first time, we demonstrated the presence of joint-like structures within the scales, which increase scale deformability during downward bending, but prevent scale deformation during upward bending by interlocking. Our results shed lights on the material-structure-function relationships in ctenoid scales, as well as on their functional adaptations to the specific environment.Graphical abstractGraphical abstract for this article
       
  • The Construction of Retinal Pigment Epithelium (RPE) Sheets with Enhanced
           RPE Characteristics and Cilium Assembly Using iPS Conditioned Medium and
           Small Incision Lenticule Extraction Derived Lenticules
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Jianing Gu, Yini Wang, Zekai Cui, Hong Li, Shenyang Li, Xu Yang, Xin Yan, Chengcheng Ding, Shibo Tang, Jiansu Chen In vitro generation of a functional retinal pigment epithelium (RPE) monolayer sheet is useful and promising for RPE cell therapy. Here, for the first time, we used induced pluripotent stem (iPS) supernatant as the conditioned medium (iPS-CM) and femtosecond laser intrastromal lenticule (FLI-lenticule) as a scaffold to construct an engineered RPE sheet. There are significant enhancements in RPE cell density, transepithelial electrical resistance (TER) and inhibitions of ultraviolet C (UVC)-irradiated apoptosis when RPE cells are cultured in iPS supernatant/Dulbecco’s modified Eagle’s medium (DMEM)-F12 of 1/2 (iPS-CM) compared with those in normal medium (NM, DMEM-F12). Using the assay of a panel of cytokines, combined with transcriptome and protein analyses, we discover that iPS-CM contains high levels of platelet-derived growth factor AA (PDGF-AA), insulin-like growth factor binding protein (IGFBP)-2, transforming growth factor (TGF)-α and IGFBP-6, which are responsible for the upregulation of gene and protein markers with RPE phenotypes and downregulation of gene and protein markers with epithelial-mesenchymal transition (EMT) phenotypes for RPE cells in iPS-CM when compared to those in NM. Moreover, compared to cultures on tissue culture plates (TCP), RPE cells on FLI-lenticule display more microvilli and cilium in accordance with the results in terms of RNA-Seq data, quantitative polymerase chain reaction (qPCR) expression, immunofluorescence staining, and western blot assays. Furthermore, acellular FLI-lenticule exhibits biocompatibility after rabbit subretinal implantation by 30 days through electroretinography and histological examination. Thus, we determined that engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffold aid in enhanced RPE characteristics and cilium assembly. Such a strategy to construct RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools.Statement of SignificanceIn vitro generation of a functional RPE monolayer sheet is useful and promising for RPE cell therapy. Here, we constructed engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffolds to help in enhanced RPE characteristics and cilium assembly. Such a strategy to generate RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools.Graphical abstractGraphical abstract for this article
       
  • Engineered Heart Tissue Models from hiPSC-Derived Cardiomyocytes and
           Cardiac ECM for Disease Modeling and Drug Testing Applications
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Idit Goldfracht, Yael Efraim, Rami Shinnawi, Ekaterina Kovalev, Irit Huber, Amira Gepstein, Gil Arbel, Naim Shaheen, Malte Tiburcy, Wolfram H. Zimmerman, Marcelle Machluf, Lior Gepstein Cardiac tissue engineering provides unique opportunities for cardiovascular disease modeling, drug testing, and regenerative medicine applications. To recapitulate human heart tissue, we combined human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a chitosan-enhanced extracellular-matrix (ECM) hydrogel, derived from decellularized pig hearts. Ultrastructural characterization of the ECM-derived engineered heart tissues (ECM-EHTs) revealed an anisotropic muscle structure, with embedded cardiomyocytes showing more mature properties than 2D-cultured hiPSC-CMs. Force measurements confirmed typical force-length relationships, sensitivity to extracellular calcium, and adequate ionotropic responses to contractility modulators. By combining genetically-encoded calcium and voltage indicators with laser-confocal microscopy and optical mapping, the electrophysiological and calcium-handling properties of the ECM-EHTs could be studied at the cellular and tissue resolutions. This allowed to detect drug-induced changes in contraction rate (isoproterenol, carbamylcholine), optical signal morphology (E-4031, ATX2, isoproterenol, ouabin and quinidine), cellular arrhythmogenicity (E-4031 and ouabin) and alterations in tissue conduction properties (lidocaine, carbenoxolone and quinidine). Similar assays in ECM-EHTs derived from patient-specific hiPSC-CMs recapitulated the abnormal phenotype of the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Finally, programmed electrical stimulation and drug-induced pro-arrhythmia led to the development of reentrant arrhythmias in the ECM-EHTs.In conclusion, a novel ECM-EHT model was established, which can be subjected to high-resolution long-term serial functional phenotyping, with important implications for cardiac disease modeling, drug testing and precision medicine.Statement of SignificanceOne of the main objectives of cardiac tissue engineering is to create an in-vitro muscle tissue surrogate of human heart tissue. To this end, we combined a chitosan-enforced cardiac-specific ECM hydrogel derived from decellularized pig hearts with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from healthy-controls and patients with inherited cardiac disorders. We then utilized genetically-encoded calcium and voltage fluorescent indicators coupled with unique optical imaging techniques and force-measurements to study the functional properties of the generated engineered heart tissues (EHTs). These studies demonstrate the unique potential of the new model for physiological/pathophysiological studies (assessing contractility, conduction and reentrant arrhythmias), novel disease modeling strategies (“disease-in-a-dish” approach for studying inherited arrhythmogenic disorders), and for drug testing applications (safety pharmacology).Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Bone tissue engineering strategy based on the
           synergistic effects of silicon and strontium ions” [Acta Biomater. 72
           (2018) 381–395]
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Min Xing, Xiaoya Wang, Endian Wang, Long Gao, Jiang Chang
       
  • Influence of hydrogel network microstructures on mesenchymal stem cell
           chondrogenesis in vitro and in vivo
    • Abstract: Publication date: Available online 2 May 2019Source: Acta BiomaterialiaAuthor(s): Jirong Yang, Yuanqi Li, Yanbo Liu, Dongxiao Li, Lei Zhang, Qiguang Wang, Yumei Xiao, Xingdong Zhang Hydrogels, which provide three-dimensional (3D) niches for encapsulating bone marrow mesenchymal stem cells (BMSCs), are becoming a promising tissue engineering solution for chondrogenic differentiation of BMSCs. However, it remains a challenge to design a hydrogel material for effective chondrogenesis of BMSCs because of the complexity of cartilage ECM and cell–matrix interactions. Thus far, various studies have shown the physical–chemical cues of hydrogel materials to impact BMSCs chondrogenesis, but the design of the 3D network microstructure of the hydrogel to induce BMSCs chondrogenesis is still far from optimized. In this study, we successfully prepared two types of collagen hydrogels, namely, the fibrous network and porous network, with the same chemical composition and similar mechanical strength but with two distinct network microstructures. The two different network microstructures significantly influenced mass transfer, protein adsorption, degradability, and contraction of the collagen hydrogels. Moreover, the cells presented distinct proliferation and morphology in the two hydrogels, which consequently modulated chondrogenic differentiation of BMSCs derived from rat. Collagen hydrogels with a fibrous network promoted more chondrogenic differentiation of BMSCs without additional growth factors in vitro and subcutaneous implantation in vivo than those with a porous network. Moreover, fibrous network resulted in less ECM calcification than porous network. However, the fibrous network could not prevent hypertrophy of the chondrogenic cells induced by BMSCs. Overall, these results revealed that the 3D network microstructure of a hydrogel was a key design parameter for the chondrogenic differentiation of BMSCs.Statement of significanceHydrogels had been used to induce the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in cartilage tissue engineering, but the key design parameters remain unoptimized. This was mainly due to the different material properties including composition, strength, and microstructure, which would interplay with each other and result in difficulties to investigate the effects for one factor. In this study, we fabricated two collagen hydrogels with the same chemical composition and mechanical strength, but two distinct network microstructures. The effects of the two network microstructures on the chondrogenic differentiation of BMSCs were investigated by in vitro and in vivo assays. The results highlight the effects of network microstructures and provide important information about optimizing the design of future hydrogels in cartilage tissue engineering.Graphical abstractGraphical abstract for this article
       
  • Quantitative Ultrasound Imaging of Cell-laden Hydrogels and Printed
           Constructs
    • Abstract: Publication date: Available online 2 May 2019Source: Acta BiomaterialiaAuthor(s): Andres Ruland, Kerry J. Gilmore, Luciana Y. Daikuara, Cormac D. Fay, Zhilian Yue, Gordon G. Wallace In the present work we have revisited the application of quantitative ultrasound imaging (QUI) to cellular hydrogels, by using the reference phantom method (RPM) in combination with a local attenuation compensation algorithm. The investigated biological samples consisted of cell-laden collagen hydrogels with PC12 neural cells. These cell-laden hydrogels were used to calibrate the integrated backscattering coefficient (IBC) as a function of cell density, which was then used to generate parametric images of local cell density. The image resolution used for QUI and its impact on the relative IBC error was also investigated. Another important contribution of our work was the monitoring of PC12 cell proliferation. The cell number estimates obtained via the calibrated IBC compared well with data obtained using a conventional quantitative method, the MTS assay. Evaluation of spectral changes as a function of culture time also provided additional information on the cell cluster size, which was found to be in close agreement with that observed by microscopy. Last but not least, we also applied QUI on a 3D printed cellular construct in order to illustrate its capabilities for the evaluation of bioprinted structures.Statement of significanceWhile there is intensive research in the areas of polymer science, biology, and 3D bio-printing, there exists a gap in available characterisation tools for the non-destructive inspection of biological constructs in the three-dimensional domain, on the macroscopic scale, and with fast data acquisition times. Quantitative ultrasound imaging is a suitable characterization technique for providing essential information on the development of tissue engineered constructs. These results provide a detailed and comprehensive guide on the capabilities and limitations of the technique.Graphical abstractGraphical abstract for this article
       
  • Effect of copper substitution on the local chemical structure and
           dissolution property of copper-doped β-tricalcium phosphate
    • Abstract: Publication date: Available online 26 April 2019Source: Acta BiomaterialiaAuthor(s): Toshiisa Konishi, Yasuyuki Nagano, Marina Maegawa, Poon Nian Lim, Eng San Thian Substitution of inorganic ions into β-tricalcium phosphate (β-TCP) is a well-known approach for facilitating biological functions of bioceramics. However, the dissolution mechanism of those β-TCPs is still under intensive debates. In the present study, the effect of copper substitution into β-TCP crystal structure on the local chemical structure and dissolution property of the copper-doped β-TCP (CuTCP) was investigated to clarify the dissolution mechanism of β-TCP. A copper-dependent decrease in the dissolution rate of CuTCP with time was observed. The 1H → 31P nuclear magnetic resonance (NMR) spectra of 10 mol% copper-doped β-TCP after the dissolution test demonstrated an amorphous hydrated layer on the surface of β-TCP core particles, which contained hydroxyapatite and dicalcium phosphate dihydrate and anhydrate. As such, all the dissolution curves could be curve-fitted by a heterogeneous dissolution model composing of fast and slow dissolution components. Overall, dissolution mechanism could be proposed as follows: the CuTCP particles initially dissolved by hydrolysis based on the fast dissolution component. Subsequently, the amorphous hydrated layers were formed on their surface, and caused the diffusion-controlled dissolution. As the result, the slow dissolution component would be dominant, and led to the decreased dissolution rate.Statement of SignificanceUnderstanding the dissolution mechanism of copper doped β-tricalcium phosphate (CuTCP) is crucial for designing an angiogenetic controlled copper release CuTCP for therapeutic biomaterials. However, dissolution mechanism of β-TCP or CuTCP is still under intensive debates. This study demonstrated for the first time, that amorphous hydrated layers were formed on the CuTCP particle surface during its dissolution process, which caused a diffusion-controlled dissolution, and decreased the dissolution rate of CuTCP. This work not only provided a novel dissolution mechanism of β-TCP or CuTCP, but also a new finding for designing an angiogenetic controlled copper release CuTCP for therapeutic biomaterials.Graphical abstractGraphical abstract for this article
       
  • Trade-off between fracture resistance and translucency of zirconia and
           lithium-disilicate glass ceramics for monolithic restorations
    • Abstract: Publication date: Available online 26 April 2019Source: Acta BiomaterialiaAuthor(s): Fei Zhang, Helen Reveron, Benedikt C. Spies, Bart Van Meerbeek, Jérôme Chevalier High strength and translucency are generally not coincident in one restorative material and there is still a continuous development for a better balance between these two properties. Zirconia and lithium-disilicate glass-ceramics are currently the most popular alternatives for monolithic restorations. In this work, the mechanical properties and more important, the slow crack growth (SCG) resistance, which rules long-term durability, were thoroughly studied for three zirconia ceramics stabilized by 3, 4 and 5 mol% yttria in comparison to lithium-disilicate glass-ceramic. Translucency versus strength maps revealed that the more translucent zirconia compositions (i.e. with higher yttria contents) fill the gap between the standard 3 mol% yttria stabilized zirconia (3Y-TZP) and lithium-disilicate. Moreover, increasing yttria content did not always result in lower strength, as values for 3 mol% and 4 mol% yttria were the same. Independent on the yttria contents, all zirconia showed similar relative susceptibility to SCG under static and cyclic conditions and were significantly more SCG-resistant than lithium-disilicate glass ceramic. A concern with higher yttria contents (5 and 4 mol%) however could lie in the higher sensitivity to defects, resulting in a larger scatter in strength.Statement of SignificanceIn addition to the common investigations on the generally reported strength, toughness and translucency, V-KI diagrams (crack velocity versus stress-intensity factor) from fast fracture to threshold for three newly developed zirconia were directly measured by double torsion methods under static and cyclic loading conditions. The crack-growth mechanisms were analyzed in depth. Results were compared with another popular dental ceramic, namely lithium-disilicate glass-ceramic, revealing the pros and cons of polycrystalline and glass-ceramics in terms of long-term durability. This is the first time that V-KI curves are compared for the major ceramic and glass-ceramic used for dental restorations. Strength versus translucency maps for different CAD/CAM dental restorative materials were described, showing the current indication range for zirconia ceramics.Graphical abstractGraphical abstract for this article
       
  • AKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasis of
           lung cancer cells in a multi-organ microfluidic chip model
    • Abstract: Publication date: Available online 26 April 2019Source: Acta BiomaterialiaAuthor(s): Wenwen Liu, Jing Song, Xiaohui Du, Yang Zhou, Yang Li, Rui Li, Li Lyu, Yeting He, Junxia Hao, Jing Ben, Wei Wang, Haibin Shi, Qi Wang Brain metastasis (BM) is a leading cause of mortality in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying BM of NSCLC remain largely unknown because of the lack of models to accurately investigate such a dynamic and complex process. Here we developed a multi-organ microfluidic chip as a new methodological platform to study BM. The chip consisted of two bionic organ units – an upstream “lung” and a downstream “brain” characterized by a functional “blood-brain barrier (BBB)” structure, allowing real-time visual monitoring of the entire BM process, from the growth of primary tumor to its breaking through the BBB, and finally reaching the brain parenchyma. The chip was verified by lung cancer cell lines with differing metastatic abilities and then applied for the BM research where we first demonstrated that the protein expression of Aldo-keto reductase family 1 B10 (AKR1B10) was significantly elevated in lung cancer BM. Silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model, in our ex vivo microfluidic chip, as well as the in vivo model of brain metastasis in nude mice. Moreover, AKR1B10 downregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-9 via MEK/ERK signaling in metastatic lung cancers. These data suggest that our multi-organ microfluidic chip is a practical alternative to study BM pathogenesis, and AKR1B10 is a diagnostic biomarker and a prospective therapeutic target for NSCLC BM.Statement of significanceBrain metastasis (BM) of non-small cell lung cancer (NSCLC) is a complex cascade, and in particular, the process of lung cancer cells penetrating the blood-brain barrier (BBB) is very unique. However, due to the lack of reliable models that can faithfully mimic the dynamic process of BBB breaking, its molecular mechanisms have not well elucidated so far. In addition, although Aldo-keto reductase family 1 B10 (AKR1B10) has been implicated to the tumor development of liver cancer and many other cancers, little is known on its roles in the BM. Here, we established a multi-organ microfluidic bionic chip platform to recapitulate the entire BM process, and applied it to the BM pathology research, especially BBB extravasation. By using the chip and traditional models synergistically, we first demonstrated that AKR1B10 was significantly elevated in lung cancer BM, and defined the value of AKR1B10 as a diagnostic serum biomarker for lung cancer patients suffering from BM. Further, we investigated the role and mechanisms of AKR1B10 in BM that it promotes the extravasation of cancer cells through the BBB.Graphical abstractGraphical abstract for this article
       
  • Synergistic Effects of Laminin-1 Peptides, VEGF and FGF9 on Salivary Gland
           Regeneration
    • Abstract: Publication date: Available online 25 April 2019Source: Acta BiomaterialiaAuthor(s): Kihoon Nam, Spencer M. Dean, Callie T. Brown, Randall J. Smith, Pedro Lei, Stelios T. Andreadis, Olga J. Baker Hyposalivation is associated with radiation therapy, Sjögren’s syndrome and/or aging, and is a significant clinical problem that decreases oral health and overall health in many patients and currently lacks effective treatment. Hence, methods to regenerate salivary glands and restore saliva secretion are urgently needed. To this end, this study describes the modification of fibrin hydrogels with a combination of laminin-1 peptides (YIGSR and A99) and human growth factors (vascular endothelial growth factor and fibroblast growth factor 9) to enhance regeneration in a salivary gland injury mouse model. Our results indicate that these fortified hydrogels enhanced angiogenesis and neurogenesis while promoting formation of acinar structures, thereby leading to enhanced saliva secretion. Such functional recovery indicates salivary gland regeneration and suggests that our technology may be useful in promoting gland regeneration and reversing hyposalivation in a clinical setting.Statement of SignificanceWe engineered Fibrin Hydrogels (FH) to contain multiple regenerative cues including laminin-1 peptides (L1p) and growth factors (GF). L1p and GF modified FH were used to induce salivary gland regeneration in a wounded mouse model. Treatment with L1p and GF modified FH promoted salivary epithelial tissue regeneration, vascularization, neurogenesis and healing as compared to L1p-FH or FH alone. Results indicate that L1p and GF modified FH can be used for future therapeutic applications.Graphical abstractGraphical abstract for this article
       
  • Improving Hard Palate Wound Healing Using Immune Modulatory Autotherapies
    • Abstract: Publication date: Available online 25 April 2019Source: Acta BiomaterialiaAuthor(s): Samir A. Ballestas, Thomas Turner, Archana Kamalakar, Yvonne Stephenson, Nick Willett, Steven L. Goudy, Edward A. Botchwey Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response during oral cavity wound healing and ONF formation. Immunophenotyping of the inflammatory infiltrate following hard palate injury showed delayed recruitment of non-classical LY6Clo monocytes and failure to resolve inflammation. To induce a pro-regenerative inflammatory response, delivery of FTY720 nanofiber scaffolds following hard palate mucosal injury promoted complete ONF healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Alteration in gene expression with FTY720 delivery included increased Sox2 expression, reduction in pro-inflammatory IL-1, IL-4 and IL-6 and increased pro-regenerative IL-10 expression. Increased keratinocyte proliferation during ONF healing was observed at day 5 following FTY720 delivery. Our results show that local delivery of FTY720 from nanofiber scaffolds in the oral cavity enhances healing of ONF, occurring through multiple immunomodulatory mechanisms.Statement of significanceWound healing complications occur in up to 60% of patients undergoing cleft palate repair where an oronasal fistula (ONF) develops, allowing food and air to escape from the nose. Using a mouse model of palate mucosal injury, we explored the role of immune cell infiltration during ONF formation. Delivery of FTY720, an immunomodulatory drug, using a nanofiber scaffold into the ONF was able to attract anti-inflammatory immune cells following injury that enhanced the reepithelization process. ONF healing at day 5 following FTY720 delivery was associated with altered inflammatory and epithelial transcriptional gene expression, increased anti-inflammatory immune cell infiltration, and increased proliferation. These findings demonstrate the potential efficacy of immunoregenerative therapies to improve oral cavity wound healing.Graphical abstractGraphical abstract for this article
       
  • Fracture Modes and Hybrid Toughening Mechanisms in Oscillated/Twisted
           Plywood Structure
    • Abstract: Publication date: Available online 24 April 2019Source: Acta BiomaterialiaAuthor(s): Zhaoqiang Song, Yong Ni, Shengqiang Cai Twisted or oscillated plywood structure can be often found in biological composites such as claws of lobsters, bone of mammals, dactyl club of mantis shrimps, and exoskeleton of beetles, which exhibits a combination of high stiffness, high fracture toughness and low density. However, there lacks a quantitative understanding of the relationship between the fracture toughness of the composite and its internal geometry. In this article, we propose that a combination of crack tilting and crack bridging determines the effective fracture toughness of the fiber-reinforced composite with the plywood structure. During the fracturing process, a crack plane initially propagates in the matrix-fiber interface following the twisted fiber alignment. Such crack tilting mechanism can significantly enlarge the area of cracking surface and thus enhance the effective fracture toughness of the composite. With the propagation of the tilted crack plane, the local energy release rate becomes too small to maintain the growth of the tilted crack plane, leading the crack to grow into the matrix, crossing the fibers. Because of the high strength of the fiber, a few fibers can maintain unbroken behind the crack tip, corresponding to crack bridging mechanism. Based on our quantitative analysis, it is found that the effective fracture toughness of the composite can be maximized for a certain pitch angle of the oscillated/twisted plywood structure, which agrees well with experiments.Statements of significanceFiber-reinforced composites can be widely found in nature and engineering applications. Recently, it has been discovered that many fiber-reinforced composites in biology have twisted or oscillated plywood structure with high fracture toughness, high mechanical stiffness and low density. Detailed experiments have indicated that an optimal pitch angle may exist for the plywood structure to maximize the fracture toughness of the composites. However, there lacks a quantitative model of revealing such pitch angle-dependent fracture toughness. In this work, we propose a hybrid toughening mechanism and predict the optimal pitch angle in twisted/oscillated plywood structure for maximizing the fracture toughness. Our predictions agree reasonably well with experimental results. As such, the theory may help the design of better fiber-reinforced composites.Graphical abstractGraphical abstract for this article
       
  • Silk fibroin film-coated MgZnCa alloy with enhanced in vitro and in vivo
           performance prepared using surface activation
    • Abstract: Publication date: Available online 24 April 2019Source: Acta BiomaterialiaAuthor(s): Chenxi Wang, Hui Fang, Xiaoyun Qi, Chunjin Hang, Yaru Sun, Zhibin Peng, Wei Wei, Yansong Wang Magnesium and its alloys have generated considerable interest as one of the most promising biodegradable metals for biomedical bone implants. However, the enormous challenges are to improve their rapid corrosion excessively as well as to endow them with biocompatibility and biosafety. Herein, we introduce a natural silk fibroin protein coating to control the corrosion resistance and enhance the biocompatibility of MgZnCa alloy. To obtain a robust and reliable coated structure, different surface-activation processes are employed to increase the available functional groups on MgZnCa surfaces before coating. Compared to oxygen plasma activation, our unique vacuum ultraviolet-ozone (VUV/O3) activation method is effective in realizing uniform silk fibroin films as a protective barrier on MgZnCa alloy surfaces, and the nanoscratch test verified the superior adhesion strength of the silk fibroin-coated magnesium alloy structure. Long-term immersion results combined with electrochemical tests showed the preferable in vitro anticorrosion behavior and a low degradation rate of coated Mg alloy (1/8 times that of uncoated Mg alloy). Cell adhesion and cytotoxicity tests demonstrated that silk fibroin-coated MgZnCa presented improved biocompatibility with bone marrow mesenchymal stem cells. An animal study involving silk fibroin-coated MgZnCa implanted on one side of a rabbit spine for 180 days showed remarkably improved in vivo corrosion resistance, with 1/18 times the degradation rate of uncoated MgZnCa. These results not only comprehensively confirmed the validity of the VUV/O3-activation method as a coating strategy but also implied the tremendous potential of the modified Mg alloy for application as a degradable biomedical implant material.Statement of SignificanceMgZnCa alloy is a promising material in clinical implantation. Silk fibroin (SF) is a natural organic material with biocompatibility and biodegradability. To date, the combination of SF and MgZnCa alloy has exhibited considerable prospects for orthopedic applications. The realization of a direct coating is an enormous challenge because strong chemical bonds cannot be easily formed between organic and inorganic materials. To solve this bottleneck, we proposed a unique vacuum ultraviolet-ozone (VUV/O3) surface-activation method for the first time to modify the Mg alloy surface before SF coating, which significantly enhanced both in vitro and in vivo performance, such as superior biocompatibility and remarkably improved corrosion resistance of magnesium alloys (∼1/18 the in vivo degradation rate of uncoated MgZnCa).Graphical abstractGraphical abstract for this article
       
  • Anti-EpCAM-conjugated adeno-associated virus serotype 2 for systemic
           delivery of EGFR shRNA: its retargeting and antitumor effects on OVCAR3
           ovarian cancer in vivo
    • Abstract: Publication date: Available online 23 April 2019Source: Acta BiomaterialiaAuthor(s): Sungjin Lee, Hyung Jun Ahn Adeno-associated virus (AAV) is a promising vector for systemic delivery of siRNA because of its long-term expression ability without immunogenicity and pathogenicity. However, its broad host tropism and lack of tissue specificity have limited clinical applications such as cancer therapy. Therefore, redirecting the natural tropism of AAV vectors to unique cell surface antigens is an important requirement for in vivo RNAi-based cancer therapy. To use the overexpression property of epithelial cell adhesion molecule (EpCAM) in specific cancer types, we herein created anti-EpCAM anitibody-conjugated AAV serotype 2 (AAV2) vectors through a streptavidin-biotin bridge. Upon intravenous injection, anti-EpCAM-conjugated AAV2 vectors showed prominent tumor-specific accumulation in EpCAM-positive tumor-bearing mice without undesirable sequestration in liver. In addition, when loaded with transgenes to express shRNA against epidermal growth factor receptor (EGFR), systemically injected anti-EpCAM-conjugated AAV2/shEGFR vectors induced significant downregulation of EGFR expression in tumors and eventually suppressed tumor growth even at the long dosing interval of two weeks. This in vivo antitumor effect represents the increased infection efficacy of tropism-modified AAV2 vectors and prolonged expression of EGFR shRNA in tumor tissues. Thus, this study suggests the great potential of anti-EpCAM-conjugated AAV2/shEGFR vectors as RNAi-based cancer therapeutics.Statement of significanceAdeno-associated virus (AAV) is a promising vector for systemic delivery of siRNA, but its broad host tropism has limited clinical applications. By using the overexpression property of epithelial cell adhesion molecule (EpCAM) on tumors, we demonstrate that anti-EpCAM-conjugated AAV2 vectors through a streptavidin-biotin bridge are redirected to EpCAM-positive tumors in vivo. In addition, when loaded with transgenes to express shRNA against epidermal growth factor receptor (EGFR), systemically injected anti-EpCAM-conjugated AAV2/shEGFR vectors significantly downregulate EGFR expression in tumors, eventually suppressing tumor growth for long periods. We herein suggest the potential of anti-EpCAM-AAV2/shEGFR vectors as an antitumor agent. Furthermore, redirection of AAV2 infection through EpCAM would provide a powerful means for systemic delivery of short hairpin RNA to tumor sites.Graphical abstractGraphical abstract for this article
       
  • Antimicrobial Polymer Modifications to Reduce Microbial Bioburden on
           Endotracheal Tubes and Ventilator Associated Pneumonia
    • Abstract: Publication date: Available online 22 April 2019Source: Acta BiomaterialiaAuthor(s): Megan Barnes, Corbin Feit, Trudy-Ann Grant, Elizabeth J. Brisbois Hospital associated infections (HAIs), infections acquired by patients during care in a hospital, remain a prevalent issue in the healthcare field. These infections often occur with the use of indwelling medical devices such as endotracheal tubes (ETTs) that can result in ventilator-associated pneumonia (VAP). When examining the various routes of infection, VAP is associated with the highest incidence, rate of morbidity, and economic burden. Although ETTs are essential for the survival of patients requiring mechanical ventilation, their use comes with complications. The presence of an ETT in the airway impairs physiological host defense mechanisms for clearance of pathogens and provides a platform for oropharynx microorganism transport to the sterile tracheobronchial network. Administration of antibiotics is administered to treat lower respiratory infections; however, they are not always effective and consequently can result in increased antibiotic resistance. Prophylactic approaches by altering the surface of ETTs to prevent the establishment and growth of bacteria have shown promising. Passive surface modifications that prevent bacterial establishment and growth, or active coatings that possess a bactericidal effect have proven effective. In this review we aim to highlight the importance of preventing biofilm establishment on indwelling medical devices, focusing on ETTs. We will investigate successful antimicrobial modifications to ETTs and the future avenues that will ultimately decrease HAIs and improve patient care.Statement of SignificanceInfections that occur with indwelling medicals devices remain a constant concern in the medical field and can result in hospital-acquired infections. Specifically, ventilator associated pneumonia (VAP) occurs with the use of an endotracheal tube (ETT). Infections often require use of antibiotics and can result in patient mortality. Our review includes a summary of the recent collective work of antimicrobial ETT modifications and potential avenues for further investigations in effort to reduce VAP from ETTs. Polymer modifications with antibacterial nature have been developed and tested; however, a focus on ETTs is lacking and clinical availability of new antimicrobial ETT devices being limited. Our collective work shows the successful and prospective applications to the surfaces of ETTs that can support researchers and physicians to create safer medical devices.Graphical abstractGraphical abstract for this article
       
  • In vivo and in vitro bioactivity of a “precursor of apatite” treatment
           on polyetheretherketone
    • Abstract: Publication date: Available online 19 April 2019Source: Acta BiomaterialiaAuthor(s): Kazutaka Masamoto, Shunsuke Fujibayashi, Takeshi Yabutsuka, Tomoko Hiruta, Bungo Otsuki, Yaichiro Okuzu, Koji Goto, Takayoshi Shimizu, Yu Shimizu, Chihiro Ishizaki, Keito Fukushima, Toshiyuki Kawai, Makoto Hayashi, Kazuaki Morizane, Tomotoshi Kawata, Masashi Imamura, Shuichi Matsuda We recently developed a surface treatment, “precursor of apatite” (PrA), for polyetheretherketone (PrA-PEEK) via a simple, low-temperature process aiming to achieve stronger and faster adhesion to bone. The treatment involves three steps: H2SO4 immersion, exposure to O2 plasma discharge, and alkaline simulated body fluid (alkaline SBF) treatment. This method produces homogeneous fine particles of amorphous calcium phosphate on the PEEK, and we confirmed that PrA-PEEK had excellent apatite formation ability in an SBF immersion test. In the present study using PEEK implants in rabbit tibia, mechanical tests, and histological and radiological analyses revealed that PrA provided the PEEK substrate with excellent bone-bonding properties and osteo-conductivity at early stages (4 and 8 weeks), extending to 16 weeks. In vitro study using MC3T3-E1 cells revealed via XTT assay that PrA on the PEEK substrate resulted in no cytotoxicity, though PrA treatment seemed to suppress gene expression of integrin β-1 and Alp after 7-day incubation as shown by real-time PCR. On the whole, PrA treatment succeeded in giving in vivo bone-bonding properties to the PEEK substrate, and the treatment is a safe and promising method that can be applied in clinical settings. There was an inconsistency between in vivo and in vitro bioactivity, and this discrepancy indicated that apatite formation does not always need activation of osteoblasts at very early stage and that optimal conditions at cell and organism level may be different.Statement of SignificancePolyetheretherketone (PEEK) is an attractive engineering polymer used for spine and dental surgery. To further improve clinical outcome of PEEK-based materials, we developed “Precursor of apatite” (PrA) treatment on the PEEK surface to confer bone-bonding properties. The advantages of this treatment are that it does not require high-temperature processing or special chemicals, and it is inexpensive. The present study clarified excellent in vivo bone-bonding property of PrA treatment. In addition, the results revealed important insights indicating that optimal conditions, especially wettability and crystallinity in calcium phosphate, differ at cell and organism levels. Moreover, our results indicated that prediction of in vivo bioactivity should be done in combination with multiple in vitro testsGraphical abstractGraphical abstract for this article
       
  • Thermal insulation design bioinspired by microstructure study of penguin
           feather and polar bear hair
    • Abstract: Publication date: Available online 18 April 2019Source: Acta BiomaterialiaAuthor(s): Sara Metwally, Sara Martínez Comesaña, Mateusz Zarzyka, Piotr K. Szewczyk, Joanna E. Karbowniczek, Urszula Stachewicz Nature is an amazing source of inspiration for the design of thermal insulation strategies, which are key for saving energy. In nature, thermal insulation structures, such as penguin feather and polar bear hair, are well developed; enabling the animals’ survival in frigid waters. The detailed microscopy investigations conducted in this study, allowed us to perform microstructural analysis of these thermally insulating materials, including statistical measurements of keratin fiber and pore dimensions directly from high resolution Scanning Electron Microscope (SEM) images. The microscopy study revealed many similarities in both materials, and showed the importance of their hierarchically-organized porous structure. Finally, we propose the schematic configuration of a thermally-insulating structure, based on the penguin feather and polar bear hair. These optimized thermal-insulator systems indicate the road maps for future development, and new approaches in the design of material properties.Statement of significanceWe present the first detail comparison of microstructure of penguin feather and polar bear hair for designing the optimum thermal insulation properties. This unique study allowed to measure the sizes of pores and fibers of these two keratin-based materials, including the investigation of their 3D arrangements. We reveled porosity interconnection especially in polar bear hair, which is one of the key strategies in thermally insulating materials.Graphical abstractGraphical abstract for this article
       
  • Microstructured Hydrogel Scaffolds Containing Differential Density
           Interfaces Promote Rapid Cellular Invasion and Vascularization
    • Abstract: Publication date: Available online 18 April 2019Source: Acta BiomaterialiaAuthor(s): Karel-Bart Celie, Yoshiko Toyoda, Xue Dong, Kerry A. Morrison, Peipei Zhang, Ope Asanbe, Julia Jin, Rachel C. Hooper, Matthew R. Zanotelli, Omer Kaymakcalan, Ryan Bender, Jason A. Spector IntroductionInsufficient vascularization of currently available clinical biomaterials has limited their application to optimal wound beds. We designed a hydrogel scaffold with a unique internal microstructure of differential collagen densities to induce cellular invasion and neovascularization.MethodsMicrosphere scaffolds (MSS) were fabricated by encasing 1% (w/v) type 1 collagen microspheres 50-150 μm in diameter in 0.3% collagen bulk. 1% and 0.3% monophase collagen scaffolds and Integra® disks served as controls. Mechanical characterization as well as in vitro and in vivo invasion assays were performed. Cell number and depth of invasion were analyzed using ImarisTM. Cell identity was assessed immunohistochemically.ResultsIn vitro, MSS exhibited significantly greater average depth of cellular invasion than Integra® and monophase collagen controls. MSS also demonstrated significantly higher cell counts than controls. In vivo, MSS revealed significantly more cellular invasion spanning the entire scaffold depth at 14 days than Integra®. CD31+ expressing luminal structures suggestive of neovasculature were seen within MSS at 7 days and were more prevalent after 14 days. Multiphoton microscopy of MSS demonstrated erythrocytes within luminal structures after 14 days.ConclusionBy harnessing simple architectural cues to induce cellular migration, MSS holds great potential for clinical translation as the next generation dermal replacement product.Statement of SignificanceLarge skin wounds require tissue engineered dermal substitutes in order to promote healing. Currently available dermal replacement products do not always adequately incorporate into the body, especially in complex wounds, due to poor neovascularization. In this paper, we present a hydrogel with an innovative microarchitecture that is composed of dense type I collagen microspheres suspended in a less-dense collagen bulk. We show that cell invasion into the scaffold is driven solely by mechanical cues inherent within this differential density interface, induces robust vascular cell invasion both in vitro and in a rodent model. Our hydrogel performs favorably compared to the current clinical gold standard, Integra®. We believe this hydrogel scaffold may be first of the next generation of dermal replacement products.Graphical abstractGraphical abstract for this article
       
  • Triple co-culture of human alveolar epithelium, endothelium and
           macrophages for studying the interaction of nanocarriers with the
           air-blood barrier
    • Abstract: Publication date: Available online 18 April 2019Source: Acta BiomaterialiaAuthor(s): Ana Costa, Cristiane de Souza Carvalho-Wodarz, Vítor Seabra, Bruno Sarmento, Claus-Michael Lehr Predictive in vitro models are valuable alternatives to animal experiments for evaluating the transport of molecules and (nano)particles across biological barriers. In this work, an improved triple co-culture of air-blood barrier was set-up, being exclusively constituted by human cell lines that allowed to perform experiments at air-liquid interface. Epithelial NCI-H441 cells and endothelial HPMEC-ST1.6R cells were seeded at the apical and basolateral sides of a Transwell® membrane, respectively. Differentiated THP-1 cells were also added on the top of the epithelial layer to mimetize alveolar macrophages.Translocation and permeability studies were also performed. It was observed that around 14-18% of 50-nm Fluorospheres®, but less than 1% of 1.0 µm- Fluorospheres® could pass through the triple co-culture as well as the epithelial monoculture and bi-cultures, leading to the conclusion that both in vitro models represented a significant biological barrier and could differentiate the translocation of different sized systems. The permeability of isoniazid was similar between the epithelial monoculture and bi-cultures when compared with the triple co-culture. However, when in vitro models were challenged with lipopolysaccharide, the release of interleukin-8 increased in the bi-cultures and triple co-culture, whereas the NCI-H441 monoculture did not show any proinflammatory response.Overall, this new in vitro model is a potential tool to assess the translocation of nanoparticles across the air-blood barrier both in healthy state and proinflammatory state.Statement of SignificanceThe use of in vitro models for drug screening as an alternative to animal experiments is increasing over the last years, in particular, models to assess the permeation through biological membranes. Cell culture models are mainly constituted by one type of cells forming a confluent monolayer, but due to its oversimplicity they are being replaced by three-dimensional (3D) in vitro models, that present a higher complexity and reflect more the in vivo-like conditions.Being the pulmonary route one of the most studied approaches for drug administration, several in vitro models of alveolar epithelium have been used to assess the drug permeability and translocation and toxicity of nanocarriers. Nevertheless, there is still a lack of 3D in vitro models that mimic the morphology and the physiological behavior of the alveolar-capillary membrane.In this study, a 3D in vitro model of the air-blood barrier constituted by three different relevant cell lines was established and morphologically characterized. Different permeability/translocation studies were performed to achieve differences/similarities comparatively to each monoculture (epithelium, endothelium, and macrophages) and bi-cultures (epithelial cells either cultured with endothelial cells or macrophages). The release of pro-inflammatory cytokines (namely interleukin-8) after incubation of lipopolysaccharide, a pro-inflammatory inductor, was also evaluated in this work.Graphical abstractGraphical abstract for this article
       
  • Calcium Carbonate: Adored and Ignored in Bioactivity Assessment
    • Abstract: Publication date: Available online 18 April 2019Source: Acta BiomaterialiaAuthor(s): Masoud Mozafari, Sara Banijamali, Francesco Baino, Saeid Kargozar, Robert G. Hill The title of this article could sound a bit curious to some readers since a layer of apatite – and not calcium carbonate – is well-known to form on the surface of bioactive glasses upon immersion in simulated body fluids. However, calcium carbonate (commonly reported as calcite crystals) can form on the surface of bioactive glasses as well, instead of or in competition with hydroxyapatite, during in vitro tests. Major factors that govern calcium carbonate formation are a high concentration of Ca2+ ions in the testing solution – and, in this regard, glass composition/texture and type of medium play key roles – along with the volume of solution used during in vitro tests. To date, this phenomenon has received relatively little attention and is still partly unexplored. This article provides a critical overview of the available literature on this topic in order to stimulate constructive discussion among biomaterials scientists and further research for better understanding the mechanisms involved in glass bioactivity.Statement of significanceThe title of this review could sound a bit curious to some readers since a layer of apatite – and not calcium carbonate – is well known to form on the surface of biomaterials. However, calcium carbonate can form on the surface as well, instead of or in competition with apatite. To date, this phenomenon has received relatively little attention and is still partly unexplored. This review provides a critical overview of the available literature on this topic in order to stimulate constructive discussion among biomaterials scientists and further research for better understanding the mechanisms involved in bioactivity assessment.Graphical abstractGraphical abstract for this article
       
  • Outer membrane vesicles engineered to express membrane-bound antigen
           program dendritic cells for cross-presentation to CD8+ T cells
    • Abstract: Publication date: Available online 17 April 2019Source: Acta BiomaterialiaAuthor(s): Sjoerd T.T. Schetters, Wouter S.P. Jong, Sophie K. Horrevorts, Laura Kruijssen, Steef Engels, Dorian Stolk, Maria H. Daleke-Schermerhorn, Juan Garcia-Vallejo, Diane Houben, Wendy W.J. Unger, Joke M.M. den Haan, Joen Luirink, Yvette van Kooyk Outer membrane vesicles (OMVs) are vesicular nano-particles produced by Gram-negative bacteria that are recently being explored as vaccine vector. The fact that OMVs can be efficiently produced by a hypervesiculating Salmonella typhimurium strain, are packed with naturally-occurring adjuvants like lipopolysaccharides (LPS), and can be engineered to express any antigen of choice, makes them ideal candidates for vaccinology. However, it is unclear whether OMVs induce dendritic cell (DC)-mediated antigen-specific T cell responses and how immune activation is coordinated. Here, we show that OMVs induce maturation of human monocyte-derived DCs, murine bone marrow-derived DCs and CD11c+ splenic DCs. OMV-induced DC maturation was dependent on the presence of LPS and the myeloid differentiation primary response 88 (MyD88) adapter protein downstream of toll like receptor signaling. Importantly, OMVs did not induce pyroptosis/cell death, but instead provided a significant survival benefit in DCs over non-stimulated DCs. OMVs displaying a sizeable ovalbumin fragment at the vesicle surface induce potent cross-presentation in BMDCs and splenic CD11c+ DCs to OTI CD8+ T cells, dependent on MyD88. Interestingly, the OMV-induced preference to cross-presentation was only partly dependent on the BATF3-dependent CD8a+ professional cross-presenting DC subset. Hence, an OMV-specific programming of DCs that induces maturation and provides a survival benefit for antigen presentation to T cells is identified. Additionally, for the first time, antigen-specific and potent cross-presentation of antigen-loaded OMVs to CD8+ T cells is demonstrated. These data provide mechanistical insight into the processes needed for the DC-mediated cross-presentation of OMV-derived antigens to CD8+ T cells with implications for therapeutic strategies.Statement of significanceBacteria are primarily known to cause disease. However, recent research has focused on using engineered bacteria and its byproducts as vaccine agents. In particular, outer membrane vesicles (OMVs) have shown promise in eliciting potent immunity against a variety of pathogens. While most vaccines rely on the generation of antibodies, the control of viral replication and tumor growth is driven by cytotoxic CD8+ T cells induced by dendritic cells (DCs). As such, there is a dire need for vaccines that use DCs to elicit CD8+ T cell responses. Studying OMVs as engineered biomaterial and its interaction with DCs allows tailored induction of immunity. This study includes important findings on OMV-dendritic cell interactions and for the first time supports OMVs as vehicles for the induction of antigen-specific CD8+ T cell responses. Additionally, important mechanistical insight into the molecular pathways needed for the cross-presentation of OMV-derived antigens to CD8+ T cells is provided.Graphical abstractGraphical abstract for this article
       
  • 3D chitosan scaffolds impair NLRP3 inflammasome response in macrophages
    • Abstract: Publication date: Available online 17 April 2019Source: Acta BiomaterialiaAuthor(s): Daniela P. Vasconcelos, Carlos de Torre-Minguela, Ana I. Gomez, Artur P. Águas, Mário A. Barbosa, Pablo Pelegrín, Judite N. Barbosa Chitosan (Ch) is used in different biomedical applications to promote tissue repair. However, tissue injury caused by biomaterial implantation lead to the release of danger signals that engage different inflammatory pathways on the host. Different implanted materials activate the inflammasome leading to the modulation of the immune response. Here we have studied how macroscopic biomaterials, Ch scaffolds with different chemical composition: 4% or 15% degree of acetylation (DA) modulate the activation of the NLRP3 inflammasome in vitro. For that, we assessed the NLRP3 inflammasome in bone marrow derived mouse macrophages (BMDM) and human macrophages cultured within 3D Ch scaffolds. We found that both Ch scaffolds did not trigger the NLRP3 inflammasome activation in macrophages. Furthermore, BMDMs and human macrophages cultured in both Ch scaffolds presented a reduction in the number of apoptosis-associated speck-like protein containing a caspase activating recruitment domain (ASC) specks and in IL-1β release upon classical NLRP3 inflammasome stimulation. We also found a decrease in proIL-1β in BMDMs after priming with LPS when cultured in Ch scaffolds with DA 4% DA after priming with LPS when compared to Ch scaffolds with 15% DA or to macrophages cultured in cell-culture plates. Our results shows that 3D Ch scaffolds with different DA impair NLRP3 inflammasome priming and activation.Statement of SignificanceIn this research work we have assessed the role of the NLRP3 inflammasome in the macrophage response to 3D chitosan scaffolds with different degrees of acetylation (DA). To our knowledge this is the first work that demonstrates the modulatory capacity of 3D porous chitosan scaffolds in the NLRP3 inflammasome activation, because our results show that Ch scaffolds impair NLRP3 inflammasome assembly in macrophages.Interestingly, our results are in contrast with studies reported in the literature that indicate that chitosan is a powerful activator of the NLRP3 inflammasome in nanoscale chitosan products. Our studies that were performed in large scale chitosan scaffolds, stress out that the process of phagocytosis is pivotal in inflammasome assembly and activation, are rather important since they clearly illustrate the different role of the inflammasome in the biological response to large scale and nanoscale biomaterials.Graphical abstractGraphical abstract for this article
       
  • Downstream Platelet Adhesion and Activation Under Highly Elevated Upstream
           Shear Forces
    • Abstract: Publication date: Available online 17 April 2019Source: Acta BiomaterialiaAuthor(s): Shekh Rahman, Vladimir Hlady Elevated shear force caused by an anastomotic stenosis is a common complication at the blood vessel-vascular implant interface. Although elevated shear forces were found to cause platelet aggregation around a stenotic region, transient platelet exposure to elevated shear forces and subsequent downstream events occurring under lower shear force were not extensively studied. We hypothesize that effects of elevated shear forces on pre-activation of platelets for downstream adhesion and activation are relevant in understanding the increased thrombotic risk associated with blood-contacting devices. We designed a microfluidic flow system to mimic the hemodynamic environment of vasculature with an upstream anastomotic stenosis with five wall shear strain rates ranging from 1620 s-1 to 11560 s-1. Under shear flow conditions, transient exposure of whole blood to elevated shear forces resulted in higher downstream platelet adhesion onto three different immobilized platelet agonists: fibrinogen, collagen, or von Willebrand factor. Platelet expression of four activation markers (P-selectin, GPIIb/IIIa, lysosomal glycoprotein, and phosphatidylserine) significantly increased after transient exposure to higher upstream wall shear strain rates of 2975 - 11560 s-1. A significant lysis was observed when platelets were primed by upstream wall shear strain rate of 11560 s-1. These experimental results could be helpful to understand how altered hemodynamics around an anastomotic stenosis promotes thrombus formation downstream.Statement of SignificanceStudying the downstream response of platelets following transient exposure to an upstream agonist is important because of significant clinical implications to the implantation of vascular devices. Due to intimal fibrous hyperplasia, vascular biomaterials such as synthetic small-diameter vascular grafts sometimes become stenotic (narrow), leading to transient platelet exposure to elevated shear forces. In this study, a microfluidic flow system was developed to mimic a stenosed vascular graft and to investigate how highly elevated, transient upstream shear forces, typically found in severe stenosis, results in the pre-activation of platelets for downstream adhesion and activation. The findings of the present study have implications for optimizing the design of blood-contacting biomaterials in order to minimize thrombotic risk associated with transiently elevated shear forces. The findings also provide additional insights into the mechanisms of thrombus formation at the post-stenotic regions of vascular implants.Graphical abstractGraphical abstract for this article
       
  • Fabricated Tropoelastin-Silk Yarns and Woven Textiles for Diverse Tissue
           Engineering Applications
    • Abstract: Publication date: Available online 17 April 2019Source: Acta BiomaterialiaAuthor(s): Behnaz Aghaei-Ghareh-Bolagh, Suzanne M. Mithieux, Matti A. Hiob, Yiwei Wang, Avelyn Chong, Anthony S. Weiss Electrospun yarns offer substantial opportunities for the fabrication of elastic scaffolds for flexible tissue engineering applications. Currently available yarns are predominantly made of synthetic elastic materials. Thus scaffolds made from these yarns typically lack cell signaling cues. This can result in poor integration or even rejection on implantation, which drive demands for a new generation of yarns made from natural biologically compatible materials. Here, we present a new type of cell-attractive, highly twisted protein-based yarns made from blended tropoelastin and silk fibroin. These yarns combine physical and biological benefits by being rendered elastic and bioactive through the incorporation of tropoelastin and strengthened through the presence of silk fibroin. Remarkably, the process delivered multi-meter long yarns of tropoelastin-silk mixture that were conducive to fabrication of meshes on hand-made frames. The resulting hydrated meshes are elastic and cell interactive. Furthermore, subcutaneous implantation of the meshes in mice demonstrates their tolerance and persistence over 8 weeks. This combination of mechanical properties, biocompatibility and processability into diverse shapes and patterns underscores the value of these materials and platform technology for tissue engineering applications.Statement of SignificanceSynthetic yarns are used to fabricate textile materials for various applications such as surgical meshes for hernia repair and pelvic organ prolapse. However, synthetic materials lack the attractive biological and physical cues characteristic of extracellular matrix and there is a demand for materials that can minimize postoperative complications. To address this need, we made yarns from a combination of recombinant human tropoelastin and silk fibroin using a modified electrospinning approach that blended these proteins into functional yarns. Prior to this study, no protein-based yarns using tropoelastin were available for the fabrication of functional textile materials. Multimeter-long, uniform and highly twisted yarns based on these proteins were elastic and cell interactive and demonstrated processing to yield textile fabrics. By using these yarns to weave fabrics, we demonstrate that an elastic human matrix protein blend can deliver a versatile platform technology to make textiles that can be explored for efficacy in tissue repair.Graphical abstractGraphical abstract for this article
       
 
 
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: 18.215.161.19
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-