Publisher: Elsevier   (Total: 3147 journals)

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Showing 1 - 200 of 3147 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 106, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 44, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 7)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 446, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 30, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 12, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 324, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, 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: 2, SJR: 1.793, CiteScore: 6)
Acta Psychologica     Hybrid Journal   (Followers: 26, 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   (Followers: 1)
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: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 13, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 189, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 13, 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: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 30, 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: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, 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: 1, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, 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: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, 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: 21, 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: 16)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 14)
Advances in Digestive Medicine     Open Access   (Followers: 13)
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: 45, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 30, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 51, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 2)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 68, 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: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 8, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 4, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, 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: 9, 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: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 17, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 26)
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: 5)
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: 18, 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: 6, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 10, 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: 11)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
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: 69)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, 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: 7)
Advances in Space Research     Full-text available via subscription   (Followers: 431, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, 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: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 57, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 395, 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: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 488, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 47, 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: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, 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: 12)
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: 11, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 55, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 48, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 40, 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: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
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: 265, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 67, 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: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 30, 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: 67, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 25, 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: 6, 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: 213, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, 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: 25, 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: 237, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 8, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 3, SJR: 0.451, CiteScore: 1)

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Similar Journals
Journal Cover
Acta Biomaterialia
Journal Prestige (SJR): 1.967
Citation Impact (citeScore): 7
Number of Followers: 30  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3147 journals]
  • Encapsulation of collagen mimetic peptide-tethered vancomycin liposomes in
           collagen-based scaffolds for infection control in wounds
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Raj Kumar Thapa, Kristi L. Kiick, Millicent O. SullivanWound infections are a significant clinical problem affecting millions of people worldwide. Topically applied antibacterial formulations with longer residence time and controlled antimicrobial release would offer significant benefits for improved prevention and treatment of infected wounds. In this study, we developed collagen mimetic peptide (CMP) tethered vancomycin (Van)-containing liposomes (Lipo) (CMP-Van-Lipo) hybridized to collagen-based hydrogels (‘co-gels,’ e.g., collagen/fibrin combination hydrogels) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in vitro and in vivo. Tethering CMP-Van-Lipo nanostructures to co-gels enabled sustained Van release and enhanced in vitro antibacterial effects against MRSA as compared to Van loaded co-gels or Van-Lipo loaded co-gels following multiple fresh bacterial inoculations over a period of 48 h. These results were successfully translated in vivo wherein MRSA infected wounds were effectively treated with CMP-Van-Lipo loaded co-gels for up to 9 days, whereas the activity of Van loaded co-gels and Van-Lipo loaded co-gels were limited to
  • Additively manufactured iron-manganese for biodegradable porous
           load-bearing bone scaffold applications
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Danilo Carluccio, Chun Xu, Jeffrey Venezuela, Yuxue Cao, Damon Kent, Michael Bermingham, Ali Gökhan Demir, Barbara Previtali, Qingsong Ye, Matthew DarguschSelective laser melting (SLM) can produce complex hierarchical architectures paving the way for highly customisable biodegradable load-bearing bone scaffolds. For the first time, an in-depth analysis on the performance of SLM-manufactured iron-manganese bone scaffolds suitable for load-bearing applications is presented. Microstructural, mechanical, corrosion and biological characterisations were performed on SLM-manufactured iron-manganese scaffolds. The microstructure of the scaffold consisted primarily of γ-austenite, leading to high ductility. The mechanical properties of the scaffold were sufficient for load-bearing applications even after 28 days immersion in simulated body fluids. Corrosion tests showed that the corrosion rate was much higher than bulk pure iron, attributed to a combination of the manufacturing method, the addition of Mn to the alloy and the design of the scaffold. In vitro cell testing showed that the scaffold had good biocompatibility and viability towards mammalian cells. Furthermore, the presence of filopodia showed good osteoblast adhesion. In vivo analysis showed successful bone integration with the scaffold, with new bone formation observed after 4 weeks of implantation. Overall the SLM manufactured porous Fe-35Mn implants showed promise for biodegradable load-bearing bone scaffold applications.Statement of significanceBiodegradable iron scaffolds are emerging as a promising treatment for critical bone defects. Within this field, selective laser melting (SLM) has become a popular method of manufacturing bespoke scaffolds. There is limited knowledge on SLM-manufactured iron bone scaffolds, and no knowledge on their application for load-bearing situations. The current manuscript is the first study to characterise SLM manufactured iron-manganese bone scaffolds for load-bearing applications and also the first study to perform In vivo testing on SLM produced biodegradable iron scaffolds. In this study, for the first time, the mechanical, corrosion and biological properties of an iron-manganese scaffold manufactured using SLM were investigated. In summary the SLM-manufactured porous iron-manganese implants displayed great potential for biodegradable load-bearing bone scaffolds.Graphical abstractImage, graphical abstract
  • Glass-activated regeneration of volumetric muscle loss
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Weitao Jia, Haoran Hu, Aize Li, Huayun Deng, Carrie L. Hogue, John C. Mauro, Changqing Zhang, Qiang FuVolumetric muscle loss (VML) resulting from injuries to skeletal muscles has profound consequences in healthcare. Current VML treatment based on the use of soft materials including biopolymers and decellularized extracellular matrix (dECM) is challenging due to their incapability of stimulating the formation of satellite cells (SCs), muscle stem cells, which are required for muscle regeneration. Additional stem cells and/or growth factors have to be incorporated in these constructs for improved efficacy. Here we report an approach by using bioactive glasses capable of regenerating VML without growth factors or stem cells. One silicate and two borate compositions with different degradation rates (2.4% for silicate 45S5; 5.3% and 30.4% for borate 8A3B and 13-93B3, respectively, in simulated body fluid (SBF) at 37 °C for 30 days) were used for this study. Our in vitro models demonstrate the ability of ions released from bioactive glasses in promoting angiogenesis and stimulating cells to secrete critical muscle-related growth factors. We further show the activation of SCs and the regeneration of skeletal muscles in a rat VML model. Considering these promising results, this work reveals a potentially simple and safe approach to regenerating skeletal muscle defects.Statement of significance(1) This is the first report on an inorganic material used in skeletal muscle regeneration through in vitro and in vivo models.(2) Bioactive glass is found to activate the production of satellite cells (SCs), muscle stem cells, without the incorporation of extra stem cells or growth factors.(3) The work represents a simple, safe, low-cost yet efficient means for healing muscle defects.Graphhic abstractImage, graphical abstract
  • A programmable, fast-fixing, osteo-regenerative, biomechanically robust
           bone screw
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Yuanchi Zhang, Jinlian Hu, Ruiqi Xie, Yuhe Yang, Jie Cao, Yunhu Tu, Yi Zhang, Tingwu Qin, Xin ZhaoThe use of a screw for repairing defected bones is limited by the dilemma between stiffness, bioactivity and internal fixation ability in current products. For polymer bone screw, it is difficult to achieve the bone stiffness and osteo-induction. Polymer composites may enhance bioactivity and mechanical properties but sacrifice the shape memory properties enormously. Herein, we fabricated a programmable bone screw which is composed of shape memory polyurethane, hydroxyapatite and arginylglycylaspartic acid to resolve the above problem. This composite has significantly improved mechanical and shape-memory properties with a modulus of 250 MPa, a shape fixity ratio of ~90% and a shape recovery ratio of ~96%. Moreover, shape fixity and recovery ratios of the produced SMPC screw in the simulative biological condition were respectively ~80% and ~82%. The produced screw could quickly recover to its original shape in vitro within 20 s leading to easy internal fixation. Additionally, the composite could support mesenchymal stem cell survival, proliferation and osteogenic differentiation in vitro tests. It also promoted tissue growth and showed beneficial mechanical compatibility after implantation into a rabbit femoral intracondyle for 12 weeks with little inflammation. Such bone screw exhibited a fast-fixing, tightened fitting, enhanced supporting and boosted bioactivity simultaneously in the defective bone, which provides a solution to the long-standing problem for bone repairing. We envision that our composite material will provide valuable insights into the development of a new generation of bone screws with good fixation and osteogenic properties.Statement of SignificanceThe main obstacles to a wider use of a bone screw are unsatisfied stiffness, inflammatory response and screw loosening issues. Herein, we report a programmable screw with mechanically robust, bioactive and fast-fixing performances. The shape memory polymer composite takes advantage of the component in the natural bone and possesses a stable bush-like structure inside through the covalent bonding, and thus achieve significantly improved mechanical and memory properties. Based on its shape memory effect, the produced screw was proved to offer a recovery force to surroundings and promote the bone regeneration effectively. Therefore, the composite realizes our expectations on functions through structure design and paves a practical and effective way for the development of a new generation of bone screws.Graphical abstractImage, graphical abstract
  • Bioactive iron oxide nanoparticles suppress osteoclastogenesis and
           ovariectomy-induced bone loss through regulating the TRAF6-p62-CYLD
           signaling complex
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Li Liu, Rongrong Jin, Jimei Duan, Li Yang, Zhongyuan Cai, Wencheng Zhu, Yu Nie, Jing He, Chunchao Xia, Qiyong Gong, Bin Song, James M. Anderson, Hua AiIron oxide nanoparticles (IONPs) have been widely used as contrast agents for magnetic resonance imaging (MRI) and other biomedical applications in both clinical and preclinical cases. In the present study, we show that two clinically used IONPs, ferumoxytol and ferucarbotran, have an intrinsic inhibitory effect on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis of bone marrow-derived monocytes/macrophages (BMMs). IONPs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and functional actin ring structures. More importantly, the inhibitory effect was also verified in vivo by its capacity to rescue the bone loss of ovariectomized (OVX) mice after intravenous injection with IONPs. Mechanistically, we found that IONPs trigger the upregulation of p62 which result in recruitment of CYLD and enhanced deubiquitination of TRAF6, a master controller of RANKL signaling. The downstream activation of NF-κB and MAPK signals was accordingly attenuated, ultimately leading to reduced expression of osteoclatogenesis-related genes. Taken together, clinically used IONPs can inhibit osteoclastogenesis through regulating TRAF6-p62-CYLD signaling complex, and they may be considered as alternative options for treatment of osteoporosis.Statement of SignificanceNanoparticles have been developed as drug delivery systems for treatment of osteoporosis, mostly an age-related health problem with risk of fractures. In this work, we show that two clinically used iron oxide nanoparticles (IONPs) ferumoxytol and ferucarbotran themselves can significantly reduce the osteoporosis of ovariectomized (OVX) mice through inhibiting Osteoclastogenesis. We found that IONPs trigger the upregulation of p62 which result in recruitment of CYLD and enhanced deubiquitination of TRAF6, a master controller of RANKL signaling. The downstream activation of NF-κB and MAPK signals was accordingly attenuated, leading to reduced expression of osteoclatogenesis-related genes. Taken together, clinically used IONPs inhibit osteoclastogenesis through regulating TRAF6-p62-CYLD signaling complex, and they may be considered as alternative options for treatment of osteoporosis.Graphical abstractImage, graphical abstract
  • Self-assembling as regular nanoparticles dramatically minimizes
           photobleaching of tumour-targeted GFP
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Ugutz Unzueta, Mònica Roldán, Mireia Pesarrodona, Raul Benitez, Alejandro Sánchez-Chardi, Oscar Conchillo-Solé, Ramón Mangues, Antonio Villaverde, Esther VázquezFluorescent proteins are useful imaging and theranostic agents, but their potential superiority over alternative dyes is weakened by substantial photobleaching under irradiation. Enhancing protein photostability has been attempted through diverse strategies, with irregular results and limited applicability. In this context, we wondered if the controlled oligomerization of Green Fluorescent Protein (GFP) as nanoscale supramolecular complexes could stabilize the fluorophore through the newly formed protein-protein contacts, and thus, enhance its global photostability. For that, we have here analyzed the photobleaching profile of several GFP versions, engineered to self-assemble as tumour-homing nanoparticles with different targeting, size and structural stability. This has been done under prolonged irradiation in confocal laser scanning microscopy and by small-angle X-ray scattering. The results show that the oligomerization of GFP at the nanoscale enhances, by more than seven-fold, the stability of fluorescence emission. Interestingly, GFP nanoparticles are much more resistant to X-ray damage than the building block counterparts, indicating that the gained photostability is linked to enhanced structural resistance to radiation. Therefore, the controlled oligomerization of self-assembling fluorescent proteins as protein nanoparticles is a simple, versatile and powerful method to enhance their photostability for uses in precision imaging and therapy.Statement of significanceFluorescent protein assembly into regular and highly symmetric nanoscale structures has been identified to confer enhanced structural stability against radiation stresses dramatically reducing their photobleaching. Being this the main bottleneck in the use of fluorescent proteins for imaging and theranostics, this protein architecture engineering principle appears as a powerful method to enhance their photostability for a broad applicability in precision imaging, drug delivery and theranostics.Graphical abstractImage, graphical abstract
  • ROS and GSH-responsive S-nitrosoglutathione functionalized polymeric
           nanoparticles to overcome multidrug resistance in cancer
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Wen Wu, Min Chen, Tingrong Luo, Ying Fan, Jinqiang Zhang, Yan Zhang, Qianyu Zhang, Anne Sapin-Minet, Caroline Gaucher, Xuefeng XiaMultidrug resistance of cancer cells is one of the major obstacle for chemotherapeutic efficiency. Nitric oxide (NO) has raised the potential to overcome multidrug resistance (MDR) with low side effects. Herein, we report a reactive oxygen species (ROS) and glutathione (GSH) responsive nanoparticle for the delivery of NO prodrug such as S-nitrosoglutathione (GSNO), which was chemically conjugated to an amphiphilic block copolymer. The GSNO functionalized nanoparticles show high NO loading capacity, good stability and sustained NO release with specific GSH activated NO-releasing kinetics. Such GSNO functionalized nanoparticles delivered doxorubicin (DOX) in a ROS triggered manner and increased the intracellular accumulation of DOX. However, in normal healthy cells, showing physiological concentrations of ROS, these nanoparticles presented good biocompatibility. The present work indicated that these multifunctional nanoparticles can serve as effective co-delivery platforms of NO and DOX to selectively kill chemo-resistant cancer cells through increasing chemo-sensitivity.Statement of significanceIn this work, we constructed nitric oxide donor (S-nitrosoglutathione, GSNO) functionalized amphiphilic copolymer (PEG-PPS-GSNO) to deliver doxorubicin (DOX). The developed PEG-PPS-GSNO@DOX nanoparticles presented high NO capacity, ROS triggered DOX release and GSH triggered NO release. Thus NO reversed the chemo-resistance in HepG2/ADR cells increasing intrcellular accumulation of DOX. Furthermore, these PEG-PPS-GSNO@DOX nanoparticles exhibited biocompatibility to healthy cells and toxicity to cancer cells, due to elevated ROS.Graphical abstractImage, graphical abstract
  • Gene/paclitaxel co-delivering nanocarriers prepared by framework-induced
           self-assembly for the inhibition of highly drug-resistant tumors
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Chenglong Wang, Wencai Guan, Jinliang Peng, Yuetan Chen, Guoxiong Xu, Hongjing DouWhile drug resistance has been recognized as the main cause of unsuccessful chemotherapy, the efficient inhibition of highly drug-resistant tumors still remains a significant challenge, especially for in vivo treatments. Drug resistance has been associated with the high expression of the multi-drug resistance gene 1 (MDR1), which can encode an efflux transporter known as P-glycoprotein (P-gp) that is located in the cellular membrane. Therefore, the combined delivery of MDR1-inhibited genes and chemotherapeutic drugs is anticipated to enable the effective inhibition of drug-resistant tumors. Herein, highly paclitaxel (PTX)-resistant ovarian (OV) cancer with a drug resistance index reaching up to ~ 60 was chosen to evaluate the performance of an efficient gene/drug co-delivery nanocarrier. Inspired by the self-assembly that occurs in cells and exosomes, we designed a biomimetic lipid/dextran hybrid nanocarrier with a diameter of ~ 100 nm to enhance the endocytosis and the efficiency of drug/gene release within the cells. This nanocarrier was fabricated via the frame-guided self-assembly of lipid amphiphiles on the surfaces of redox-cleavable dextran-based nanogels. The anionic MDR1-siRNA and the hydrophobic drug PTX were respectively loaded into the cationic lipid shell and the hydrophobic internal core of the hybrid nanocarriers. MDR1-siRNA can knock down MDR1, promoting the accumulation of PTX in cells, and thus is expected to achieve an efficient inhibitory effect against highly PTX-resistant cancer cells. Both in vitro and in vivo studies revealed that this dual-delivery system significantly enhanced the therapeutic effect in comparison with that provided by a PTX-only system. Thus, the construction of gene/chemo co-delivered lipid/dextran nanocarriers provides a new strategy to inhibit highly drug-resistant tumors both in vitro and in vivo. In addition, this work will contribute toward the development of urgently needed tumor nanotherapy that is able to overcome drug resistance while also offering an unmatched range of effective therapeutic nanocarriers.Statement of significanceThe biomimetic lipid/dextran hybrid nanocarrier with a diameter of ~ 100 nm, which was fabricated via the frame-guided self-assembly of lipid amphiphiles onto the surface of redox-cleavable dextran-based nanogels, provides a model carrier to co-deliver MDR1-siRNA and PTX.  The MDR1-siRNA/PTX co-loaded biomimetic lipid/dextran hybrid nanocarriers demonstrate good capability in overcoming the PTX-resistance in highly chemo-resistant human ovarian (OV) cancer cells both in vitro and in vivo.Graphical abstractImage, graphical abstract
  • Biocompatible chitosan-carbon nanocage hybrids for sustained drug release
           and highly efficient laser and microwave co-irradiation induced cancer
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Yuliang Guo, Yang Chen, Pomchol Han, Yuxiong Liu, Wenhao Li, Fangliang Zhu, Kai Fu, Maoquan ChuGraphitic carbon nanocages (GCNCs) are unique graphene-based nanomaterials that can be used for cancer photothermal therapy (PTT). However, low toxicity GCNC-based organic/inorganic hybrid biomaterials for microwave irradiation assisted PTT have not yet been reported. In the present study, chitosan (CS)-coated GCNCs (CS-GCNCs) loaded with 5-fluorouracil (5Fu) were used for cancer therapy when activated by 808-nm laser and microwave co-irradiation. The cytotoxicity of GCNCs was significantly reduced after coating with CS. For example, fewer cell-cycle defects were caused by CS-GCNCs in comparison with non-coated GCNCs. The release rate of 5Fu from CS-GCNCs was significantly slower than that of 5Fu from GCNCs, providing sustained release. The release rate could be accelerated by 808-nm laser and microwave co-irradiation. The 5Fu in CS-GCNCs retained high cancer cell killing bioactivity by enhancing the caspase-3 expression level. The cancer cell killing and tumor inhibition efficiencies of the 5Fu-loaded nanomaterials increased significantly under 808-nm laser and microwave co-irradiation. The strong cell killing and tumor ablation activities were due to the synergy of the enhanced GCNC thermal effect caused by laser and microwave co-irradiation and the chemotherapy of 5Fu. Our research opens a door for the development of drug-loaded GCNC-based nano-biomaterials for chemo-photothermal synergistic therapy with the assistance of microwave irradiation.Statement of SignificanceGraphitic carbon nanocages (GCNCs) are graphene-based nanomaterials that can be used for both drug loading and cancer photothermal therapy (PTT). Herein, we showed that chitosan (CS)-GCNCs hybrid biomaterials had very low cytotoxicity, high ability for loading drug, and exhibited sustained drug release. In particular, although low-power microwaves alone are unable to trigger cancer cell damage by GCNCs, the cell killing and mouse tumor inhibition efficiencies were significantly improved by near-infrared (NIR) laser and microwave co-irradiation compared with laser-triggered PTT alone. This combined use of laser and microwave co-irradiation promises essential therapeutic modality and opens a new avenue for PTT.Graphical abstractImage, graphical abstract
  • Antibody-directed metal-organic framework nanoparticles for targeted drug
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Vladimir R. Cherkasov, Elizaveta N. Mochalova, Andrey V. Babenyshev, Julian M. Rozenberg, Ilya L. Sokolov, Maxim P. NikitinNanosized metal-organic frameworks (nMOFs) have shown great promise as high-capacity carriers for a variety of applications. For biomedicine, numerous nMOFs have been proposed that can transport virtually any molecular drug, can finely tune their payload release profile, etc. However, perspectives of their applications for the targeted drug delivery remain relatively unclear. So far, only a few works have reported specific cell targeting by nMOFs exclusively through small ligands such as folic acid or RGD peptides. Here we show feasibility of targeted drug delivery to specific cancer cells in vitro with nMOFs functionalized with such universal tool as an antibody. We demonstrate ca. 120 nm magnetic core/MOFs shell nanoagents loaded with doxorubicin/daunorubicin and coupled with an antibody though a hydrophilic carbohydrate interface. We show that carboxymethyl-dextran coating of nMOFs allows extensive loading of the drug molecules (up to 15.7 mg/g), offers their sustained release in physiological media and preserves antibody specificity. Reliable performance of the agents is illustrated with trastuzumab-guided selective targeting and killing of HER2/neu-positive breast cancer cells in vitro. The approach expands the scope of nMOF applications and can serve as a platform for the development of potent theranostic nanoagents.Statement of significanceThe unique combination of exceptional drug capacity and controlled release, biodegradability and low toxicity makes nanosized metal-organic frameworks (nMOFs) nearly ideal drug vehicles for various biomedical applications. Unfortunately, the prospective of nMOF applications for the targeted drug delivery is still unclear since only a few examples have been reported for nMOF cell targeting, exclusively for small ligands. In this work, we fill the important gap and demonstrate nanoagent that can specifically kill target cancer cells via drug delivery based on recognition of HER2/neu cell surface receptors by such universal and specific tool as antibodies. The proposed approach is universal and can be adapted for specific biomedical tasks using antibodies of any specificity and nMOFs of a various composition.Graphical abstractImage, graphical abstract
  • siRNA release kinetics from polymeric nanoparticles correlate with RNAi
           efficiency and inflammation therapy via oral delivery
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Chunbai He, Haimei Yue, Lu Xu, Yifu Liu, Yudong Song, Cui Tang, Chunhua YinDespite many efforts in the rational design of nanoparticles (NPs) to overcome the biological barriers to small interfering RNA (siRNA) delivery for improving gene silencing efficiency, little is known about the correlations between siRNA release kinetics and RNA interference (RNAi) efficiency and inflammation therapy via oral delivery. On the basis of mannose-modified trimethyl chitosan-cysteine (MTC) polymers, seven types of MTC NPs containing tumor necrosis factor (TNF)-α siRNA were prepared through ionic gelation. The siRNA release kinetics from MTC NPs were finely tuned by adjusting the kinds and amounts of the crosslinkers involved. These MTC NPs exhibited no disparities in siRNA protection against enzymatic degradation in physiological fluids and cellular uptake in macrophages; however, they showed distinct in vitro siRNA release profiles and intracellular unpacking kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for efficient, prompt, and prolonged RNAi, contributing to desired therapeutic efficacy in acute and chronic inflammatory murine models following oral delivery. However, MTC NPs insufficiently releasing siRNA could not elicit effective RNAi. Collectively, the present investigation might provide broad insights into the optimization of siRNA nanocarriers with respect to their release kinetics for improving RNAi efficacies aiming at different types of inflammatory diseases.Statement of significancesiRNA release kinetics in the cytoplasm and pathological characteristics of diseases themselves determine the therapeutic efficacy of siRNA delivery. Herein, by adjusting the kinds and amounts of the crosslinkers involved, we developed seven types of MTC NPs containing TNF-α siRNA with distinct siRNA release kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for prompt and prolonged RNAi, respectively, contributing to desired therapeutic efficacy in acute and chronic inflammation following oral delivery. These results might provide broad insights into the optimization of siRNA nanocarriers in respect to their release kinetics for improving therapeutic outcomes toward different clinical requirements.Graphical abstractImage, graphical abstract
  • Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture
           healing by the transfer of miR-126
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Wei Liu, Linwei Li, Yuluo Rong, Dingfei Qian, Jian Chen, Zheng Zhou, Yongjun Luo, Dongdong Jiang, Lin Cheng, Shujie Zhao, Fanqi Kong, Jiaxing Wang, Zhimin Zhou, Tao Xu, Fangyi Gong, Yifan Huang, Changjiang Gu, Xuan Zhao, Jianling Bai, Feng WangIncreasing evidence has suggested that paracrine mechanisms might be involved in the underlying mechanism of mesenchymal stem cells (MSCs) transplantation, and exosomes are an important component of this paracrine role. However, MSCs are usually exposed to normoxia (21% O2) in vitro but experience large differences in oxygen concentration in the body under hypoxia. Indeed, hypoxic precondition of MSCs can enhance their paracrine effects. The main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (Hypo-Exos) exhibit greater effects on bone fracture healing than those under normoxia (Exos). Using in vivo bone fracture model and in vitro experiments including cell proliferation assay, cell migration assay and so on, we confirmed that Hypo-Exos administration promoted angiogenesis, proliferation and migration to a greater extent when compared to Exos. Furthermore, utilizing a series in vitro and in vivo gain and loss of function experiments, we confirmed a functional role for exosomal miR-126 in the process of bone fracture healing. Meanwhile, we found that knockdown of hypoxia inducible factor 1 (HIF-1α) resulted in a significant decrease of miR-126 in MSCs and exosomes, thereby abolishing the effects of Hypo-Exos. In conclusion, our results demonstrated a mechanism by which Hypo-Exos promote bone fracture healing through exosomal miR-126. Moreover, hypoxia preconditioning mediated enhanced production of exosomal miR-126 through the activation of HIF-1α. Hypoxia preconditioning represents an effective and promising method for the optimization of the therapeutic actions of MSC-derived exosomes for bone fracture healing.Statement of significanceStudies have confirmed that transplantation of exosomes exhibit similar therapeutic effects and functional properties to directly-transplanted stem cells but have less significant adverse effects. However, during in vitro culture conditions, MSCs are usually exposed to normoxia (21% O2) which is very different to the oxygen concentrations found in the body under natural physiological conditions. Our results demonstrated a mechanism by which Hypo-Exos promote bone fracture healing through exosomal miR-126 and the SPRED1/Ras/Erk signaling pathway. Moreover, hypoxia preconditioning mediated enhanced production of exosomal miR-126 through the activation of HIF-1α. Hypoxia preconditioning represents an effective and promising method for the optimization of the therapeutic actions of MSC-derived exosomes for bone fracture healing.Graphical abstractImage, graphical abstract
  • Cuticle sclerotization determines the difference between the elastic
           moduli of locust tibiae
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Chuchu Li, Stanislav N. Gorb, Hamed RajabiA striking characteristic of insect cuticle is the wide range of its material property values, with respect to stiffness, strength and toughness. The elastic modulus of cuticle, for instance, ranges over seven orders of magnitude in different structures and different species. Previous studies suggested that this characteristic is influenced by the microstructure and sclerotization of cuticle. However, the relative role of the two factors in determining the material properties of cuticle is unknown. Here we used a combination of scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) and nanoindentation, to investigate the effect of microstructure and sclerotization on the elastic modulus of tibiae of desert locusts. Our results showed that tibial cuticle is an anisotropic material with the highest elastic modulus along the tibial axis. This is likely because majority of the fibers in the cuticle are oriented along this axis. We also found that the hind tibia has a significantly higher elastic modulus, compared with the fore and mid tibiae. This is likely due to the higher sclerotization level of the hind tibia cuticle, and seems to be an adaptation to the locust locomotion by jumping, in which axial loads in the hind tibiae may reach several times the insect body weight. Our results suggest that while sclerotization determines the difference between the elastic moduli of the tibiae, anisotropic properties of each tibia is controlled by the specific fiber orientation. Our study provides one of only a few comprehensive investigations on insect cuticle, and helps to better understand the structure-material-function relationship in this complex biological composite.Statement of significanceInsect cuticle is a biological composite with strong anisotropy and wide ranges of material properties. Using an example of the tibial cuticle of desert locusts, we examined the role of two influential factors on the elastic modulus of cuticle: microstructure and sclerotization. Our results suggested the strong influence of sclerotization on the variation of the elastic modulus among fore, mid and hind tibiae, and that of the microstructure on the anisotropy of each tibia. Our results deepens the current understanding of the structure-material-function relationship in complex insect cuticle.Graphical abstractImage, graphical abstract
  • Mechanical and structural changes in human thoracic aortas with age
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Majid Jadidi, Mahmoud Habibnezhad, Eric Anttila, Kaspars Maleckis, Anastasia Desyatova, Jason MacTaggart, Alexey KamenskiyAortic mechanical and structural characteristics have profound effects on pathophysiology, but many aspects of physiologic stress-stretch state and intramural changes due to aging remain poorly understood in human tissues. While difficult to assess in vivo due to residual stresses and pre-stretch, physiologic stress-stretch characteristics can be calculated using experimentally-measured mechanical properties and constitutive modeling. Mechanical properties of 76 human descending thoracic aortas (TA) from 13 to 78-year-old donors (mean age 51±18 years) were measured using multi-ratio planar biaxial extension. Constitutive parameters were derived for aortas in 7 age groups, and the physiologic stress-stretch state was calculated. Intramural characteristics were quantified from histological images and related to aortic morphometry and mechanics. TA stiffness increased with age, and aortas became more nonlinear and anisotropic. Systolic and diastolic elastic energy available for pulsation decreased with age from 30 to 8 kPa and from 18 to 5 kPa, respectively. Cardiac cycle circumferential stretch dropped from 1.14 to 1.04, and circumferential and longitudinal physiologic stresses decreased with age from 90 to 72 kPa and from 90 to 17 kPa, respectively. Aortic wall thickness and radii increased with age, while the density of elastin in the tunica media decreased. The number of elastic lamellae and circumferential physiologic stress per lamellae unit remained constant with age at 102±10 and 0.85±0.04 kPa, respectively. Characterization of mechanical, physiological, and structural features in human aortas of different ages can help understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs.Statement of significanceThis manuscript describes mechanical and structural changes occurring in human thoracic aortas with age, and presents material parameters for 4 commonly used constitutive models. Presented data can help better understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs.Graphical abstractImage, graphical abstract
  • Waveguiding and focusing in a bio-medium with an optofluidic cell chain
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Tianli Wu, Xixi Chen, Zhiyong Gong, Yuchao Li, Yao ZhangLong-distance waveguiding and submicron focusing of light in a bio-medium are crucial for biomedical sensing and imaging. Disordered bio-mediums usually exhibit high scattering and absorption, which limits effective waveguiding and focusing. Here, we demonstrate an optofluidic cell chain, assembled via an optical trapping force from an optical fiber probe, to achieve long-distance waveguiding and submicron light focusing in a disordered bio-medium. By applying a trapping light at 980 nm to generate an optical force, stable binding of E. faecalis cells was achieved in a fluid to assemble cell chains of different lengths. The length could reach up to 360 µm and the incident light (at 675, 532 and 473 nm) could be focused into a beam with a waist radius of 400 nm. As a potential practical application, backscattered signals from human red blood cells were detected using the cell chains, which is expected to benefit biomedical sensing and single cell analysis.Statement of significanceWith the assistance of optofluidic techniques, we assembled an E. faecalis cell chain with a length up to 360 µm to achieve long-distance waveguiding and submicron focusing at a propagation loss of 0.03 dB/µm in the bio-medium. Visible lights were launched into the cell chain and the incident lights can converge into a beam with a waist radius of 400 nm. The cell chain was further used to detect the backscattering signals from human red blood cells (RBCs), and the results indicate that the cell chain can be applied as a fully biocompatible extension of the probe for the real-time detection of RBCs in healthy and pathological states.Graphical abstractImage, graphical abstract
  • 3D-microenvironments initiate TCF4 expression rescuing nuclear β-catenin
           activity in MCF-7 breast cancer cells
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Sara Sergio, Addolorata Maria Luce Coluccia, Enrico Domenico Lemma, Barbara Spagnolo, Daniele Vergara, Michele Maffia, Massimo De Vittorio, Ferruccio PisanelloMechanical cues sensed by tumor cells in their microenvironment can influence important mechanisms including adhesion, invasion and proliferation. However, a common mechanosensitive protein and/or pathway can be regulated in different ways among diverse types of tumors. Of particular interest are human breast epithelial cancers, which markedly exhibit a heterogeneous pattern of nuclear β-catenin localization, a protein known to be involved in both mechanotransduction and tumorigenesis. β-catenin can be aberrantly accumulated in the nucleus wherein it binds to and activates lymphoid enhancer factor/T cell factor (LEF/TCF) transcription factors. At present, little is known about how mechanical cues are integrated into breast cancer cells harboring impaired mechanisms of β-catenin's nuclear uptake and/or retention. This prompted us to investigate the influence of mechanical cues on MCF-7 human breast cancer cells which are known to fail in relocating β-catenin into the nucleus due to very low baseline levels of LEF/TCFs. Exploiting three-dimensional (3D) microscaffolds realized by two-photon lithography, we show that surrounding MCF-7 cells have not only a nuclear pool of β-catenin, but also rescue from their defective expression of TCF4 and boost invasiveness. Together with heightened amounts of vimentin, a β-catenin/TCF-target gene regulator of proliferation and invasiveness, such 3D-elicited changes indicate an epithelial-to-mesenchymal phenotypic switch of MCF-7 cells. This is also consistent with an increased in situ MCF-7 cell proliferation that can be abrogated by blocking β-catenin/TCF-transcription activity. Collectively, these data suggest that 3D microenvironments are per se sufficient to prime a TCF4-dependent rescuing of β-catenin nuclear activity in MCF-7 cells. The employed methodology could, therefore, provide a mechanism-based rationale to dissect further aspects of mechanotranscription in breast cancerogenesis, somewhat independent of β-catenin's nuclear accumulation. More importantly, by considering the heterogeneity of β-catenin signaling pathway in breast cancer patients, these data may open alternative avenues for personalized disease management and prevention.Statement of significanceMechanical cues play a critical role in cancer pathogenesis. Little is known about their influence in breast cancer cells harboring impaired mechanisms of β-catenin's nuclear uptake and/or retention, involved in both mechanotransduction and tumorigenesis. We engineered 3D scaffold, by two-photon lithography, to study the influence of mechanical cues on MCF-7 cells which are known to fail in relocating β-catenin into the nucleus. We found that 3D microenvironments are per se sufficient to prime a TCF4-dependent rescuing of β-catenin nuclear activity that boost cell proliferation and invasiveness. Thus, let us suggest that our system could provide a mechanism-based rationale to further dissect key aspects of mechanotranscription in breast cancerogenesis and progression, somewhat independent of β-catenin's nuclear accumulation.Graphical abstractImage, graphical abstract
  • In situ forming and reactive oxygen species-scavenging gelatin hydrogels
           for enhancing wound healing efficacy
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Phuong Le Thi, Yunki Lee, Dieu Linh Tran, Thai Thanh Hoang Thi, Jeon Il Kang, Kyung Min Park, Ki Dong ParkThe overexpression of reactive oxygen species (ROS) contributes to the pathogenesis of numerous diseases such as atherosclerosis, myocardial infarction, cancer, and chronic inflammation. Therefore, the development of materials that can locally control the adverse effects resulting from excessive ROS generation is of great significance. In this study, the antioxidant gallic acid-conjugated gelatin (GGA) was introduced into gelatin-hydroxyphenyl propionic (GH) hydrogels to create an injectable hydrogel with enhanced free radical scavenging properties compared to pure GH hydrogels. The modified hydrogels were rapidly formed by an HRP-catalyzed cross-linking reaction with high mechanical strength and biodegradability. The resulting GH/GGA hydrogels effectively scavenged the hydroxyl radicals and DPPH radicals, and the scavenging capacity could be modulated by varying GGA concentrations. Moreover, in an in vitro H2O2-induced ROS microenvironment, GH/GGA hydrogels significantly suppressed the oxidative damage of human dermal fibroblast (hDFBs) and preserved their viability by reducing intracellular ROS production. More importantly, the ROS scavenging hydrogel efficiently accelerated the wound healing process with unexpected regenerative healing characteristics, shown by hair follicle formation; promoted neovascularization; and highly ordered the alignment of collagen fiber in a full-thickness skin defect model. Therefore, we expect that injectable GH/GGA hydrogels can serve as promising biomaterials for tissue regeneration applications, including wound treatment and other tissue repair related to ROS overexpression.Statement of significanceRecently, many researchers have endeavored to develop injectable hydrogel matrices that can modulate the ROS level to normal physiological processes for the treatment of various diseases. Here, we designed an injectable gelatin hydrogel in which gallic acid, an antioxidant compound, was conjugated onto a gelatin polymer backbone. The hydrogels showed tunable properties and could scavenge the free radicals in a controllable manner. Because of the ROS scavenging properties, the hydrogels protected the cells from the oxidative damage of ROS microenvironment and effectively accelerated the wound healing process with high quality of healed skin. We believe that this injectable ROS scavenging hydrogel has great potential for wound treatment and tissue regeneration, where oxidative damage by ROS contributes to the pathogenesis.Graphical abstractImage, graphical abstract
  • Paracrine signalling from monocytes enables desirable extracellular matrix
           accumulation and temporally appropriate phenotype of vascular smooth
           muscle cell-like cells derived from adipose stromal cells
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Xiaoqing Zhang, Craig A. Simmons, J. Paul SanterreIn vascular tissue engineering, the ability to obtain a robust and safe vascular tissue cell source (e.g. vascular smooth muscle cells (VSMCs)) and to promote vascular tissue-specific extracellular matrix (ECM) protein production is critically important. Mature blood vessel-derived VSMCs are not practical for in vitro vascular tissue regeneration. The authors have conceived a strategy to differentiate adipose derived stromal cells (ASCs) into VSMC-like cells (ASC-VSMCs) that were similar to mature umbilical artery VSMCs at the transcriptional, protein and contraction function levels. Monocytes/macrophages are known as important regulators of the inflammation and regeneration processes within different tissue types of the body. However, our understanding of the potential interactions between specific tissue-like cells differentiated from stem/stromal cells (e.g. ASC-VSMCs) and monocytes/macrophages (cued by specific biomaterial scaffolds) is still limited. In this study, indirect and direct ASC-VSMC-monocyte co-cultures were constructed within a porous polyurethane scaffold (D-PHI) previously shown to have an immunomodulatory character. The effects of monocytes/macrophages on the cellularity (cell number detected with DNA quantification assay), ECM (glycosaminoglycan (GAG), collagen, and elastin) accumulation as well as the maintenance of contractile VSMC markers (calponin and smoothelin) of the ASC-VSMCs after a month of co-culture were investigated. It was found that monocyte paracrine signalling in D-PHI positively affected the cellularity and ECM accumulation of ASC-VSMCs in co-culture. Cause-effect relationships were also identified between the release of pro-inflammatory/anti-inflammatory factors (i.e. IL6, TGF-β1) in co-culture and the expression of contractile proteins (calponin and smoothelin) by ASC-VSMCs. This study demonstrated the importance of combining an immune cell strategy with stromal cell derived VSMCs (i.e. ASC-VSMCs) to achieve a practical vascular tissue engineering outcome.Statement of significanceAdipose stromal cell derived-vascular smooth muscle cells (ASC-VSMCs) are a promising cell source for vascular tissue engineering. Monocytes/monocyte derived macrophages can be harnessed as an immune-assisted strategy to promote vascular tissue regeneration. This study demonstrated that the co-culture of human ASC-VSMCs with monocytes significantly enhanced the cellularity and extracellular matrix (ECM) accumulation within anionic polyurethane (D-PHI) scaffolds, partially mediated by monocyte paracrine signalling mechanisms. In addition, specific VSMC contractile markers (calponin and smoothelin) were still present in ASC-VSMCs when the cells were exposed to monocytes for a month in vitro. This study corroborated the potential selection of ASC-VSMCs for in vitro engineering of vascular tissue in an immunomodulatory biomaterial scaffold (e.g. D-PHI) based co-culture system containing monocytes.Graphical abstractImage, graphical abstract
  • Correlations between macrophage polarization and osteoinduction of porous
           calcium phosphate ceramics
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Xuening Chen, Menglu Wang, Fuying Chen, Jing Wang, Xiangfeng Li, Jie Liang, Yujiang Fan, Yumei Xiao, Xingdong ZhangThe host immune response is critical for in situ osteogenesis, but correlations between local inflammatory reactions and biomaterial osteoinduction are still poorly understood. This study used a murine intramuscular implantation model to demonstrate that calcium phosphate ceramics with different phase compositions exhibited divergent osteoinductivities. The osteoinductive potential of each ceramic was closely associated with the immunomodulatory capacity of the material, and especially with the regulation of macrophage polarization and functional status. Biphasic calcium phosphate (BCP) ceramics with superior osteoinductive potential enhanced the fraction of CD206+ M2 macrophages, up-regulated expression of M2 phenotypic markers in vitro, and increased the ARG+ M2 population in vivo. This suggested that BCP ceramics could ameliorate long-term inflammation and build a pro-osteogenic microenvironment. However, β-tricalcium phosphate (β-TCP) ceramics with no obvious osteoinductivity increased the fraction of CCR7+ M1 macrophages, promoted the secretion of M1 phenotypic markers in vitro, and maintained a high proportion of iNOS+ M1 macrophages in vivo. It indicated that β-TCP ceramics could exacerbate inflammation and inhibit ectopic bone formation. Hydroxyapatite ceramics with an intermediate osteoinductivity exhibited a moderate amount of both M1 and M2 macrophages. These findings highlight the critical role of macrophage polarization in biomaterial-dependent osteoinduction, which not only deepens our understanding of osteoinductive mechanisms but also provides a strategy to design bone substitutes by endowing materials with the proper immunomodulatory abilities to achieve the desired clinic performance.Statement of SignificanceCalcium phosphate (CaP) ceramics with osteoinductive capacities are able to induce ectopic bone formation in non-osseous sites. However, its underlying mechanism is largely unknown. Previous studies have demonstrated an indispensable role of macrophages in osteogenesis, inspiring us that local inflammatory reaction may affect material-dependent osteoinduction. This study indicated that CaP ceramics with different phase composition could present divergent osteoinductive capacities through modulating polarization and functional status of macrophages, as biphasic calcium phosphate with potent osteoinductivity ameliorated long-term inflammation and induced a healing-associated M2 phenotype to initiate bone formation. These findings not only get an insight into the mechanism of CaP-involved osteoinduction, but also help the design of tissue-inducing implants by endowing biomaterials with proper immunomodulatory ability.Graphical abstractImage, graphical abstract
  • A self-assembling peptide hydrogel-based drug co-delivery platform to
           improve tissue repair after ischemia-reperfusion injury
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Shuyun Liu, Meng Zhao, Yijie Zhou, Ling Li, Chengshi Wang, Yujia Yuan, Lan Li, Guangneng Liao, William Bresette, Younan Chen, Jingqiu Cheng, Yanrong Lu, Jingping LiuIschemia-reperfusion (I/R)-induced organ injury is a serious health problem worldwide, and poor recovery of acute phase injury leads to chronic fibrosis and further organ dysfunction. Thus, a more precise approach to enhance tissue repair is needed. By using a renal I/R model, we aimed to evaluate the role of a hydrogel-based dual-drug delivery platform on promoting tissue repair. An injectable, self-assembling peptide/heparin (SAP/Hep) hydrogel was used to co-deliver TNF-α neutralizing antibody (anti-TNF-α) and hepatocyte growth factor (HGF). The microstructure and controlled release properties of KLD2R/Hep hydrogel were analyzed. The effects of the drug-loaded hydrogel (SAP-drug) on renal injury were evaluated in mice with I/R injury. In vitro, the SAP/Hep hydrogel allowed for a faster release of anti-TNF-α with a sustained release of HGF, and both drugs maintained their bioactivities after release. In vivo, combined anti-TNF-α/HGF showed better renal protective potential than anti-TNF-α or HGF alone. SAP-drug (anti-TNF-α/HGF in SAP hydrogel) treatment reduced the level of serum creatinine (Scr), blood urea nitrogen (BUN), tubular apoptosis, renal inflammatory factors, and macrophage infiltration compared to Free-drug (anti-TNF-α/HGF in solution) or SAP alone. Moreover, the SAP-drug group had better efficacy on promoting tubular cell proliferation and dedifferentiation than SAP or Free-drug alone, and thus reduced chronic renal fibrosis in I/R mice. This study highlighted that SAP could sequentially deliver the two drugs to achieve anti-inflammatory and pro-proliferative effects with one injection and thus is a promising delivery platform for tissue repair.Statement of significanceIschemia-reperfusion (I/R)-induced organ injury is a serious health issue, and delayed tissue repair leads to chronic fibrosis and organ failure. Systemic administration of anti-inflammatory agents or growth factors have shown some benefits on I/R injury, but their therapeutic efficacy was limited by side effects, poor bioavailability, and absent key signals of tissue repair. To address these issues, a hydrogel-based drug co-delivery platform was used to treat I/R injury. This platform could achieve sequential release kinetics with faster rate of anti-TNF-ɑ and slower rate of HGF, and effectively promoted tissue repair by targeting inflammation and proliferation in mice with renal I/R. This nanoscale delivery platform represents a promising strategy for solid organs (heart, liver and kidney) regeneration after I/RGraphical abstractImage, graphical abstract
  • Catechol-thiol-based dental adhesive inspired by underwater mussel
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Dohoon Lee, Hyogeun Bae, Jinsoo Ahn, Taegon Kang, Deog-Gyu Seo, Dong Soo HwangThe critical problem associated with the underwater mussel adhesive catechol-based 3,4-dihydroxy-L-phenylalanine (DOPA) is its sensitivity to oxidation. To overcome this problem, mussels underwent etching in the presence of acidic pH conditions (
  • Evaluation of a conducting elastomeric composite material for
           intramuscular electrode application
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): X. Sally Zheng, Azante Y. Griffith, Emily Chang, Michael J. Looker, Lee E. Fisher, Brady Clapsaddle, X. Tracy CuiElectrical stimulation of the muscle has been proven efficacious in preventing atrophy and/or reanimating paralyzed muscles. Intramuscular electrodes made from metals have significantly higher Young's Moduli than the muscle tissues, which has the potential to cause chronic inflammation and decrease device performance. Here, we present an intramuscular electrode made from an elastomeric conducting polymer composite consisting of PEDOT-PEG copolymer, silicone and carbon nanotubes (CNT) with fluorosilicone insulation. The electrode wire has a Young's modulus of 804 (±99) kPa, which better mimics the muscle tissue modulus than conventional stainless steel (SS) electrodes. Additionally, the non-metallic composition enables metal-artifact free CT and MR imaging. These soft wire (SW) electrodes present comparable electrical impedance to SS electrodes of similar geometric surface area, activate muscle at a lower threshold, and maintain stable electrical properties in vivo up to 4 weeks. Histologically, the SW electrodes elicited significantly less fibrotic encapsulation and less IBA-1 positive macrophage accumulation than the SS electrodes at one and three months. Further phenotyping the macrophages with the iNOS (pro-inflammatory) and ARG-1 (pro-healing) markers revealed significantly less presence of pro-inflammatory macrophage around SW implants at one month. By three months, there was a significant increase in pro-healing macrophages (ARG-1) around the SW implants but not around the SS implants. Furthermore, a larger number of AchR clusters closer to SW implants were found at both time points compared to SS implants. These results suggest that a softer implant encourages a more intimate and healthier electrode-tissue interface.Statement of significanceIntramuscular electrodes made from metals have significantly higher Young's Moduli than the muscle tissues, which has the potential to cause chronic inflammation and decrease device performance. Here, we present an intramuscular electrode made from an elastomeric conducting polymer composite consisting of PEDOT-PEG copolymer, silicone and carbon nanotubes with fluorosilicone insulation. This elastomeric composite results in an electrode wire with a Young's modulus mimicking that of the muscle tissue, which elicits significantly less foreign body response compared to stainless steel wires. The lack of metal in this composite also enables metal-artifact free MRI and CT imaging.Graphical abstractImage, graphical abstract
  • Vascular reconstruction: A major challenge in developing a functional
           whole solid organ graft from decellularized organs
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Kamal Hany Hussein, Kyung-Mee Park, Lina Yu, Su-Hyeon Song, Heung-Myong Woo, Ho-Hyun KwakBioengineering a functional organ holds great potential to overcome the current gap between the organ need and shortage of available organs. Whole organ decellularization allows the removal of cells from large-scale organs, leaving behind extracellular matrices containing different growth factors, structural proteins, and a vascular network with a bare surface. Successful application of decellularized tissues as transplantable organs is hampered by the inability to completely reline the vasculature by endothelial cells (ECs), leading to blood coagulation, loss of vascular patency, and subsequent death of reseeded cells. Therefore, an intact, continuous layer of endothelium is essential to maintain proper functioning of the vascular system, which includes the transfer of nutrients to surrounding tissues and protecting other types of cells from shear stress. Here, we aimed to summarize the available cell sources that can be used for reendothelialization in addition to different trials performed by researchers to reconstruct vascularization of decellularized solid organs. Additionally, different techniques for enhancing reendothelialization and the methods used for evaluating reendothelialization efficiency along with the future prospective applications of this field are discussed.Statement of significanceDespite the great progress in whole organ decellularization, reconstruction of vasculature within the engineered constructs is still a major roadblock. Reconstructed endothelium acts as a multifunctional barrier of vessels, which can reduce thrombosis and help delivering of oxygen and nutrients throughout the whole organ. Successful reendothelialization can be achieved through reseeding of appropriate cell types on the naked vasculature with or without modification of its surface. Here, we present the current research milestones that so far established to reconstruct the vascular network in addition to the methods used for evaluating the efficiency of reendotheilization. Thus, this review is quite significant and will aid the researchers to know where we stand toward biofabricating a transplantable organ from decellularizd extracellular matrix.Graphical abstractImage, graphical abstract
  • Topical antimicrobial peptide formulations for wound healing: Current
           developments and future prospects
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Raj Kumar Thapa, Dzung B. Diep, Hanne Hjorth TønnesenAntimicrobial peptides (AMPs) are the natural antibiotics recognized for their potent antibacterial and wound healing properties. Bare AMPs have limited activity following topical application attributable to their susceptibility to environment (hydrolysis, oxidation, photolysis), and wound (alkaline pH, proteolysis) related factors as well as minimal residence time. Therefore, the formulation of AMPs is essential to enhance stability, prolong delivery, and optimize effectiveness at the wound site. Different topical formulations of AMPs have been developed so far including nanoparticles, hydrogels, creams, ointments, and wafers to aid in controlling bacterial infection and enhance wound healing process in vivo. Herein, an overview is provided of the AMPs and current understanding of their formulations for topical wound healing applications along with suitable examples. Furthermore, future prospects for the development of effective combination AMP formulations are discussed.Statement of SignificanceChronic wound infection and subsequent development of antibiotic resistance are serious clinical problems affecting millions of people worldwide. Antimicrobial peptides (AMPs) possess great potential in effectively killing the bacteria with minimal risk of resistance development. However, AMPs susceptibility to degradation following topical application limits their antimicrobial and wound healing effects. Therefore, development of an optimized topical formulation with high peptide stability and sustained AMP delivery is necessary to maximize the antimicrobial and wound healing effects. The present review provides an overview of the state-of-art in the field of topical AMP formulations for wound healing. Current developments in the field of topical AMP formulations are reviewed and future prospects for the development of effective combination AMP formulations are discussed.Graphical abstractImage, graphical abstract
  • Silk biomaterials in wound healing and skin regeneration therapeutics:
           From bench to bedside
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Dimple Chouhan, Biman B. MandalSilk biomaterials are known for biomedical and tissue engineering applications including drug delivery and implantable devices owing to their biocompatible and a wide range of ideal physico-chemical properties. Herein, we present a critical overview of the progress of silk-based matrices in skin regeneration therapeutics with an emphasis on recent innovations and scientific findings. Beginning with a brief description of numerous varieties of silks, the review summarizes our current understanding of the biological properties of silk that help in the wound healing process. Various silk varieties such as silkworm silk fibroin, silk sericin, native spider silk and recombinant silk materials have been explored for cutaneous wound healing applications from the past few decades. With an aim to harness the regenerative properties of silk, numerous strategies have been applied to develop functional bioactive wound dressings and viable bio-artificial skin grafts in recent times. The review examines multiple inherent properties of silk that aid in the critical events of the healing process such as cell migration, cell proliferation, angiogenesis, and re-epithelialization. A detailed insight into the progress of silk-based cellular skin grafts is also provided that discusses various co-culture strategies and development of bilayer and tri-layer human skin equivalent under in vitro conditions. In addition, functionalized silk matrices loaded with bioactive molecules and antibacterial compounds are discussed, which have shown great potential in treating hard-to-heal wounds. Finally, clinical studies performed using silk-based translational products are reviewed that validate their regenerative properties and future applications in this area.Statement of significanceThe review article discusses the recent advances in silk-based technologies for wound healing applications, covering various types of silk biomaterials and their properties suitable for wound repair and regeneration. The article demonstrates the progress of silk-based matrices with an update on the patented technologies and clinical advancements over the years.The rationale behind this review is to highlight numerous properties of silk biomaterials that aid in all the critical events of the wound healing process towards skin regeneration. Functionalization strategies to fabricate silk dressings containing bioactive molecules and antimicrobial compounds for drug delivery to the wound bed are discussed. In addition, a separate section describes the approaches taken to generate living human skin equivalent that have recently contributed in the field of skin tissue engineering.Graphical abstractImage, graphical abstract
  • Prospects and strategies for magnesium alloys as biodegradable implants
           from crystalline to bulk metallic glasses and composites—A review
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Faisal Kiani, Cuie Wen, Yuncang LiAs a biodegradable metal (BM), alloys of magnesium (Mg) offer great potential as an alternative to the permanent metallic implants currently being used for fracture repairs and tissue-healing processes. These alloys exhibit superior biocompatibility and appropriate mechanical strength and dissolution behavior in the physiological environment, essential prerequisites for a BM. However, rapid and generally non-uniform corrosion has been the major drawback of Mg alloys. Abrupt deterioration in mechanical strength is experienced due to the inhomogeneous corrosion, which is also considered detrimental to the surface passivation process. This review has analyzed a variety of strategies that can be adopted to address the core challenges with Mg alloy biomaterials. In addition, the review provides fundamental understanding of the mechanisms associated with these challenging problems, including discussion of crystalline and bulk metallic glasses (BMGs) and composites. Comparison among the properties and mechanisms observed in other metal alloy systems, including zinc (Zn) and iron (Fe) alloys and prominent BMGs, are also presented for analysis in order to provide new approaches to resolving the critical issues of Mg alloys.Statement of SignificanceThe effects of alloying elements, microstructure, heat treatment and deformation on the mechanical and corrosion properties of biodegradable metals such as Mg-based alloys and bulk metal glasses (BMGs) are identified. Theoretical models and experimental findings are comprehensively analyzed to corroborate the actual corrosion and deformation mechanisms observed in biodegradable metals (BMs). This work also provides an in-depth comparison of mechanical and corrosion properties among the prominent biodegradable metal alloy systems, illustrating a clear outlook on their potentials. The proposed strategies to address the current challenges in BMs are substantiated with fundamental theories and experimental evidence.Graphical abstractImage, graphical abstract
  • A soft-chemistry approach to the synthesis of amorphous calcium
           ortho/pyrophosphate biomaterials of tunable composition
    • Abstract: Publication date: February 2020Source: Acta Biomaterialia, Volume 103Author(s): Laëtitia Mayen, Nicholai D. Jensen, Danielle Laurencin, Olivier Marsan, Christian Bonhomme, Christel Gervais, Mark E. Smith, Cristina Coelho, Guillaume Laurent, Julien Trebosc, Zhehong Gan, Kuizhi Chen, Christian Rey, Christèle Combes, Jérémy SouliéThe development of amorphous phosphate-based materials is of major interest in the field of biomaterials science, and especially for bone substitution applications. In this context, we herein report the synthesis of gel-derived hydrated amorphous calcium/sodium ortho/pyrophosphate materials at ambient temperature and in water. For the first time, such materials have been obtained in a large range of tunable orthophosphate/pyrophosphate molar ratios. Multi-scale characterization was carried out thanks to various techniques, including advanced multinuclear solid state NMR. It allowed the quantification of each ionic/molecular species leading to a general formula for these materials: [(Ca2+y Na+z H+3+x-2y-z)(PO43−)1-x(P2O74−)x](H2O)u. Beyond this formula, the analyses suggest that these amorphous solids are formed by the aggregation of colloids and that surface water and sodium could play a role in the cohesion of the whole material. Although the full comprehension of mechanisms of formation and structure is still to be investigated in detail, the straightforward synthesis of these new amorphous materials opens up many perspectives in the field of materials for bone substitution and regeneration.Statement of significanceThe metastability of amorphous phosphate-based materials with various chain length often improves their (bio)chemical reactivity. However, the control of the ratio of the different phosphate entities has not been yet described especially for small ions (pyrophosphate/orthophosphate) and using soft chemistry, whereas it opens the way for the tuning of enzyme- and/or pH-driven degradation and biological properties. Our study focuses on elaboration of amorphous gel-derived hydrated calcium/sodium ortho/pyrophosphate solids at 70 °C with a large range of orthophosphate/pyrophosphate ratios. Multi-scale characterization was carried out using various techniques such as advanced multinuclear SSNMR (31P, 23Na, 1H, 43Ca). Analyses suggest that these solids are formed by colloids aggregation and that the location of mobile water and sodium could play a role in the material cohesion.Graphical abstractImage, graphical abstract
  • Surface modification of corneal prosthesis with nano-hydroxyapatite to
           enhance in vivo biointegration
    • Abstract: Publication date: Available online 22 January 2020Source: Acta BiomaterialiaAuthor(s): Andri K. Riau, Nyein C. Lwin, Larisa Gelfand, Huanlong Hu, Bo Liedberg, James Chodosh, Subbu S. Venkatraman, Jodhbir S. MehtaABSTRACTThe majority of clinical corneal prostheses (KPros) adopt a core-skirt configuration. This configuration is favored owing to the optic core (generally a cylindrical, acrylic-based material, such as PMMA), that not only provides a clear window for the patients’ vision, but also confers resistance to biodegradability. The surrounding skirt (typically a biological material, such as corneal tissue) allows for host tissue integration. However, due to poor biointegration between the dissimilar core and skirt materials, it results in a weak adhesion at the interface, giving rise to clinical complications, such as bacterial infections in the tissue-PMMA interface and device extrusion. Here, we physically immobilized nano-hydroxyapatite (nHAp) on a PMMA cylinder via a dip-coating technique, to create a bioactive surface that improved biointegration in vivo. We established that the nHAp coating was safe and stable in the rabbit cornea over five weeks. More importantly, we found that apoptotic, wound healing and inflammatory responses to nHAp-coated PMMA were substantially milder than to non-coated PMMA. More mature collagen, similar to the non-operated cornea, was maintained in the corneal stroma adjacent to the nHAp-coated implant edge. However, around the non-coated cylinder, an abundant new and loose connective tissue formed, similar to bone tissue response to bioinert scaffolds. As a result of superior biointegration, tissue adhesion with nHAp-coated PMMA cylinders was also significantly enhanced compared to non-coated cylinders. This study set a precedent for the future application of the nHAp coating on clinical KPros.Statement of SignificanceCurrently, all clinical corneal prostheses utilize as-manufactured, non-surface modified PMMA optic cylinder. The bioinert cylinder, however, has poor biointegration and adhesion with the surrounding biological tissue, which can give rise to postoperative complications, such as microbial invasion in the tissue-PMMA loose interface and PMMA optic cylinder extrusion. In the current study, we showed that surface modification of the PMMA cylinder with bioactive nano-hydroxyapatite (nHAp) significantly enhanced its biointegration with corneal stromal tissue in vivo. The superior biointegration of the nHAp-coated PMMA was signified by a more attenuated corneal wound healing, inflammatory and fibrotic response, and better tissue apposition, as well as a significantly improved corneal stromal tissue adhesion when compared to the non-coated PMMA.Graphical abstractImage, graphical abstract
  • Graft Alignment Impacts the Regenerative Response of Skeletal Muscle After
           Volumetric Muscle Loss in a Rat Model
    • Abstract: Publication date: Available online 22 January 2020Source: Acta BiomaterialiaAuthor(s): John Kim, Ben Kasukonis, Kevin Roberts, Grady Dunlap, Lemuel Brown, Tyrone Washington, Jeffrey WolchokA key event in the etiology of volumetric muscle loss (VML) injury is the bulk loss of structural cues provided by the underlying extracellular matrix (ECM). To re-establish the lost cues, there is broad consensus within the literature supporting the utilization of implantable scaffolding. However, while scaffold based regenerative medicine strategies have shown potential, there remains a significant amount of outcome variability observed across the field. We suggest that an overlooked source of outcome variability is differences in scaffolding architecture. The goal of this study was to test the hypothesis that implant alignment has a significant impact on genotypic and phenotypic outcomes following the repair of VML injuries. Using a rat VML model, outcomes across three autograft implant treatment groups (aligned implants, 45° misaligned, and 90° misaligned) and two recovery time points (2 weeks and 12 weeks) were examined (n=6-8/group). At 2 weeks post-repair there were no significant differences in muscle mass and torque recovery between the treatment groups, however we did observe a significant upregulation of MyoD (2.5 fold increase) and Pax7 (2 fold increase) gene expression as well as the presence of immature myofibers at the implant site for those animals repaired with aligned autografts. By 12 weeks post-repair, functional and structural differences between the treatment groups could be detected. Aligned autografts had significantly greater mass and torque recovery (77±10% of normal) when compared to 45° and 90° misaligned autografts (64±10% and 61±11%, respectively). Examination of tissue structure revealed extensive fibrosis and a significant increase in non-contractile tissue area fraction for only those animals treated using misaligned autografts. When taken together, the results suggest that implant graft orientation has a significant impact on in-vivo outcomes and indicate that the effect of graft alignment on muscle phenotype may be mediated through genotypic changes to myogenesis and fibrosis at the site of injury and repair.Statement of SignificanceA key event in the etiology of volumetric muscle loss injury is the bulk loss of architectural cues provided by the underlying extracellular matrix. To re-establish the lost cues, there is broad consensus within the literature supporting the utilization of implantable scaffolding. Yet, although native muscle is a highly organized tissue with network and cellular alignment in the direction of contraction, there is little evidence within the field concerning the importance of re-establishing native architectural alignment. The results of this study suggest that critical interactions exist between implant and native muscle alignment cues during healing, which influence the balance between myogenesis and fibrosis. Specifically, it appears that alignment of implant architectural cues with native muscle cues is necessary to create a pro-myogenic environment and contractile force recovery. The results also suggest that misaligned cues may be pathological, leading to fibrosis and poor contractile force recovery.Graphical Image, graphical abstract
  • Tough Combinatorial Poly(urethane-isocyanurate) Polymer Networks and
    • Abstract: Publication date: Available online 21 January 2020Source: Acta BiomaterialiaAuthor(s): P.J. Driest, D.J. Dijkstra, D. Stamatialis, D.W. GrijpmaThe development of tough hydrogels is an essential but challenging topic in biomaterials research that has received much attention over the past years. By the combinatorial synthesis of polymer networks and hydrogels based on prepolymers with different properties, new materials with widely varying characteristics and unexpected properties may be identified. In this paper, we report on the properties of combinatorial poly(urethane-isocyanurate) (PUI) type polymer networks that were synthesized by the trimerization of mixtures of NCO-functionalized poly(ethylene glycol) (PEG), poly(propylene gylcol) (PPG), poly(ε-caprolactone) (PCL) and poly(trimethylene carbonate) (PTMC) prepolymers in solution. The resulting polymer networks showed widely varying material properties.Combinatorial PUI networks containing at least one hydrophilic PEG component showed high water uptakes of>100wt%. The resulting hydrogels demonstrated elastic moduli of up to 10.1 MPa, ultimate tensile strengths of up to 9.8 MPa, elongation at break values of up to 624.0% and toughness values of up to 53.4 MJ•m−3. These values are exceptionally high and show that combinatorial PUI hydrogels are among the toughest hydrogels reported in the literature. Also, the simple two-step synthesis and wide range of suitable starting materials make this synthesis method more versatile and widely applicable than the existing methods for synthesizing tough hydrogels. An important finding of this work is that the presence of a hydrophobic network component significantly enhances the toughness and tensile strength of the combinatorial PUI hydrogels in the hydrated state. This enhancement is the largest when the hydrophobic network component is crystallizable in nature. In fact, the PUI hydrogels containing a crystallizable hydrophobic network component are shown to be semi-crystalline in the water-swollen state. Due to their high toughness values in the water-swollen state together with their water uptake values, elastic moduli and ultimate tensile strengths, the developed hydrogels are expected to be promising materials for biomedical coating- and adhesive applications, as well as for tissue-engineering.Graphical Image, graphical abstract
  • Controllable biodegradation and enhanced osseointegration of ZrO2 nanofilm
           coated Zn-Li alloy: in vitro and in vivo studies
    • Abstract: Publication date: Available online 20 January 2020Source: Acta BiomaterialiaAuthor(s): Wei Yuan, Dandan Xia, Yufeng Zheng, Xiangmei Liu, Shuilin Wu, Bo Li, Yong Han, Zhaojun Jia, Donghui Zhu, Liqun Ruan, Kazuki Takashima, Yunsong Liu, Yongsheng ZhouABSTRACTZinc and its alloys have emerged as a new research direction of biodegradable metals (BMs) due to the significant physiological functions of Zn2+ ions in human body. However, low inhibitory concentration threshold value to cause cytotoxicity by Zn2+ ions during in vitro study and delayed osseointegration in vivo are two key flaws for the bulk Zn-based BMs. To combat these issues, we constructed a barrier layer of ZrO2 nanofilm on the surface of Zn-0.1(wt.%) Li alloy via atomic layer deposition (ALD). A decreased release of Zn2+ ions accompanied with accelerated release of Li+ ions was observed on account of galvanic coupling between the coating compositions and Zn-0.1Li alloy substrate. Cytocompatibility assay reflected that ZrO2 nanofilm coated Zn-0.1Li alloy exhibited improved cell adhesion and viability. Histological analysis also demonstrated better in vivo osseointegration for the ZrO2 nanofilm coated Zn-0.1Li alloy. Hence, the present study elucidated that the ALD of ZrO2 nanofilm on Zn-based BMs can effectively promote osseointegration and control their biodegradation behavior.Statement of SignificanceZn-Li binary alloy was reported recently to be the promising biodegradable metals with ultimate tensile strength over 500MPa, yet the low inhibitory concentration threshold value to cause cytotoxicity by Zn2+ ions is the obstacle needed to be overcome. As a pilot study, a systematic investigation on the ZrO2 nanofilm coated Zn-Li alloy, prepared by atomic layer deposition (ALD) technique, was conducted in the present study, which involved in the formation process, in vitro and in vivo degradation behavior as well as biocompatibility evaluation. We found a controllable corrosion rate and better in vivo osseointegration can be achieved by ZrO2 nanofilm coating on Zn-Li alloy, which provides new insight into the surface modification on biodegradable Zn alloys for usage within bone.Graphical abstractImage, graphical abstract
  • Self-healing DNA-based Injectable Hydrogels with Reversible Covalent
           Linkages for Controlled Drug Delivery
    • Abstract: Publication date: Available online 20 January 2020Source: Acta BiomaterialiaAuthor(s): Sayantani Basu, Settimio Pacelli, Arghya PaulABSTRACTInjectable hydrogels represent a valuable tool for the delivery of therapeutic molecules aimed to restore the functionality of damaged tissues. In this study, we report the design of a nanocomposite DNA-based hydrogel crosslinked with oxidized alginate (OA) via the formation of reversible imine linkages. The formulated hydrogel functioned as an injectable carrier for the sustained delivery of a small molecule drug, simvastatin. The degree of oxidation of alginate and the concentration of silicate-based nanoparticles (nSi) were varied to modulate the rheological properties of the hydrogels. Specifically, the formulations consisting of OA with higher degree of oxidation displayed the highest value of storage moduli, yield stress, yield strain, and rapid recovery after removal of cyclic stress. The hydrogel formulations exhibited self-healing and shear-thinning properties due to the reversible nature of the covalent imine bonds formed between the aldehyde groups of OA and the amine groups present in the DNA nucleotides. Moreover, the incorporation of charged nSi further enhanced the shear strength of the formulated hydrogels by establishing electrostatic interactions with the phosphate groups of the DNA network. The optimized hydrogel was able to promote the sustained release of simvastatin for more than a week. The bioactivity of the released drug was confirmed by testing its ability to induce osteogenic differentiation and migration of human adipose-derived stem cells in vitro. Overall, the results obtained from this study demonstrate that DNA could be used as a natural biopolymer to fabricate self-healing injectable hydrogels with sustained release properties for minimally invasive therapeutic approaches.Statement of SignificanceDynamic covalent chemistry, especially Schiff base reactions have emerged as a promising route for the formation of injectable hydrogels. Our study demonstrated the development of a DNA-based self-healing hydrogel formed via Schiff base reaction occurring at physiological conditions. The hydrogels functioned as sustained delivery vehicles for the hydrophobic drug simvastatin, which requires a polymeric carrier for controlled delivery of therapeutic concentrations of the drug without exhibiting cytotoxic effects. Presently available hydrogel-based drug delivery systems encounter major challenges for the delivery of hydrophobic drugs due to the hydrophilic nature of the base matrix. Our strategy presents a platform technology for the design of minimally invasive approaches for the sustained delivery of hydrophobic drugs similar to simvastatin.Graphical abstractImage, graphical abstract
  • Bioresorbable Silk Grafts for Small Diameter Vascular Tissue Engineering
           Applications: In vitro and In vivo Functional Analysis
    • Abstract: Publication date: Available online 17 January 2020Source: Acta BiomaterialiaAuthor(s): Prerak Gupta, Katherine L. Lorentz, Darren G. Haskett, Eoghan M. Cunnane, Aneesh K. Ramaswamy, Justin S. Weinbaum, David A. Vorp, Biman B. MandalThe success of tissue-engineered vascular graft (TEVG) predominantly relies on the selection of a suitable biomaterial and graft design. Natural biopolymer silk has shown great promise for various tissue-engineering applications. This study is the first to investigate Indian endemic non-mulberry silk (Antheraea assama-AA) – which inherits naturally superior mechanical and biological traits (e.g., RGD motifs) compared to Bombyx mori-BM silk, for TEVG applications. We designed bi-layered biomimetic small diameter AA-BM silk TEVGs adopting a new fabrication methodology. The inner layer showed ideally sized (∼40 μm) pores with interconnectivity to allow cellular infiltration, and an outer dense electrospun layer that confers mechanical resilience. Biodegradation of silk TEVGs into amino acids as resorbable byproducts corroborates their in vivo remodeling ability. Following our previous reports, we surgically implanted human adipose tissue-derived stromal vascular fraction (SVF) seeded silk TEVGs in Lewis rats as abdominal aortic interposition grafts for 8 weeks. Adequate suture retention strength (0.45 ± 0.1 N) without any blood seepage post-implantation substantiate the grafts’ viability. AA silk-based TEVGs showed superior animal survival and graft patency compared to BM silk TEVGs. Histological analysis revealed neo-tissue formation, host cell infiltration and graft remodeling in terms of extracellular matrix turnover. Altogether, this study demonstrates promising aspects of AA silk TEVGs for vascular tissue engineering applications.Statement of SignificanceClinical ‘off the shelf’ implementation of tissue-engineered vascular grafts (TEVGs) remains a challenge. Achieving optimal blood vessel regeneration requires the use of bioresorbable materials having suitable degradation rates while producing minimal or no toxic byproducts. Host cell recruitment and preventing acute thrombosis are other pre-requisites for successful graft remodeling. In this study, for the first time we explored the use of naturally derived Indian endemic non-mulberry Antheraea assama silk in combination with Bombyx mori silk for TEVG applications by adopting a new biomimetic approach. Our bi-layered silk TEVGs were optimally porous, mechanically resilient and biodegradable. In vivo implantation in rat aorta showed long-term patency and graft remodeling by host cell infiltration and extracellular matrix deposition corroborating their clinical feasibility.Graphical abstractImage, graphical abstract
  • Co-delivery of 2-Deoxyglucose and a Glutamine Metabolism Inhibitor V9302
           via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism
           in Cancer
    • Abstract: Publication date: Available online 17 January 2020Source: Acta BiomaterialiaAuthor(s): Zhangyi Luo, Jieni Xu, Jingjing Sun, Haozhe Huang, Ziqian Zhang, Weina Ma, Zhuoya Wan, Yangwuyue Liu, Apurva Pardeshi, Song LiThe unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells’ compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier poly-(oligo ethylene glycol)-co-poly(4-((4-oxo-4-((4-vinylbenzyl)oxy)butyl)disulfaneyl)butanoic acid)-(2-deoxyglucose) (POEG-p-2DG) was developed. POEG-p-2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (∼10nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.Graphical abstractImage, graphical abstract
  • Molecular and skeletal fingerprints of scleractinian coral
           biomineralization: From the sea surface to mesophotic depths
    • Abstract: Publication date: Available online 16 January 2020Source: Acta BiomaterialiaAuthor(s): Assaf Malik, Shai Einbinder, Stephane Martinez, Dan Tchernov, Sivan Haviv, Ricardo Almuly, Paul Zaslansky, Iryna Polishchuk, Boaz Pokroy, Jarosław Stolarski, Tali MassReef-building corals, the major producers of biogenic calcium carbonate, form skeletons in a plethora of morphological forms. Here we studied skeletal modifications of Stylophora pistillata (clade 4) colonies that adapt to different depths with decreasing light availability. They show notable transitions from spherical morphologies (shallow depths, 5 m deep) to flat and branching geometries (at 60 m mesophotic depths). Such changes are typically ascribed to the algal photosymbiont physiological feedback with the coral host. We find specific fine-scale skeletal variability in accretion of structure at shallow- and mesophotic depth morphotypes that suggest underlying genomic regulation of biomineralization pathways of the coral host. To explain this, we conducted comparative morphology-based analyses, including microscopy, electron microscopy and X-ray analysis coupled with a comprehensive transcriptomic analysis of S. pistillata samples originated from Gulf of Eilat in the Red Sea collected along a depth gradient from the sea surface (5 m deep) to mesophotic depths (up to 60 m). Additional samples were experimentally transplanted from 5 m to 60 m and from 60 m to 5 m. Interestingly, both morphologically and functionally, transplanted corals partly adapt by exhibiting typical depth-specific properties. In mesophotic depths, we find that the organic matrix fraction is enriched in the coralla, results corroborated by overrepresentation of biomineralization “tool-kit” structural extracellular genes. These results provide insights into the molecular mechanisms of coral calcification and skeletal adaptation that repeatedly allowed this group to adapt to a range of environments presumably with a rich geological past.Graphical abstractImage, graphical abstract
  • High Oxygen Preservation Hydrogels to Augment Cell Survival under Hypoxic
    • Abstract: Publication date: Available online 15 January 2020Source: Acta BiomaterialiaAuthor(s): Hong Niu, Chao Li, Ya Guan, Yu Dang, Xiaofei Li, Zhaobo Fan, Jie Shen, Liang Ma, Jianjun GuanCell therapy is a promising approach for ischemic tissue regeneration. However, high death rate of delivered cells under low oxygen condition, and poor cell retention in tissues largely limit the therapeutic efficacy. Using cell carriers with high oxygen preservation has potential to improve cell survival. To increase cell retention, cell carriers that can quickly solidify at 37 °C so as to efficiently immobilize the carriers and cells in the tissues are necessary. Yet there lacks cell carriers with these combined properties. In this work, we have developed a family of high oxygen preservation and fast gelation hydrogels based on N-isopropylacrylamide (NIPAAm) copolymers. The hydrogels were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of NIPAAm, acrylate-oligolactide (AOLA), 2-hydroxyethyl methacrylate (HEMA), and methacrylate-poly(ethylene glycol)-perfluorooctane (MAPEGPFC). The hydrogel solutions exhibited sol-gel temperatures around room temperature and were flowable and injectable at 4˚C. They can quickly solidify (≤ 6 s) at 37˚C to form flexible gels. These hydrogels lost 9.4∼29.4% of their mass after incubation in Dulbecco's Phosphate-Buffered Saline (DPBS) for 4 weeks. The hydrogels exhibited a greater oxygen partial pressure than DPBS after being transferred from a 21% O2 condition to a 1% O2 condition. When bone marrow mesenchymal stem cells (MSCs) were encapsulated in the hydrogels and cultured under 1% O2, the cells survived and proliferated during the 14-day culture period. In contrast, the cells experienced extensive death in the control hydrogel that had low oxygen preservation capability. The hydrogels possessed excellent biocompatibility. The final degradation products did not provoke cell death even when the concentration was as high as 15 mg/ml, and the hydrogel implantation did not induce substantial inflammation. These hydrogels are promising as cell carriers for cell transplantation into ischemic tissues.Statement of SignificanceStem cell therapy for ischemic tissues experiences low therapeutic efficacy largely due to poor cell survival under low oxygen condition. Using cell carriers with high oxygen preservation capability has potential to improve cell survival. In this work, we have developed a family of hydrogels with this property. These hydrogels promoted the encapsulated stem cell survival and growth under low oxygen condition.Graphical abstractImage, graphical abstract
  • Biofunctionalized chondrogenic shape-memory ternary scaffolds for
           efficient cell-free cartilage regeneration
    • Abstract: Publication date: Available online 15 January 2020Source: Acta BiomaterialiaAuthor(s): Huixia Xuan, Haoran Hu, Congying Geng, Jianchun Song, Yifan Shen, Dong Lei, Qingbao Guan, Shichang Zhao, Zhengwei YouCartilage defect repair remains a great clinical challenge due to the limited self-regeneration capacity of cartilage tissue. Surgical treatment of injured cartilage is rather difficult due to the narrow space in the articular cavity and irregular defect area. Herein, we designed and fabricated chondrogenic and physiological-temperature-triggered shape-memory ternary scaffolds for cell-free cartilage repair, where the poly (glycerol sebacate) (PGS) networks ensured elasticity and shape recovery, crystallized poly (1,3-propylene sebacate) (PPS) acted as switchable phase, and immobilized bioactive kartogenin (KGN) endowed the scaffolds with chondrogenic capacity. The resultant scaffolds exhibited shape-memory properties with shape-memory fixed ratio of 98% and recovered ratio of 97% at 37°C for PPS/PGS/KGN-100, indicating a good potential for minimally invasive implantation. The scaffolds gradually degraded in Dulbecco's phosphate-buffered saline and released KGN up to 12 weeks in vitro. In addition, the scaffolds promoted chondrogenic differentiation while inhibiting osteogenic differentiation of bone marrow-derived mesenchymal stem cells in a concentration-dependent manner and cartilage regeneration in full-thickness defects of rat femoropatellar groove for 12 weeks. Consequently, the PPS/PGS/KGN-100 scaffolds stimulated the formation of an overlying layer of neocartilage mimicking the characteristic architecture of native articular cartilage even in the absence of exogenous growth factors and seeded cells. This study provides much inspiration for future research on cartilage tissue engineering.Statement of SignificanceThere are two crucial challenges for cartilage defect repair: the lack of self-regeneration capacity of cartilage tissue and difficult scaffold implantation via traditional open surgery due to space-limited joints. Herein, bioactive body-temperature-responsive shape memory scaffolds are designed to simultaneously address the challenges. The scaffolds can be readily implanted by minimally invasive approach and recover by body-temperature of patient. The integration of kartogenin endows scaffolds the bioactivity, leading to the first example of bulk shape-memory scaffolds for cell-free cartilage repair. These characteristics make the scaffolds advantageous for clinical translation. Moreover, our developed material is easy to be functionalized due to the presence of extensive free hydroxyl groups and provides a versatile platform to design diverse functional shape memory biomaterials.Graphical abstractImage, graphical abstract
  • Gelatin content governs hydration induced structural changes in
           silica-gelatin hybrid aerogels – Implications in drug delivery
    • Abstract: Publication date: Available online 15 January 2020Source: Acta BiomaterialiaAuthor(s): Mónika Kéri, Attila Forgács, Vanda Papp, István Bányai, Péter Veres, Adél Len, Zoltán Dudás, István Fábián, József KalmárSilica-gelatin hybrid aerogels of varying gelatin content (from 4wt.% to 24wt.%) can be conveniently impregnated with hydrophobic active agents (e.g. ibuprofen, ketoprofen) in supercritical CO2 and used as drug delivery systems. Contrast variation neutron scattering (SANS) experiments show the molecular level hybridization of the silica and the gelatin components of the aerogel carriers. The active agents are amorphous, and homogeneously dispersed in these porous, hybrid matrices. Importantly, both fast and retarded drug release can be achieved with silica-gelatin hybrid aerogels, and the kinetics of drug release is governed by the gelatin content of the carrier. In this paper, for the first time, a molecular level explanation is given for the strong correlation between the composition and the functionality of a family of aerogel based drug delivery systems. Characterization of the wet aerogels by SANS and by NMR diffusiometry, cryoporometry and relaxometry revealed that the different hydration mechanisms of the aerogels are responsible for the broad spectrum of release kinetics. Low-gelatin (4 – 11wt.%) aerogels retain their open-porous structure in water, thus rapid matrix erosion dictates fast drug release from these carriers. In contrast to this, wet aerogels of high gelatin content (18 – 24wt.%) show well pronounced hydrogel-like characteristics, and a wide gradual transition zone forms in the solid-liquid interface. The extensive swelling of the high-gelatin hybrid backbone results in the collapse of the open porous structure, that limits mass transport towards the release medium, resulting in slower, diffusion controlled drug release.Statement of SignificanceDeveloping new drug delivery systems is a key aspect of pharmaceutical research. Supercritically dried mesoporous aerogels are ideal carriers for small molecular weight drugs due to their open porous structures and large specific surface areas. Hybrid silica-gelatin aerogels can display both fast and retarded drug release properties based on the gelatin contents of their backbones. The structural characterization of the aerogels by SANS and by NMR diffusiometry, cryoporometry and relaxometry revealed that the different hydration mechanisms of the hybrid backbones are responsible for the broad spectrum of release kinetics. The molecular level understanding of the functionality of these hybrid inorganic-biopolymer drug delivery systems facilitates the realization of quality-by-design in this research of the field.Graphical abstractImage, graphical abstract
  • Neutrophil membrane-enveloped nanoparticles for the amelioration of renal
           ischemia-reperfusion injury in mice
    • Abstract: Publication date: Available online 15 January 2020Source: Acta BiomaterialiaAuthor(s): Zhaohui Liu, Xiangge Liu, Qiang Yang, Lili Yu, Yulin Chang, Min QuIschemia-reperfusion (I/R) injury initiates and exacerbates a series of oxidative and inflammatory events, and causes high morbidity and mortality. Despite the progress made with recent clinical use of anti-malarial drugs, the response rate of I/R injury treatment remains unsatisfactory. Here, we showed a neutrophil membrane-enveloped Coenzyme Q (N-NPCoQ10) nanoparticle strategy for I/R injury treatment. We validated the physicochemical and biological reproducibility of the nanoparticles and tested the protective effects of N-NPCoQ10 in oxygen-glucose deprivation/reperfusion model and renal I/R injury mouse model. N-NPCoQ10 nanoparticles administration exhibited synergistic protective effect against I/R injury, which significantly reduced oxidative damage in vitro and in vivo, inhibited renal cell apoptosis, attenuated inflammatory response in renal I/R injury model, and finally improved renal function of I/R injury mice. The N-NPCoQ10 nanoparticles administration provides an efficient way to deliver anti-oxidant that suppresses oxidative damages and neutralize proinflammatory cytokines during renal I/R injury, which might be a potential strategy for renal acute kidney injury treatment.Graphical abstractImage, graphical abstract
  • A Free-floating Mucin Layer to Investigate the Effect of the Local
           Microenvironment in Lungs on Mucin-Nanoparticle Interactions
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Feng Wan, Mikkel Herzberg, Zheng Huang, Tue Hassenkam, Hanne M. NielsenRespiratory tract mucus represents an important barrier for pulmonary drug delivery. Understanding of mucin-nanoparticle interactions is a prerequisite for rational design of inhalable nanoparticles. In the present study, in order to establish a reliable quartz crystal microbalance with dissipation (QCM-D) approach to reveal the effect of the lung microenvironment on the mucin-nanoparticle interactions, we investigated the intrinsic features of the mucin layers immobilized onto sensors via chemical conjugation or physical adsorption by using atomic force microscopy (AFM) and QCM-D. Our results demonstrated that the covalently-grafted mucin layer responded more sensitively than the physically-adsorbed mucin layer to the local microenvironment shifting from PBS (pH 7.35 and ionic strength 30 mM) to PBS (pH 6.25 and ionic strength 150 mM) and resulted in a softer mucin layer with more hydrophobic areas exposed. Furthermore, using the QCM-D approach with the covalently-grafted mucin layer, we demonstrated the significant influence of the local microenvironment on the interaction of mucin with poly (lactic-co-glycolic acid)-based nanoparticles with different surface hydrophilicity. The present work underlines the QCM-D approach with a covalently-grafted mucin layer as a potent tool to elucidate the potential influence of local microenvironment on mucin-nanoparticle interactions.Graphic abstractImage, graphical abstract
  • Myofibroblast activation in synthetic fibrous matrices composed of dextran
           vinyl sulfone
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Christopher D. Davidson, Danica Kristen P. Jayco, Daniel L. Matera, Samuel J. DePalma, Harrison L. Hiraki, William Y. Wang, Brendon M. BakerMechanical interactions between fibroblasts and their surrounding extracellular matrix (ECM) guide fundamental behaviors such as spreading, migration, and proliferation that underlie disease pathogenesis. The challenges of studying ECM mechanics in vivo have motivated the development of in vitro models of the fibrous ECM in which fibroblasts reside. Natural materials such as collagen hydrogels bear structural and biochemical resemblance to stromal ECM, but mechanistic studies in these settings are often confounded by cell-mediated material degradation and the lack of structural and mechanical tunability. Here, we established a new material system composed of electrospun dextran vinyl sulfone (DexVS) polymeric fibers. These fibrous matrices exhibit mechanical tunability at both the single fiber (80 – 340 MPa) and bulk matrix (0.77 – 11.03 kPa) level, as well as long-term stability in mechanical properties over a two-week period. Cell adhesion to these matrices can be either user-defined by functionalizing synthetic fibers with thiolated adhesive peptides or methacrylated heparin to sequester cell-derived ECM proteins. We utilized DexVS fibrous matrices to investigate the role of matrix mechanics on the activation of fibroblasts into myofibroblasts, a key step of the fibrotic progression. In contrast to previous findings with non-fibrous hydrogel substrates, we find that fibroblasts in soft and deformable matrices exhibit increased spreading, focal adhesion formation, proliferation, and myofibroblast activation as compared to cells on stiffer matrices with equivalent starting architecture.Graphical abstractImage, graphical abstract
  • Bio-inspired human in vitro outer retinal models: Bruch's membrane and its
           cellular interactions
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Ashley R. Murphy, Yen B. Truong, Carmel M. O'Brien, Veronica GlattauerRetinal degenerative disorders, such as age-related macular degeneration (AMD), are one of the leading causes of blindness worldwide, however, treatments to completely stop the progression of these debilitating conditions are non-existent. Researchers require sophisticated models that can accurately represent the native structure of human retinal tissue to study these disorders. Current in vitro models used to study the retina are limited in their ability to fully recapitulate the structure and function of the retina, Bruch's membrane and the underlying choroid. Recent developments in the field of induced pluripotent stem cell technology has demonstrated the capability of retinal pigment epithelial cells to recapitulate AMD-like pathology. However, such studies utilise unsophisticated, bio-inert membranes to act as Bruch's membrane and support iPSC-derived retinal cells. This review presents a concise summary of the properties and function of the Bruch's membrane-retinal pigment epithelium complex, the initial pathogenic site of AMD as well as the current status for materials and fabrication approaches used to generate in vitro models of this complex tissue. Finally, this review explores required advances in the field of in vitro retinal modelling.Graphical Image, graphical abstract
  • Identification of a calcium phosphoserine coordination network in an
           adhesive organo-apatitic bone cement system
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Fioleda P. Kesseli, Caroline S. Lauer, Ian Baker, Katherine A. Mirica, Douglas W. Van CittersCalcium phosphate-based bone cements have been widely adopted in both orthopedic and dental applications. Phosphoserine (pSer), which has a natural role in biomineralization, has been identified to possess the functionality to react with calcium phosphate phases, such as tetracalcium phosphate (TTCP) and α-tricalcium phosphate (α-TCP), and form a uniquely adhesive cement. This study investigated the chemical composition and phase evolution of a heterogeneous calcium phosphate (56% TTCP and 15% α-TCP) and pSer cement system with respect to pH. The coordination network of calcium phosphoserine monohydrate was discovered as the predominant crystalline phase of this adhesive apatitic cement system. Furthermore, it was determined that pH has a significant effect on the reaction kinetics of the system, whereby a lower pH tends to accelerate the reaction rate and favor products with lower Ca/P ratios. These findings provide a better understanding of the reaction and products of this adhesive organo-ceramic cement, which can be compositionally tuned for broad applications in the orthopedic and dental spaces.Graphical Image, graphical abstract
  • Tumor-targeted nanoplatform for in situ oxygenation-boosted immunogenic
           phototherapy of colorectal cancer
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Huamei He, Lanlan Liu, Ruijing Liang, Haimei Zhou, Hong Pan, Shengping Zhang, Lintao CaiAdvanced colorectal cancer has a high mortality rate since conventional treatments have limited therapeutic effects and poor prognosis with high risks of metastasis and recurrence. Photodynamic therapy (PDT) is a promising treatment modality for the eradication of colorectal cancer, but its curative efficacy is severely affected by tumor hypoxia. Herein, we developed a core-shell gold nanocage coated with manganese dioxide and hyaluronic acid (AMH) for targeted delivery to colorectal tumors and oxygenation-boosted immunogenic phototherapy in situ. The AMH nanoparticles can generate abundant oxygen from mild acidic/H2O2 medium, which can further enhance the PDT efficacy of AMH itself under near infrared (NIR) irradiation. Meanwhile, AMH-based PDT induced immunogenic cell death (ICD) of tumor cells with damage-associated molecular patterns (DAMPs) release and facilitated the dendritic cells (DCs) maturation to further potentiate the systematic antitumor immunity against advanced tumors. In vivo experiment results exhibited that AMH nanoparticles not only had the ability of targeting tumor but also in situ produced sufficient oxygen to relieve the tumor hypoxia. Furthermore, AMH-mediated oxygen-boosted immunogenic PDT effectively inhibited the tumor growth and recurrence. Thus, this work provides a potent targeted delivery nanoplatform for enhanced immunogenic PDT against advanced cancers.Graphical abstractIn situ oxygen-boosted immunogenic photodynamic therapy (PDT) with AMH nanoparticles was introduced for colorectal tumor elimination. AMH nanoparticles can generate abundant oxygen from mild acidic/H2O2 medium. AMH-based PDT induced immunogenic cell death (ICD) of tumor cells with damage-associated molecular patterns (DAMPs) release and facilitated the dendritic cells (DCs) maturation to further potentiate the systematic antitumor immunity against advanced tumors.Image, graphical abstract
  • Neutrophil-mediated transport is crucial for short-circulating magnetic
           nanoparticles delivery to tumors
    • Abstract: Publication date: Available online 13 January 2020Source: Acta BiomaterialiaAuthor(s): Victor Naumenko, Aleksey Nikitin, Anastasiia Garanina, Pavel Melnikov, Stepan Vodopyanov, Ksenia Kapitanova, Daria Potashnikova, Daniil Vishnevskiy, Irina Alieva, Artem Ilyasov, Barbara Z. Eletskaya, Maxim Abakumov, Vladimir Chekhonin, Alexander MajougaRecently neutrophil-based nanoparticles (NPs) drug delivery systems have gained considerable attention in cancer therapy. Numerous studies have been conducted to identify optimal NPs parameters for passive tumor targeting, while there is a fundamental dearth of knowledge about the factors governing cell-mediated delivery. Here, using intravital microscopy and magnetic resonance imaging we describe accumulation dynamics of 140 nm magnetic cubes and clusters in murine breast cancer (4T1) and colon cancer (CT26) models. Notwithstanding rapid clearance from the blood flow, NPs readily accumulated in tumors at later time points. Both NPs types were captured mostly by intravascular neutrophils immediately after injection and transmigration of NPs -bound neutrophils through the vessel wall was first shown in real-time. A dramatic drop in NPs accumulation upon Ly6G and Gr1 depletion further confirmed neutrophils role as a biocarrier for targeting tumors. Of note, for shorter circulating NPs a cell-dependent delivery route was more impactful, while the accumulation of longer circulating counterpart was less compromised by neutrophil depletion. Neutrophil-mediated transport was also shown to depend on tumor type being more efficient in neutrophil-rich tumors. Revealing NPs characteristics and host factors influencing the neutrophil-based tumor targeting will help to rationally design drug delivery systems for improved cancer treatment.Graphical abstractImage, graphical abstract
  • Stability and bioactivity of pepCD47 attachment on stainless steel
    • Abstract: Publication date: Available online 11 January 2020Source: Acta BiomaterialiaAuthor(s): Vaishali V. Inamdar, Emmett Fitzpatrick, Ivan Alferiev, Chandrasekaran Nagaswami, Lynn A. Spruce, Hossein Fazelinia, George Bratinov, Steven H. Seeholzer, Robert J. Levy, Ilia Fishbein, Stanley J. StachelekIn-stent restenosis (ISR) and late stent thrombosis are the major complications associated with the use of metal stents and drug eluting stents respectively. Our lab previously investigated the use of peptide CD47 in improving biocompatibility of bare metal stents in a rat carotid stent model and our results demonstrated a significant reduction in platelet deposition and ISR. However, this study did not characterize the stability of the pepCD47 on metal surfaces post storage, sterilization and deployment. Thus, the objective of the present study was 1) to test the stability of the peptide post - storage, sterilization, exposure to shear and mechanical stress and 2) to begin to expand our current knowledge of pepCD47 coated metal surfaces into the preclinical large animal rabbit model. Our results show that the maximum immobilization density of pepCD47 on metal surfaces is approximately 350 ng/cm2. 100% of the pepCD47 was retained on the metal surface post 24 weeks of storage at 4°C, exposure to physiological shear stress, and mechanical stress of stent expansion. The bioactivity of the pepCD47 was found to be intact post 24 weeks of storage and ethylene oxide sterilization. Finall our ex vivo studies demonstrated that compared to bare metal the rabbit pepCD47 coated surfaces showed - 45% reduced platelet adhesion, a 10-fold decrease in platelet activation, and 93% endothelial cell retention. Thus, our data suggests that pepCD47 coating on metal surfaces is stable and rabbit pepCD47 shows promising preliminary results in preventing thrombosis and not inhibiting the growth of endothelial cells.Statement of significanceBiocompatibility of bare metal stents is a major challenge owing to the significantly high rates of in-stent restenosis. Previously we demonstrated that peptide CD47 functionalization improves the biocompatibility of bare metal stents in rat model. A similar trend was observed in our ex vivo studies where rabbit blood was perfused over the rabbit pepCD47 functionalized surfaces. These results provide valuable proof of concept data for future in vivo rabbit model studies. In addition, we investigated stability of the pepCD47 on metal surface and observed that pepCD47 coating is stable over time and resistant to industrially relevant pragmatic challenges.Graphical abstractImage, graphical abstract
  • Multifunctional carboxymethyl chitosan derivatives-layered double
           hydroxide hybrid nanocomposites for efficient drug delivery to the
           posterior segment of the eye
    • Abstract: Publication date: Available online 10 January 2020Source: Acta BiomaterialiaAuthor(s): Yanyan Wang, Li Zhou, Lei Fang, Feng CaoEfficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. To explore drug delivery system of organic-inorganic hybrid nanocomposites for the efficient delivery of dexamethasone disodium phosphate (DEXP), a targeted hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives was designed. A special substrate of peptide transporter-1 (PepT-1) and glutathione was modified on CMCS. CMCS-glutathione-glycylsarcosine (CMCG-GS) and CMCS-glutathione-valyl-valine (CMCG-VV)-LDH hybrid nanocomposites were prepared and structurally confirmed. The in vitro experiments on human conjunctival epithelial cells showed noncytotoxicity (LDH concentration ≤ 100.0 μg/mL) and enhanced permeability for hybrid nanocomposites. Additionally, cellular uptake of the CMCG-GS-DEXP-LDH (10:1) nanocomposite eye drops involved clathrin-mediated endocytosis and PepT-1 mediated actively targeting transport. Results of the in vivo precorneal retention study showed an 8.35-fold, 2.87-fold and 2.58-fold increase of AUC0–6h, Cmax and MRT for CMCG-GS-DEXP-LDH (10:1) hybrid nanocomposite eye drops, respectively, compared to that of the commercial product. Fluorescence imaging of fluorescein isothiocyanate isome (FITC)-loaded LDH hybrid nanocomposites demonstrated that FITC could diffuse into the choroid-retina with the shelter of LDH and CMCG-GS. The presence of a strong fluorescence signal of FITC-conjugated LDH hybrid nanocomposites in the sclera revealed that integral LDH nanocarrier reached the sclera. In the tissue distribution evaluation of rabbit's eyes, DEXP of CMCG-GS-DEXP-LDH (10:1) nanocomposites group retained in the target of the choroid-retina for 3 h with final concentration at 120.04 ng/g. Furthermore, the results of fluorescence imaging and tissue distribution suggested that the intraocular transport pathway for the hybrid nanocomposites is the conjunctival-scleral route. Consequently, the developed hybrid nanocomposites offer a simple and efficient strategy for topically administered drug delivery to the posterior segment of the eye.Statement of SignificanceEfficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. In this manuscript, hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives were designed. The multifunctional properties of these hybrid nanocomposites were attributed to active targeting, bioadhesive capacity and penetration enhancement. Visualization of transport routes of fluorescein isothiocyanate-conjugated LDH hybrid nanocomposites demonstrated that the integral LDH nanocarrier reached the sclera through the conjunctival-scleral pathway, and the loaded drug could further diffuse to the retina. The multifunctional CMCS derivatives-LDH hybrid nanocomposites could be applied for the efficient drug delivery to the posterior segment of the eye through noninvasive topical instillation.Graphical abstract(A) Schematic design of the multifunctional carboxymethyl chitosan derivatives-layered double hydroxide hybrid nanocomposites, CMCG-GS -DEXP-LDH. (B) The scheme of drug diffusion routes into the retina for the CMCG-GS-DEXP-LDH hybrid nanocomposite eye drops.Image, graphical abstract
  • Multifunctional Gap-Enhanced Raman Tags for Preoperative and
           Intraoperative Cancer Imaging
    • Abstract: Publication date: Available online 9 January 2020Source: Acta BiomaterialiaAuthor(s): Bowen Shi, Benyan Zhang, Yuqing Zhang, Yuqing Gu, Chao Zheng, Jing Yan, Weibo Chen, Fuhua Yan, Jian Ye, Huan ZhangMulti-modality imaging agents are desirable for tumor diagnosis because they can provide more alternative and reliable information for accurate detection and therapy of diseases than single imaging technique. However, most reported conventional imaging agents have not been found to successfully overcome the disadvantages of traditional diagnoses such as sensitivity, spatial resolution, short half-decay time and complexity. Therefore, exploring a multifunctional nanocomposite with the combination of their individual modality characteristics has great impact on preoperative imaging and intraoperative diagnosis of cancer. In our study, mesoporous silica gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) specifically for preoperative and intraoperative imaging are designed and their imaging capability and biosafety are examined. They exhibit strong attenuation property for computed X-ray tomography (CT) imaging, high T1 relaxivity for magnetic resonance (MR) imaging capability and surface-enhanced Raman spectroscopy (SERS) signal with good dispersity and stability, which presents CT/MR/SERS multi-mode imaging performance of the tumor of mice within a given time. Furthermore, in vivo biodistribution and long-term toxicity studies reveal that the Gd-GERTs have good biocompatibility and bio-safety. Therefore, Gd-GERTs are of great potential as a multifunctional nanoplatform for accurate preoperative CT/MRI diagnosis and intraoperative Raman imaging-guide resection of cancers.Statement of SignificanceRecent advances in molecular imaging technology have provided a myriad of opportunities to prepare various nanomaterials for accurate diagnosis and response evaluation of cancer via different imaging modalities. However, single bioimaging modality is still challenging to overcome the issues such as sensitivity, spatial resolution, imaging speed and complexity for clinicians. In this work, we designed a kind of unique multifunctional nanoprobes with computed X-ray tomography/magnetic resonance/surface-enhanced Raman spectroscopy (CT/MR/SERS) triple-modal imaging capabilities. Multifunctional nanotags offer the capabilities of preoperative noninvasive CT/MR imaging for identification of tumors as well as intraoperative real-time SERS imaging for guidance of complete resection of tumors. These multifunctional nanoprobes show critical clinical significance on the improvement of tumor diagnosis and therapy.Graphical abstractImage, graphical abstract
  • Sequential-targeting nanocarriers with pH-controlled charge reversal for
           enhanced mitochondria-located photodynamic-immunotherapy of cancer
    • Abstract: Publication date: Available online 9 January 2020Source: Acta BiomaterialiaAuthor(s): Na Peng, Hui Yu, Wenjie Yu, Mian Yang, Hongxiang Chen, Tao Zou, Kai Deng, Shiwen Huang, Yi LiuABSTRACTTargeting delivery of photosensitizers to mitochondria as the most sensitive cellular organelles to reactive oxygen species (ROS) by positively charged polymeric nanocarriers (NCs) is one of the useful methods for efficient photodynamic therapy (PDT). However, the NCs with positively charged mitochondria-targeting moieties are easily cleaned during circulation, restricting their in vivo applications. Herein, to address this issue and enhance in vivo PDT efficacy, we developed a sequential-targeting delivery system consisting of mitochondria-targeting micelles as the core prepared from the cationic amphiphilic copolymer for loading chlorin e6 (Ce6) and a tumor-targeting pH-dependent charge transformational layer as the shell obtained from 2,3-dimethylmaleic anhydride modified Biotin-PEG4000-NH2 (BioPEGDMA) via electrostatic interaction. Concealed by the anionic shell, the as-prepared NCs showed longer retention within the first stage of tumor-targeting. Then, the accumulated NCs conversed to positive charge in tumor extracellular microenvironment (pH ∼ 6.5), which could be more effectively internalized by tumor cells, and the re-exposed triphenylphosphonium (TPP) groups endowed their second-stage targetability to the mitochondria. In vivo experiments revealed that the Ce6-loaded NCs exhibited remarkable tumor inhibition rates of 84.1% and 93.2% on BALB/c nude mice and Kunming mice, respectively, under 660 nm NIR irradiation, and stimulated immune responses with upregulated expression of IFN-γ, TNF-α and CD3+ in tumor tissues, and enhanced activation of CD3+/CD4+, CD3+/CD8+ T lymphocytes and DCs in both tumor tissues and lymph glands. This work provided a new pathway for the development of smart drug delivery system with advanced PDT efficacy.Statement of significanceAlthough the existing targeting delivery of photosensitizers to mitochondria by positively charged nanocarriers (NCs) have efficiently enhanced photodynamic therapy (PDT), their positive charges caused rapid clearance during circulation, which has restricted their in vivo applications. Therefore, we fabricated a novel sequential-targeting NC to solve the problem. The tumor accumulated NCs conversed to positive charge in tumor extracellular microenvironment, and the re-exposed triphenylphosphonium groups initiated second-stage targetability to mitochondria. This system exhibited remarkable tumor inhibition efficiency both in vitro and in vivo. Moreover, as we hypothesized, mitochondria-located PDT could promote immune response, resulting in improvement of PDT. The strategy of sequential targeting-based PDT in combination with augmented immune response showed a novel pathway for the development of smart drug delivery system with advanced PDT.Graphical abstractCe6 loaded micelles (TPPM) coated with BioPEGDMA obtained from 2, 3-dimethylmaleic anhydride modified Biotin-PEG4000-NH2 via electrostatic interaction for sequential tumor and mitochondria targeted delivery, generation of ROS under illumination, and stimulated immune responses in tumor cells. Image, graphical abstract
  • Molybdenum – A biodegradable implant material for structural
    • Abstract: Publication date: Available online 9 January 2020Source: Acta BiomaterialiaAuthor(s): Christian Redlich, Peter Quadbeck, Michael Thieme, Bernd KiebackMolybdenum as a potentially new biodegradable material was investigated. Degradation behavior of commercially high purity molybdenum was observed in simulated physiological salt solutions (Kokubo's SBF with/without TRIS-HCl, Cu2+ addition and 0.9 % NaCl solution). Potentiodynamic polarization, immersion mass loss and ion concentration measurements paired with REM/EDX analysis reveal gradual dissolution of molybdenum in the proper order of magnitude for stent application, associated with formation of thin, non-passivating corrosion products. The underlying corrosion mechanism is discussed as well as a comparison to literature data. However, formation of calcium phosphates (CaP) in SBF significantly decreases corrosion rates. In-situ polarization was found to be a potential way for overcoming this problem and simultaneously enhancing corrosion above the benchmark for a degradable stent material.Graphical Image, graphical abstract
  • Newly formed and remodeled human bone exhibits differences in the
           mineralization process
    • Abstract: Publication date: Available online 9 January 2020Source: Acta BiomaterialiaAuthor(s): Andreas Roschger, Wolfgang Wagermaier, Sonja Gamsjaeger, Norbert Hassler, Ingo Schmidt, Stéphane Blouin, Andrea Berzlanovich, Gerlinde M. Gruber, Richard Weinkamer, Paul Roschger, Eleftherios P. Paschalis, Klaus Klaushofer, Peter FratzlDuring human skeletal growth, bone is formed via different processes. Two of them are: new bone formation by depositing bone at the periosteal (outer) surface and bone remodeling corresponding to a local renewal of tissue. Since in remodeling formation is preceded by resorption, we hypothesize that modeling and remodeling could require radically different transport paths for ionic precursors of mineralization. While remodeling may recycle locally resorbed mineral, modeling implies the transport over large distances to the site of bone apposition. Therefore, we searched for potential differences of size, arrangement and chemical composition of mineral particles just below surfaces of modeling and remodeling sites in femur midshaft cross-sections from healthy children. These bone sites were mapped using scanning synchrotron X-ray scattering, Raman microspectroscopy, energy dispersive X-ray analysis and quantitative backscattered electron microscopy.The results show clear differences in mineral particle size and composition between the sites, which cannot be explained by a change in the rate of mineral apposition or accumulation. At periosteal modeling sites, mineral crystals are distinctly larger, display higher crystallinity and exhibit a lower calcium to phosphorus ratio and elevated Na and Mg content. The latter may originate from Mg used for phase stabilization of mineral precursors and therefore indicate different time periods for mineral transport. We conclude that the mineralization process is distinctively different between modeling and remodeling sites due to varying requirements for the transport distance and, therefore, the stability of non-crystalline ionic precursors, resulting in distinct compositions of the deposited mineral phase.Graphical Image, graphical abstract
  • The Role of Calcium Phosphate Surface Structure in Osteogenesis and the
           Mechanism Involved
    • Abstract: Publication date: Available online 9 January 2020Source: Acta BiomaterialiaAuthor(s): Dongqin Xiao, Jingwei Zhang, Chengdong Zhang, Davide Barbieri, Huipin Yuan, Lorenzo Moroni, Gang FengCalcium phosphate (CaP) ceramics have been widely used for bone regeneration because of their ability to induce osteogenesis. Surface properties, including chemical composition and surface structure, are known to play a crucial role in osteoconduction and osteoinduction. This review systematically analyzes the effects of surface properties, in particular the surface structure, of CaP scaffolds on cell behavior and new bone formation. We also summarize the possible signaling pathways involved in the osteogenic differentiation of bone-related cells when cultured on surfaces with various structures in vitro. The significant immune response initiated by surface structure involved in osteogenic differentiation of cells is also discussed in this review. Taken together, the new biological principle for advanced biomaterials is not only to directly stimulate osteogenic differentiation of bone-related cells but also to modulate the immune response in vivo. Although the reaction mechanism responsible for bone formation induced by CaP surface structure is not clear yet, the insights on surface structure-mediated osteogenic differentiation and osteoimmunomodulation could aid the optimization of CaP-based biomaterials for bone regeneration.Graphical abstractImage, graphical abstract
  • Peptide-Enhanced Tumor Accumulation of Upconversion Nanoparticles for
           Sensitive Upconversion Luminescence/Magnetic Resonance Dual-Mode
           Bioimaging of Colorectal Tumors
    • Abstract: Publication date: Available online 7 January 2020Source: Acta BiomaterialiaAuthor(s): Xinxin Li, Lin Liu, Yu Fu, Hongda Chen, Murad M.A. Abualrejal, Hua Zhang, Zhenxin Wang, Huimao ZhangCurrently, it is still a great challenge to develop tumor targeting nanoparticles with high sensitivity and high resolution for improving the non-invasive detection ability of colorectal cancer (CRC) at an early stage. In this study, NaErF4:Yb@NaGdF4:Yb core@shell upconversion nanoparticles (UCNPs) were prepared with high upconversion luminescence (UCL) emission in red light region through adjusting the doping ratios of Er and Yb elements in the core. For biomedical applications, the carboxyl-terminated silica shell was introduced to transfer the as-prepared UCNPs from the organic phase to the aqueous phase, and allowed conjugation with peptide ligands derived from the L-SP5 peptide (i.e., L-SP5-H and L-SP5-C), respectively. Due to the tumor-targeting affinity of the PSP motif in the peptide ligands, the as-prepared peptide functionalized UCNPs (UCNP@SiO2-L-SP5-H and UCNP@SiO2-L-SP5-C) can be used as an active tumor targeting contrast agents for UCL/T1-weighted magnetic resonance (MR) dual-mode imaging. Both the in vitro and in vivo experimental results demonstrated that UCNP@SiO2-L-SP5-C has relatively high affinity for the HCT116 CRC subtype. Moreover, UCNP@SiO2-L-SP5-C can visualize ultra-small subcutaneous xenografted HCT116 tumors (c.a. 13 mm3 in volume) by in vivo UCL imaging.Statement of Significance1. High red emission UCNPs were synthesized for tumor-targeting dual-mode bioimaging.2. With tumor-binding affinity peptide, UCNP@SiO2-L-SP5-C shows high HCT116 tumor targeting ability.3. UCNP@SiO2-L-SP5-C successfully achieves sensitive detection of ultrasmall HCT116 tumors.Graphical Image, graphical abstract
  • Additive manufacturing of an elastic poly(ester)urethane for cartilage
           tissue engineering
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Sandra Camarero-Espinosa, Andrea Calore, Arnold Wilbers, Jules Harings, Lorenzo MoroniAlthough a growing knowledge on the field of tissue engineering of articular cartilage exists, reconstruction or in-vitro growth of functional hyaline tissue still represents an unmet challenge. Despite the simplicity of the tissue in terms of cell population and absence of innervation and vascularization, the outstanding mechanical properties of articular cartilage, which are the result of the specificity of its extra cellular matrix (ECM), are difficult to mimic. Most importantly, controlling the differentiation state or phenotype of chondrocytes, which are responsible of the deposition of this specialized ECM, represents a milestone in the regeneration of native articular cartilage. In this study, we fabricated fused deposition modelled (FDM) scaffolds with different pore sizes and architectures from an elastic and biodegradable poly(ester)urethane (PEU) with mechanical properties that can be modulated by design, and that ranged the elasticity of articular cartilage. Cell culture in additive manufactured 3D scaffolds exceeded the chondrogenic potential of the gold-standard pellet culture. In-vitro cell culture studies demonstrated the intrinsic potential of elastic (PEU) to drive the re-differentiation of de-differentiated chondrocytes when cultured in-vitro, in differentiation or basal media, better than pellet cultures. The formation of neo-tissue was assessed as a high deposition of GAGs and fibrillar collagen II, and a high expression of typical chondrogenic markers. Moreover, the collagen II / collagen I ratio commonly used to evaluate the differentiation state of chondrocytes (ratio> 1 being chondrocytes and, ratio < 0 being de-differentiated chondrocytes) was higher than 5.Statement of significanceTissue engineering of articular cartilage requires material scaffolds capable of driving the deposition of a coherent and specific ECM representative of articular cartilage. Materials explored so far account for low mechanical properties (hydrogels), or are too stiff to mimic the elasticity of the native tissue (traditional polyesters). Here, we fabricated 3D fibrous scaffolds via FDM with a biodegradable poly(ester)urethane. The compressive Young`s modulus and elastic limit of the scaffolds can be tuned by designed, mimicking those of the native tissue. The designed scaffolds showed an intrinsic potential to drive the formation of a GAG and collagen II rich ECM, and to drive a stable chondrogenic cell phenotype.Graphical abstractImage, graphical abstract
  • Comparative in vitro study on binary Mg-RE (Sc, Y, La, Ce, Pr, Nd, Sm, Eu,
           Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) alloy systems
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Jianing Liu, Dong Bian, Yufeng Zheng, Xiao Chu, Yulin Lin, Ming Wang, Zefeng Lin, Mei Li, Yu Zhang, Shaokang GuanCorrect selection of alloying elements is important for developing novel biodegradable magnesium alloys with superior mechanical and biological performances. In contrast to various reports on nutrient elements (Ca, Zn, Sr, etc.) as alloying elements of biomedical magnesium alloys, there is limited information about how to choose the right rare earth elements (REEs) as alloying elements of magnesium. In this work, 16 kinds of REEs were individually added into Mg, including Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Du, Ho, Er, Tm, Yb and Lu, to fabricate binary Mg-RE model alloys with different composition points. Under the same working history, comparative studies were undertaken and the impact of each kind of rare earth element on the microstructure, mechanical property, corrosion behavior and biocompatibility of Mg were investigated. The corresponding influence level for the 16 kinds of REEs were ranked. The results showed that the second phases were detected in some Mg-RE alloys, which were mainly composed of Mg12RE. By adding different REEs into Mg with proper contents, the mechanical properties of resulting Mg-RE binary alloys could be adjusted in wide range. The corrosion resistance of Mg-light REE alloys was generally better than Mg-heavy REE alloys. As for biocompatibility, Mg-RE model alloys showed no cytotoxic effect on MC3T3-E1 cells. The hemolysis rates of all experimental Mg-RE model alloys were lower than 5% except for Mg-Lu alloy model. In general, the addition of different REEs into Mg could improve its performance from different aspects. This work provides a better understanding on suitable REEs as alloying elements for magnesium, and the future R&D direction on biomedical Mg-RE alloys was proposed.Statement of SignificanceIn contrast to various reports on nutrient elements (Ca, Zn, Sr, etc.) as alloying elements of biomedical magnesium alloys, until now there is limited information about how to choose the right rare earth elements (REEs) as alloying elements of magnesium. In this work, comparative studies were undertaken by individually adding 16 kinds of REEs, including Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Du, Ho, Er, Tm, Yb and Lu, into Mg to fabricate binary Mg-RE model alloys, with different composition points, then the impact of each kind of rare earth element on the microstructure, mechanical property, corrosion behavior and biocompatibility of Mg under the same working history were investigated, and the corresponding influence level for the 16 kinds of REEs were ranked. This work provides a better understanding on suitable REEs as alloying elements for magnesium, and the future R&D direction on biomedical Mg-RE alloys was proposed.Graphical abstractImage, graphical abstract
  • Bioactive materials: In vitro investigation of different mechanisms of
           hydroxyapatite precipitation
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): S. Ferraris, S. Yamaguchi, N. Barbani, M. Cazzola, C. Cristallini, M. Miola, E. Vernè, S. SprianoBioactive materials, able to induce hydroxyapatite precipitation in contact with body fluids, are of great interest for their bone bonding capacity. . The aim of this paper is to compare bioactive materials with different surface features to verify the mechanisms of action and the relationship with kinetics and type of precipitated hydroxyapatite over time. Four different surface treatments for Ti/Ti6Al4V alloy and a bioactive glass were selected and a different mechanism of bioactivity is supposed for each of them. Apart from the conventional techniques (FESEM, XPS and EDX), less common characterizations (zeta potential measurements on solid surfaces and FTIR chemical imaging) were applied. The results suggest that the OH groups on the surface have several effects: the total number of the OH groups mainly affects hydrophilicity of surfaces, while the isoelectric points, surface charge and ions attraction mainly depend on OH acidic/basic strength. Kinetics of hydroxyapatite precipitation is faster when it involves a mechanism of ion exchange while it is slower when it is due to electrostatic effects . The electrostatic effect cooperates with ion exchange and it speeds up kinetics of hydroxyapatite precipitation. Different bioactive surfaces are able to differently induce precipitation of type A and B of hydroxyapatite, as well as different degrees of crystallinity and carbonation.Statement of significanceThe bone is made of a ceramic phase (a specific type of hydroxyapatite), a network of collagen fibers and the biological tissue. A strong bond of an orthopedic or dental implant with the bone is achieved by bioactive materials where precipitation and growth of hydroxyapatite occurs on the implant surface starting from the ions in the physiological fluids. Several bioactive materials are already known and used, but their mechanism of action is not completely known and the type of precipitated hydroxyapatite not fully investigated. In this work, bioactive titanium and bioglass surfaces are compared through conventional and innovative methodologies. Different mechanisms of bioactivity are identified, with different kinetics and the materials are able to induce precipitation of different types of hydroxyapatite, with different degree of crystallinity and carbonation.Graphical abstractImage, graphical abstract
  • Dispersion of ceramic granules within human fractionated adipose tissue to
           enhance endochondral bone formation
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Ru-Lin Huang, Julien Guerrero, Alina Samia Senn, Elisabeth Artemis Kappos, Kai Liu, Qingfeng Li, Denis Dufrane, Dirk J. Schaefer, Ivan Martin, Arnaud ScherberichEngineering of materials consisting of hypertrophic cartilage, as physiological template for de novo bone formation through endochondral ossification (ECO), holds promise as a new class of biological bone substitutes. Here, we assessed the efficiency and reproducibility of bone formation induced by the combination of ceramic granules with fractionated human adipose tissue (“nanofat”), followed by in vitro priming to hypertrophic cartilage. Human nanofat was mixed with different volumetric ratios of ceramic granules (0.2-1 mm) and cultured to sequentially induce proliferation (3 weeks), chondrogenesis (4 weeks), and hypertrophy (2 weeks). The resulting engineered constructs were implanted ectopically in nude mouse. The presence of ceramic granules regulated tissue formation, both in vitro and in vivo. In particular, their dispersion in nanofat at a ratio of 1:16 led to significantly increased cell number and glycosaminoglycan accumulation in vitro, as well as amount and inter-donor reproducibility of bone formation in vivo. Our findings outline a strategy for efficient utilization of nanofat for bone regeneration in an autologous setting, which should now be tested at an orthotopic site.Statement of significanceIn this study, we assessed the efficiency and reproducibility of bone formation by a combination of ceramic granules and fractionated human adipose tissue, also known as nanofat, in vitro primed into hypertrophic cartilage. The resulting engineered cartilaginous constructs, when implanted ectopically in nude mouse, resulted in bone and bone marrow formation, more reproducibly and strongly that nanofat alone. This project evaluates the impact of ceramic granules on the functionality and chondrogenic differentiation of mesenchymal progenitors inside their native adipose tissue niche and outlines a novel strategy for an efficient application of nanofat for bone regeneration in an autologous setting.Graphical abstractImage, graphical abstract
  • In vitro measurement of the chemical changes occurring within
           β-tricalcium phosphate bone graft substitutes
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Yassine Maazouz, Iris Rentsch, Bin Lu, Bastien Le Gars Santoni, Nicola Doebelin, Marc BohnerSeveral mechanisms proposed to explain the osteoinductive potential of calcium phosphates involve surface mineralization (“bioactivity”) and mention the occurrence of concentration gradients between the inner and the outer part of the implanted material. Determining the evolution of the local chemical environment occurring inside the pores of an implanted bone graft substitute (BGS) is therefore highly relevant. A quantitative and fast method was developed to measure the chemical changes occurring within the pores of β-Tricalcium Phosphate (β-TCP) granules incubated in a simulated body fluid. A factorial design of experiment was used to test the effect of particle size, specific surface area, microporosity, and purity of the β-TCP granules. Large pH, calcium and phosphate concentration changes were observed inside the BGS and lasted for several days. The kinetics and magnitude of these changes (up to 2 pH units) largely depended on the processing and properties of the granules. Interestingly, processing parameters that increased the kinetics and magnitude of the local chemical changes are parameters considered to favor calcium phosphate osteoinduction, suggesting that the model might be useful to predict the osteoinductive potential of BGSs.Statement of significanceRecent results suggest that in situ mineralization of biomaterials (polymers, ceramics, metals) might be key in their ability to trigger ectopic bone formation. This is the reason why the effect on in situ mineralization of various synthesis parameters of β-tricalcium phosphate granules was studied (size, microporosity, specific surface area, and Ca/P molar ratio). To the best of our knowledge, this is the first article devoted to the chemical changes occurring within the pores of a bone graft substitute. We believe that the manuscript will prove to be highly important in the design and mechanistic understanding of drug-free osteoinductive biomaterials.Graphical abstractImage, graphical abstract
  • Biomineralization pathways in calcifying dinoflagellates: Uptake, storage
           in MgCaP-rich bodies and formation of the shell
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Anne Jantschke, Iddo Pinkas, Andreas Schertel, Lia Addadi, Steve WeinerLittle is known about shell formation of calcareous dinoflagellates, despite the fact that they are one of the major calcifying organisms of the phytoplankton. Here, calcitic cyst formation in two representative members of calcareous dinoflagellates is investigated using cryo-electron microscopy (cryo-SEM and cryo-FIB-SEM) in combination with micro-Raman and infrared spectroscopy. Only calcein-AM and not calcein enters these cells, indicating active uptake of calcium and other divalent cations. Multifunctional vacuoles containing crystalline inclusions are observed, and the crystals are identified as anhydrous guanine in the β-form. The same vacuolar enclosures contain dense magnesium-, calcium-, and phosphorous-rich mineral bodies. These bodies are presumably secreted into the outer matrix where calcite forms. Calcite formation occurs via multiple independent nucleation events, and the different crystals grow with preferred orientation into a dense reticular network that forms the mature calcitic shell. We suggest a biomineralization pathway for calcareous dinoflagellates that includes (1) active uptake of calcium through the membranes, (2) deposition of Mg2+- and Ca2+-ions inside disordered MgCaP-rich mineral bodies, (3) secretion of these bodies to the inter-membrane space, and (4) Formation and growth of calcite into a dense reticulate network. This study provides new insights into calcium uptake, storage and transport in calcifying dinoflagellates.Statement of significanceLittle is known about the shell formation of calcareous dinoflagellates, despite the fact that they are one of the major calcifying organisms of the phytoplankton. We used state-of-the-art cryo-electron microscopy (cryo-SEM and cryo-FIB-SEM) in combination with micro-Raman spectroscopy to provide new insights into mineral formation in calcifying dinoflagellates.To date, intracellular crystalline calcite was assumed to be involved in calcite shell formation. Surprisingly, we identify these crystalline inclusions as anhydrous guanine suggesting that they are not involved in biomineralization. Instead, a key finding is that MgCaP-rich bodies are probably secreted into the outer matrix where the calcite shell is formed. We suggest that these bodies are an essential part of Ca-uptake, -storage and –transport and propose a new biomineralization model.Graphical abstractImage, graphical abstract
  • Biomimetic anti-inflammatory nano-capsule serves as a cytokine blocker and
           M2 polarization inducer for bone tissue repair
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Chengcheng Yin, Qin Zhao, Wu Li, Zifan Zhao, Jinyang Wang, Tian Deng, Peng Zhang, Kailun Shen, Zubing Li, Yufeng ZhangControlling of pro-inflammation induced by pro-inflammatory cytokines and anti-inflammatory response induced by M2 macrophages is important for osteogenesis in the process of bone tissue repair. Thus, we fabricated biomimetic anti-inflammatory nano-capsule (BANC) that can block cytokines and promote M2 macrophage polarization, presenting a positive role for bone tissue repair. The BANC is a biomimic nanosystem, coated with lipopolysaccharide-treated macrophage cell membranes with cytokine receptors enveloping gold nanocage (AuNC) as “cytokine blocker”, and loaded with resolvin D1 inside into AuNC as “M2 polarization inducer” whose controlled-release could be triggered under near-infrared laser irradiation in sequence, and these chronological events were consistent with the healing process of bone tissue repair. Moreover, in vivo application of femoral bone defects revealed that the BANC composite boron-containing mesoporous bioactive glass scaffolds improved the final effects of bone tissue repair through preventing inflammatory response, promoting M2 polarization in sequence in accord with the in vitro investigation. Hence, cytokine neutralization and M2 macrophage polarization enables the BANC to enhance the bone tissue repair as a biomimetic anti-inflammation effector. Therefore, this study provides potential therapeutic strategies for trauma-mediated or inflammation-related bone defects based on a biomimetic nanomaterial with weakened pro-inflammatory and enhanced anti-inflammatory effects.Statement of significanceCell membrane-mimic nanomaterials have been popular for blocking natural cell responses for some infection diseases, yet their role in biological process of bone repair is unknown. Here, we fabricated Biomimetic Anti-inflammatory Nano-Capsule (BANC), coated with cell membrane with cytokines receptors on the surface which could neutralize the pro-inflammatory cytokine receptor to block activated pro-inflammation, loaded with Resolvin D1 inside which could be controllably released by NIR irradiation to promote M2 macrophage polarization for the following bone formation during the process of bone repair. Administration of BANC as cytokines blocker and M2 polarization inducer to enhance the bone regeneration, thus presenting a promising potential for the treatment of bone repair and regeneration.Graphical abstractImage, graphical abstract
  • Soft liquid metal nanoparticles achieve reduced crystal nucleation and
           ultrarapid rewarming for human bone marrow stromal cell and blood vessel
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Yi Hou, Chennan Lu, Mengjia Dou, Chenglin Zhang, Hao Chang, Jing Liu, Wei RaoHigh warming rates during cryopreservation are crucial and essential for successful vitrification. However, realizing a faster warming rate in low-concentration cryoprotective agents appears to be challenging for conventional warming process through convective heat transfer. Herein, we developed a liquid metal (LM) nanosystem that can act as a spatial source to significantly enhance the warming rates with near-infrared laser irradiation during the warming process. The synthetic Pluronic F127-liquid metal nanoparticles (PLM NPs) displayed multiple performances with uniform particle size, superior photothermal conversion efficiency (52%), repeatable photothermal stability, and low cytotoxicity. Particularly, it is more difficult for the liquid PLM NPs with less surface free energy to form crystal nucleation than other solid NPs such as gold and Fe3O4, which is beneficial for the cooling process during cryopreservation. The viability of human bone marrow-derived mesenchymal stem cells postcryopreservation reached 78±3%, which is threefold higher than that obtained by the conventional warming method (25±6%). Additionally, the cells postcryopreservation maintained their normal attachment, proliferation, surface marker expression, and intact multilineage differentiation properties. Moreover, the results of mouse tails including blood vessel cryopreservation showed a relatively improved intact structure when using PLM NP rewarming compared with the results of conventional warming. The new LM nanosystem provides a universal platform for cryopreservation that is expected to have potential for widespread applications including bioengineering, cell-based medicine, and clinical translation.Statement of significanceIn this study, we fabricated soft liquid metal nanoparticles with high photothermal conversion efficiency, repeatable photothermal stability, and low cytotoxicity. Particularly, soft liquid metal nanoparticles with less surface free energy and suppression effects of ice formation were first introduced to mediate cryopreservation. Superior ice-crystallization inhibition is achieved as a result of less crystal nucleation and ultrarapid rewarming during the freezing and warming processes of cryopreservation, respectively. Collectively, cryopreservation of human bone marrow stromal cells (HBMSCs) and mouse tails including blood vessels can be successfully performed using this new nanoplatform, showing great potential in the application of soft nanoparticles in cryopreservation.Graphical abstractImage, graphical abstract
  • Red fluorescent AuNDs with conjugation of cholera toxin subunit B (CTB)
           for extended-distance retro-nerve transporting and long-time neural
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Yueqi Zhao, Suraj Maharjan, Yuanqing Sun, Zhe Yang, Enfeng Yang, Nan Zhou, Laijin Lu, Andrew K. Whittaker, Bai Yang, Quan LinA retrograde transportation nerve probe, Au nanodots-cholera toxin B subunit (AuNDs-CTB), are prepared and fully characterized, which emit bright red fluorescence and show high quantum yield (7.2%) and good stability. The fluorescence emitted by the AuNDs is constant across a wide pH range (4–10) and after prolonged UV irradiation (>4 h). Previously, CTB has shown targeting characteristic for nerve cells with high sensitivity and effectiveness. After linking CTB to AuNDs through amidation reactions, AuNDs-CTB are obtained with excellent fluorescence property, nerve target characteristic, and, particularly, neural retrograde transportation feature. The red emission of the AuNDs-CTB is well distinguished from the blue autofluorescence of normal tissues, which provides potential for detection by naked eyes. Further, the fluorescence emission intensity maintains for 10 days in vivo, suggesting great utility for long-time monitoring and sensing of the nerve tissue. Furthermore, the AuNDs-CTB with bright red fluorescence can travel through the peripheral nerve to the spinal cord rapidly by retrograde transportation. The transportation occurs for a long distance (>5 cm) within only 2 days after injection of the AuNDs-CTB into the sciatic nerve. The present study exhibits a novel method for nerve visualization and drug delivery.Statement of significanceAu nanodots (AuNDs) conjugated with cholera toxin subunit B (CTB) have been developed for nerve labeling and neural retro-transporting. The red fluorescence from AuNDs-CTB is stable in vitro (pH 4–10 and 4 h UV irradiation) and in vivo (for a long time, more than 10 days). When injecting AuNDs-CTB into the sciatic nerve located at the midpiece of the thigh, the targeted nerve emits bright red fluorescence under UV light. Furthermore, the nerve can retrograde transport the AuNDs-CTB to the spinal cord for a distance of more than 5 cm just in 2 days. This work exhibits a novel method for nerve visualization by naked eyes and demonstrates the potential for intraoperative navigation.Graphical abstractImage, graphical abstract
  • Dispersion stability and biocompatibility of four ligand-exchanged NaYF4:
           Yb, Er upconversion nanoparticles
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Yinghui Chen, Claudia D'Amario, Alex Gee, Hien T.T. Duong, Olga Shimoni, Stella M. ValenzuelaSurface modification to obtain high dispersion stability and biocompatibility is a key factor for bio-application of upconversion nanoparticles (UCNPs). A systematic study of UCNPs modified with four hydrophilic molecules separately, comparing their dispersion stability in biological buffers and cellular biocompatibility is reported here. The results show that carboxyl-functionalized UCNPs (modified by 3,4-dihydrocinnamic acid (DHCA) or poly(monoacryloxyethyl phosphate (MAEP)) with negative surface charge have superior even-distribution in biological buffers compared to amino-functionalized UCNPs (modified by (aminomethyl)phosphonic (AMPA) or (3-Aminopropyl)triethoxysilane (APTES)) with positive surface charge. Subsequent investigation of cellular interactions revealed high levels of non-targeted cellular uptake of the particles modified with either of the three small molecules (AMPA, APTES, DHCA) and high levels of cytotoxicity when used at high concentrations. The particles were seen to be trapped as particle-aggregates within the cellular cytoplasm, leading to reduced cell viability and cell proliferation, along with dysregulation of the cell cycle as assessed by DNA content measurements. The dramatically reduced proportion of cells in G1 phase and the slightly increased proportion in G2 phase indicates inhibition of M phase, and the appearance of sub-G1 phase reflects cell necrosis. In contrast, MAEP-modified UCNPs are bio-friendly with increased dispersion stability in biological buffers, are non-cytotoxic, with negligible levels of non-specific cellular uptake and no effect on the cell cycle at both low and high concentrations. MAEP-modified UCNPs were further functionalized with streptavidin for intracellular microtubule imaging, and showed clear cytoskeletal structures via their upconversion luminescence.Statement of significanceUpconversion nanoparticles (UCNP) are an exciting potential nanomaterial for bio-applications. Their anti-Stokes luminescence makes them especially attractive to be used as imaging probes and thermal therapeutic reagents. Surface modification is the key to achieving stable and compatible hydrophilic-UCNPs. However, the lack of criteria to assess molecular ligands used for ligand exchange of nanoparticles has hampered the development of surface modification, and further limits UCNP’s bio-application. Herein, we report a systematic comparative study of modified-UCNPs with four distinct hydrophilic molecules, assessing each particles’ colloidal stability in biological buffers and their cellular biocompatibility. The protocol established here can serve as a potential guide for the surface modification of UCNPs in bio-applications.Graphical abstractImage, graphical abstract
  • A sequential targeting nanoplatform for anaplastic thyroid carcinoma
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Qimeihui Wang, Guoqing Sui, Xiaoli Wu, Dengke Teng, Lingyu Zhu, Shihui Guan, Haitao Ran, Zhigang Wang, Hui WangEffective accumulation of nanoparticles (NPs) in tumor regions is one of the major motivations in nanotechnology research and that the establishment of an efficient targeting nanoplatform for the treatment of malignant tumors is urgently needed for theranostic applications. In this study, we engineered multifunctional sequential targeting NPs for achieving synergistic antiangiogenic photothermal therapy (PTT) and multimodal imaging-guided diagnosis for anaplastic thyroid carcinoma (ATC) theranostics. Antibody bevacizumab with an affinity towards vascular endothelial growth factor (VEGF) on the tumor cell surface was conjugated onto the surface of polymer NPs for VEGF targeting and antiangiogenic therapy. Encapsulated IR825 was employed as a photothermal agent (PTA) with a mitochondrial targeting capability, which further cascades NPs into mitochondria to enhance hyperthermic efficiency in the ablation of tumor cells. Importantly, the combination of bevacizumab and IR825 in a single nanosystem achieved desirable accumulations of NPs and that sequential targeted PTT combined with antiangiogenesis significantly promoted the therapeutic efficiency in eradicating tumors by near-infrared (NIR) laser irradiation. Furthermore, these NPs are extraordinary contrast agents for photoacoustic, ultrasound and fluorescence imaging applications, providing multimodal imaging capabilities for therapeutic monitoring and a precise diagnosis. Therefore, this multifunctional nanoplatform provides a promising theranostic strategy for extremely malignant ATC.Statement of significanceAnaplastic thyroid carcinoma (ATC), with extremely aggressive behavior, lacks a satisfactory therapeutic method and a comprehensive early diagnostic strategy. Herein, we successfully synthesized a sequential targeting nanoplatform (IR825@Bev-PLGA-PFP NPs) with theranostic function, which specifically binds to VEGF on the tumor cell surface and further cascades into mitochondria to achieve effective accumulation of NPs in the tumor regions. As a result, it solves the urgent demand for ATC detection and therapy. By breaking the limitation of traditional target, such as low efficacy and frequent recurrence as the results of low accumulation, sequential targeting combined with synergistic antiangiogenic PTT completely eradicates tumors without any residual tissue and side effect. Therefore, this strategy paves a solid way for further investigation in the theranostic progressing of ATC.Graphic abstractImage, graphical abstract
  • A systematic comparison of lipopolymers for siRNA delivery to multiple
           breast cancer cell lines: In vitro studies
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Hamidreza Montazeri Aliabadi, Remant Bahadur K.C., Emira Bousoik, Ryley Hall, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan UludağSmall interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were effective in all cell types used in this study, indicating the possibility of universal carriers for siRNA therapy. The delivery efficiency for effective lipopolymers was not correlated with dextran uptake in the cells tested, which indicated a receptor-mediated internalization for siRNA complexes with lipopolymers, unlike fluid-phase transfer associated with dextran uptake. Consistent with this, specific inhibitors involved in clathrin- and caveolin-mediated endocytosis significantly (>50%) reduced the internalization of siRNA complexes in all cell types. Using JAK2 and STAT3 silencing in MDA-MB-231 and MDA-MB-468 cells, a general correlation between the uptake and silencing efficiency at the mRNA level was evident, but it appeared that the choice of the target rather than the cell type was more critical for consistent silencing. We conclude that siRNA therapy with lipopolymers can be undertaken in multiple breast cancer cell phenotypes with similar efficiency, indicating the general applicability of non-viral RNAi in clinical management of molecularly heterogeneous breast cancers.Statement of significanceThe manuscript investigated the efficacy of siRNA carriers across multiple breast cancer cell lines. The lipopolymeric carriers were capable of delivering effective dose of siRNA to a range of breast cancer cells. Despite some differences in uptake efficiency among cell types, the mechanism of delivery was similar, with CME and CvME significantly involved in the internalization of polyplexes, while fluid-phase endocytosis was not significant. Specific target silencing was correlated to delivery efficiency, but we did notice the presence of lipopolymers that achieved high silencing with minimal siRNA delivery. Silencing specific targets in different cell types were more uniformly achieved as compared to targeting different targets in the same cells. Our studies enhance the feasibility of delivering siRNA to different types of breast cancer cells.Graphical abstractImage, graphical abstract
  • Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to
           miscibility with phospholipids and improve the efficiency of delivering
           short interfering RNA by small-sized lipid nanoparticles
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Yusuke Sato, Nana Okabe, Yusuke Note, Kazuki Hashiba, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi HarashimaDespite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, their poor stability and intracellular trafficking significantly hinders their use as potent small-sized LNPs. It has been reported that both the diffusion of lipid components from LNPs and the adsorption of proteins on the surface of LNPs are responsible for their decreased potency. To overcome this issue, we focused on the chemical structure of hydrophobic scaffolds of pH-sensitive cationic lipids with various lengths and shapes. LNPs composed of a pH-sensitive cationic lipid with long, linear scaffolds induced gene silencing in a dose-dependent manner, while LNPs with a classical scaffold length (C18) failed. Replacing the helper lipid from cholesterol to egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of ~22 nm and enhanced gene silencing activity. Most of the ESMs were located in the outer layer and functioned to stabilize the LNPs. Long, linear scaffolds contributed to immiscibility with phosphocholine-containing lipids including ESM. This contribution was dependent on the scaffold length of pH-sensitive cationic lipids. Although phosphocholine-containing lipids usually inhibit membrane fusion-mediated endosomal escape, long, linear scaffolds contributed to avoiding the inhibitory effect and to enhance the potency of the LNPs. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and the selection of appropriate helper lipids and will facilitate the development of highly potent small-sized LNPs.Statement of significanceDespite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, the size reduction-associated decrease in the stability and intracellular trafficking significantly hinders the development of potent small-sized LNPs. Our limited understanding of the mechanism underlying the reduced potency has also hindered the development of more potent small-sized LNPs. The findings of the present study indicate that long and linear hydrophobic scaffolds of pH-sensitive cationic lipids could overcome the loss of efficiency for nucleic acid delivery. In addition, the long hydrophobic scaffolds led to immiscibility with neutral phospholipids, resulting in efficient endosomal escape. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and will facilitate the development of highly potent small-sized LNPs.Graphical abstractImage, graphical abstract
  • Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded
           agarose implant for enhanced osteochondral repair
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Robert M. Stefani, Andy J. Lee, Andrea R. Tan, Saiti S. Halder, Yizhong Hu, X. Edward Guo, Aaron M. Stoker, Gerard A. Ateshian, Kacey G. Marra, James L. Cook, Clark T. HungArticular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent graft and host tissue while also attenuating inflammation caused by iatrogenic injury. An acellular agarose hydrogel carrier with embedded DEX-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (DLMS) was developed to provide sustained release for at least 99 days. The DLMS implant was first evaluated in an in vitro pro-inflammatory model of cartilage degradation. The implant was chondroprotective, as indicated by maintenance of Young's modulus (EY) (p = 0.92) and GAG content (p = 1.0) in the presence of interleukin-1β insult. In a subsequent preliminary in vivo experiment, an osteochondral autograft transfer was performed using a pre-clinical canine model. DLMS implants were press-fit into the autograft donor site and compared to intra-articular DEX injection (INJ) or no DEX (CTL). Functional scores for DLMS animals returned to baseline (p = 0.39), whereas CTL and INJ remained significantly worse at 6 months (p 
  • Oligonucleotide-functionalized hydrogels for sustained release of small
           molecule (aptamer) therapeutics
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Nikunj K. Agrawal, Peter Allen, Young Hye Song, Rebecca A. Wachs, Yan Du, Andrew D. Ellington, Christine E. SchmidtNatural and synthetic hydrogels have been widely investigated as biomaterial scaffolds to promote tissue repair and regeneration. Nevertheless, the scaffold alone is often insufficient to drive new tissue growth, instead requiring continuous delivery of therapeutics, such as proteins or other biomolecules that work in concert with structural support provided by the scaffold. However, because of the high-water content, hydrogels tend to be permeable and cause rapid release of the encapsulated drug, which could lead to serious complications from local overdose and may result in the significant waste of encapsulated therapeutic(s). To this end, we designed an oligonucleotide-functionalized hydrogel that can provide sustained and controlled delivery of therapeutics for up to 4 weeks. To prove this concept, we successfully achieved sustained release (for over 28 days) of model anti-Nogo receptor (anti-NgR) RNA aptamer from oligonucleotide-functionalized hyaluronic acid-based hydrogel by changing the complementarity between the short antisense sequences and the aptamer. Furthermore, the released aptamer successfully blocked neuro-inhibitory effects of myelin-derived inhibitors and promoted neurite outgrowth from rat dorsal root ganglia in vitro. Because antisense sequences can be designed to bind to proteins, peptides, and aptamer, our oligonucleotide-functionalized hydrogel offers a promising therapeutic delivery system to obtain controlled release (both bolus and sustained) of various therapeutics for the treatment of complex diseases and injury models, such as spinal cord injury.Statement of significanceProducing a therapeutic effect often requires the administration of multiple injections with high dosages. This regimen causes discomfort to the patient and raises cost of treatment. Additionally, systemic delivery of therapeutics often results in adverse effects; therefore, local delivery at the site of injury is desirable. Therefore, in this study, we designed an oligonucleotide-functionalized biomaterial platform using ssDNA oligonucleotides (immobile species) as antisense sequences to increase residence time and fine-tune the release of anti-nogo receptor aptamer (mobile species) for spinal cord injury application. Because antisense sequences can be designed to bind proteins, peptides, and aptamer, our hydrogel offers a promising delivery system to obtain controlled release of various therapeutics for the treatment of complex diseases and injury models.Graphical abstractImage, graphical abstract
  • Naturally-occurring bacterial cellulose-hyperbranched cationic
           polysaccharide derivative/MMP-9 siRNA composite dressing for wound healing
           enhancement in diabetic rats
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Na Li, Liqun Yang, Chenglin Pan, Phei Er Saw, Meng Ren, Biyun Lan, Junfeng Wu, Xiaoyi Wang, Tingting Zeng, Liyan Zhou, Li-Ming Zhang, Chuan Yang, Li YansThe anomalous high expression of matrix metalloproteinase 9 (MMP-9) is one important factor that impedes diabetic wound healing. Therefore, inhibition of MMP-9 expression in a diabetic wound could be a feasible method to promote wound healing. In this study, we studied the possibility of self-therapy using wound dressings that contain bacterial cellulose-hyperbranched cationic polysaccharide (BC-HCP) derivatives that encapsulate siRNA (BC-HCP/siMMP-9) and have controlled release properties. Herein, we used four HCPs (Gly-DMAPA, Gly-D4, Amyp-DMAPA, Amyp-D4) as gene carriers. Our results showed that all HCP derivatives were minimally toxic to cells in vitro, while the cationic properties of HCP could be used as a complexation agent for MMP-9 siRNA (siMMP-9). Upon exposure to bacterial cellulose (BC), the BC slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein levels of MMP-9 in a human immortalized epithelial cell line (HaCAT) and in diabetic rat wounds. Inhibition of MMP-9 in the wounds of diabetic rats resulted in a significant enhancement of wound healing, suggesting that the BC-HCP/siMMP-9 composite dressing could be used as a safe and effective dressing to promote wound healing in diabetic rats.Statement of significanceIn this work, we evaluated the possibility of using bacterial cellulose-hyperbranched cationic polysaccharide derivatives (BC-HCP) as a self-therapeutic wound dressing with siRNA encapsulated and controlled release properties. Our results showed that the BC-HCP/siMMP-9 composite dressing slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein level of MMP-9 in human immortalized epithelial cell line and in the wound of diabetic rats. The BC-HCP/siMMP-9 composite dressing promoted diabetic wound healing by the unique nanostructure of BC and by releasing siMMP-9 for specific MMP-9 inhibition. Therefore, it could be used as a safe and effective dressing to promote wound healing in diabetic rats. This is the first evidence on the study of using BC as a dressing composite by encapsulating HCP/siRNA complexes for efficient RNAi gene silencing for better wound healing in diabetic rats.Graphical abstractImage, graphical abstract
  • Fractional CO2 laser micropatterning of cell-seeded electrospun collagen
           scaffolds enables rete ridge formation in 3D engineered skin
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Britani N. Blackstone, Megan M. Malara, Molly E. Baumann, Kevin L. McFarland, Dorothy M. Supp, Heather M. PowellRete ridges are interdigitations of the epidermis and dermis of the skin that play multiple roles in homeostasis, including enhancing adhesion via increased contact area and acting as niches for epidermal stem cells. These structures, however, are generally absent from engineered skin (ES). To develop ES with rete ridges, human fibroblast-seeded dermal templates were treated with a fractional CO2 laser, creating consistently spaced wells at the surface. Constructs with and without laser treatment were seeded with keratinocytes, cultured for 10 days, and grafted onto athymic mice for four weeks. Rete-ridge like structures were observed in the laser-patterned (ridged) samples at the time of grafting and were maintained in vivo. Ridged grafts displayed improved barrier function over non-lasered (flat) grafts at the time of grafting and 4 weeks post-grafting. Presence of ridges in vivo corresponded with increased keratinocyte proliferation, epidermal area, and basement membrane length. These results suggest that this method can be utilized to develop engineered skin grafts with rete ridges, that the ridge pattern is stable for at least 4 weeks post-grafting, and that the presence of these ridges enhances epidermal proliferation and establishment of barrier function.Statement of significanceRete ridges play a role in epidermal homeostasis, enhance epidermal-dermal adhesion and act as niches for epidermal stem cells. Despite their role in skin function, these structures are not directly engineered into synthetic skin. A new method to rapidly and reproducibly generate rete ridges in engineered skin was developed using fractional CO2 laser ablation. The resulting engineered rete ridges aided in the establishment of epidermal barrier function, basement membrane protein deposition and epidermal regeneration. This new model of engineered skin with rete ridges could be utilized as an in vitro system to study epidermal stem cells, a testbed for pharmaceutical evaluation or translated for clinical use in full-thickness wound repair.Graphical abstractImage, graphical abstract
  • Enhanced structural maturation of human induced pluripotent stem
           cell-derived cardiomyocytes under a controlled microenvironment in a
           microfluidic system
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Tomasz Jan Kolanowski, Mathias Busek, Mario Schubert, Anna Dmitrieva, Björn Binnewerg, Jessie Pöche, Konstanze Fisher, Florian Schmieder, Stefan Grünzner, Sinah Hansen, Andreas Richter, Ali El-Armouche, Frank Sonntag, Kaomei GuanThe lack of a fully developed human cardiac model in vitro hampers the progress of many biomedical research fields including pharmacology, developmental biology, and disease modeling. Currently, available methods may only differentiate human induced pluripotent stem cells (iPSCs) into immature cardiomyocytes. To achieve cardiomyocyte maturation, appropriate modulation of cellular microenvironment is needed. This study aims to optimize a microfluidic system that enhances maturation of human iPSC-derived cardiomyocytes (iPSC-CMs) through cyclic pulsatile hemodynamic forces. Human iPSC-CMs cultured in the microfluidic system show increased alignment and contractility and appear more rod-like shaped with increased cell size and increased sarcomere length when compared to static cultures. Increased complexity and density of the mitochondrial network in iPSC-CMs cultured in the microfluidic system are in line with expression of mitochondrial marker genes MT-CO1 and OPA1. Moreover, the optimized microfluidic system is capable of stably maintaining controlled oxygen levels and inducing hypoxia, revealed by increased expression of HIF1α and EGLN2 as well as changes in contraction parameters in iPSC-CMs. In summary, this microfluidic system boosts the structural maturation of iPSC-CM culture and could serve as an advanced in vitro cardiac model for biomedical research in the future.Statement of SignificanceThe availability of in vitro human cardiomyocytes generated from induced pluripotent stem cells (iPSCs) opens the possibility to develop human in vitro heart models for disease modeling and drug testing. However, iPSC-derived cardiomyocytes remain structurally and functionally immature, which hinders their application. In this manuscript, we present an optimized and complete microfluidic system that enhances maturation of iPSC-derived cardiomyocytes through physiological cyclic pulsatile hemodynamic forces. Furthermore, we improved our microfluidic system by using a closed microfluidic recirculation and oxygen exchangers to achieve and maintain low oxygen in the culture chambers, which is suitable for mimicking the hypoxic condition and studying the pathophysiological mechanisms of human diseases in vitro. In the future, a variety of technologies including 3D tissue engineering could be integrated into our system, which may greatly extend the use of iPSC-derived cardiac models in drug development and disease modeling.Graphical abstractImage, graphical abstract
  • Glycaemic control in diabetic rats treated with islet transplantation
           using plasma combined with hydroxypropylmethyl cellulose hydrogel
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Anaïs Schaschkow, Séverine Sigrist, Carole Mura, Julien Barthes, Nihal Engin Vrana, Elodie Czuba, Florent Lemaire, Romain Neidl, Caroline Dissaux, Anne Lejay, Philippe Lavalle, Catherine Bruant-Rodier, Karim Bouzakri, Michel Pinget, Elisa MaillardIslet transplantation is one of the most efficient cell therapies used in clinics and could treat a large proportion of patients with diabetes. However, it is limited by the high requirement of pancreas necessary to provide the sufficient surviving islet mass in the hepatic tissue and restore normoglycaemia. Reduction in organ procurement requirements could be achieved by extrahepatic transplantation using a biomaterial that enhances islet survival and function. We report a plasma-supplemented hydroxypropyl methylcellulose (HPMC) hydrogel, engineered specifically using a newly developed technique for intra-omental islet infusion, known as hOMING (h-Omental Matrix Islet filliNG). The HPMC hydrogel delivered islets with better performance than that of the classical intrahepatic infusion. After the validation of the HPMC suitability for islets in vivo and in vitro, plasma supplementation modified the rheological properties of HPMC without affecting its applicability with hOMING. The biomaterial association was proven to be more efficient both in vitro and in vivo, with better islet viability and function than that of the current clinical intrahepatic delivery technique. Indeed, when the islet mass was decreased by 25% or 35%, glycaemia control was observed in the group of plasma-supplemented hydrogels, whereas no regulation was observed in the hepatic group. Plasma gelation, observed immediately post infusion, decreased anoïkis and promoted vascularisation. To conclude, the threshold mass for islet transplantation could be decreased using HPMC-Plasma combined with the hOMING technique. The simplicity of the hOMING technique and the already validated use of its components could facilitate its transfer to clinics.Statement of significanceOne of the major limitations for the broad deployment of current cell therapy for brittle type 1 diabetes is the islets’ destruction during the transplantation process. Retrieved from their natural environment, the islets are grafted into a foreign tissue, which triggers massive cell loss.It is mandatory to provide the islets with an 3D environment specifically designed for promoting isletimplantation to improve cell therapy outcomes. For this aim, we combined HPMC and plasma.HPMC provides suitable rheological properties to the plasma to be injectable and be maintained in the omentum. Afterwards, the plasma polymerises around the graft in vivo, thereby allowing their optimal integration into their transplantation site.As a result, the islet mass required to obtain glycaemic control was reduced by 35%.Graphical abstractImage, graphical abstract
  • Urethra-inspired biomimetic scaffold: A therapeutic strategy to promote
           angiogenesis for urethral regeneration in a rabbit model
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Baoxiu Wang, Xiangguo Lv, Zhe Li, Minghao Zhang, Jingjing Yao, Nan Sheng, Mujun Lu, Huaping Wang, Shiyan ChenLimited angiogenesis and epithelialization make urethral regeneration using conventional tissue-engineered grafts a great challenge. Consequently, inspired from the native urethra, bacterial cellulose (BC) and bladder acellular matrix (BAM) were combined to design a three dimensional (3D) biomimetic scaffold. The developed BC/BAM scaffold was engineered for accelerating urethral regeneration by enhancing angiogenesis and epithelialization. The BC/BAM scaffold reveals the closest mimic of native urethra in terms of the 3D porous nanofibrous structure and component including collagen, glycosaminoglycans, and intrinsic vascular endothelial growth factor (VEGF). In vitro studies showed that the bioinspired BC/BAM scaffold promoted in vitro angiogenesis by facilitating human umbilical vein endothelial cells (HUVECs) growth, expression of endothelial function related proteins and capillary-like tube formation. Effect of the BC/BAM scaffold on angiogenesis and epithelialization was studied by its implantation in a rabbit urethral defect model for 1 and 3 months. Results demonstrated that the improved blood vessels formation in the urethra-inspired BC/BAM scaffold significantly promoted epithelialization and accelerated urethral regeneration. The urethra-inspired BC/BAM scaffold provides us a new design approach to construct grafts for urethral regeneration.Statement of significanceFindings in urethral regeneration demonstrate that an ideal tissue-engineered urethra should have adequate angiogenesis to support epithelialization for urethral regeneration in vivo. In this study, inspired from the native urethra, a bioinspired bacterial cellulose/bladder acellular matrix (BC/BAM) scaffold was developed to promote angiogenesis and epithelialization. The designed scaffold showed the closest physical structure and component to natural urethra, which is beneficial to angiogenesis and regeneration of urethral epithelium. This is the first time to utilize BC and dissolved BAM to develop biomimetic scaffold in urethral tissue engineering. Our biomimetic strategy on urethra graft design provided enhanced angiogenesis and epithelialization to achieve an accelerated and successful rabbit urethral repair. We believe that our urethra-inspired biomimetic scaffold would provide new insights into the design of urethral tissue engineering grafts.Graphical abstractImage, graphical abstract
  • Functional role of glycosaminoglycans in decellularized lung extracellular
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Franziska E. Uhl, Fuming Zhang, Robert A. Pouliot, Juan J. Uriarte, Sara Rolandsson Enes, Xiaorui Han, Yilan Ouyang, Ke Xia, Gunilla Westergren-Thorsson, Anders Malmström, Oskar Hallgren, Robert J. Linhardt, Daniel J. WeissDespite progress in use of decellularized lung scaffolds in ex vivo lung bioengineering schemes, including use of gels and other materials derived from the scaffolds, the detailed composition and functional role of extracellular matrix (ECM) proteoglycans (PGs) and their glycosaminoglycan (GAG) chains remaining in decellularized lungs, is poorly understood. Using a commonly utilized detergent-based decellularization approach in human autopsy lungs resulted in disproportionate losses of GAGs with depletion of chondroitin sulfate/dermatan sulfate (CS/DS)> heparan sulfate (HS)> hyaluronic acid (HA). Specific changes in disaccharide composition of remaining GAGs were observed with disproportionate loss of NS and NS2S for HS groups and of 4S for CS/DS groups. No significant influence of smoking history, sex, time to autopsy, or age was observed in native vs. decellularized lungs. Notably, surface plasmon resonance demonstrated that GAGs remaining in decellularized lungs were unable to bind key matrix-associated growth factors FGF2, HGF, and TGFβ1. Growth of lung epithelial, pulmonary vascular, and stromal cells cultured on the surface of or embedded within gels derived from decellularized human lungs was differentially and combinatorially enhanced by replenishing specific GAGs and FGF2, HGF, and TGFβ1. In summary, lung decellularization results in loss and/or dysfunction of specific GAGs or side chains significantly affecting matrix-associated growth factor binding and lung cell metabolism. GAG and matrix-associated growth factor replenishment thus needs to be incorporated into schemes for investigations utilizing gels and other materials produced from decellularized human lungs.Statement of significanceDespite progress in use of decellularized lung scaffolds in ex vivo lung bioengineering schemes, including use of gels and other materials derived from the scaffolds, the detailed composition and functional role of extracellular matrix (ECM) proteoglycans (PGs) and their glycosaminoglycan (GAG) chains remaining in decellularized lungs, is poorly understood. In the current studies, we demonstrate that glycosaminoglycans (GAGs) are significantly depleted during decellularization and those that remain are dysfunctional and unable to bind matrix-associated growth factors critical for cell growth and differentiation. Systematically repleting GAGs and matrix-associated growth factors to gels derived from decellularized human lung significantly and differentially affects cell growth. These studies highlight the importance of considering GAGs in decellularized lungs and their derivatives.Graphical abstractImage, graphical abstract
  • Modular design of a tissue engineered pulsatile conduit using human
           induced pluripotent stem cell-derived cardiomyocytes
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Jinkyu Park, Christopher W. Anderson, Lorenzo R. Sewanan, Mehmet H. Kural, Yan Huang, Jiesi Luo, Liqiong Gui, Muhammad Riaz, Colleen A. Lopez, Ronald Ng, Subhash K. Das, Juan Wang, Laura Niklason, Stuart G. Campbell, Yibing QyangSingle ventricle heart defects (SVDs) are congenital disorders that result in a variety of complications, including increased ventricular mechanical strain and mixing of oxygenated and deoxygenated blood, leading to heart failure without surgical intervention. Corrective surgery for SVDs are traditionally handled by the Fontan procedure, requiring a vascular conduit for completion. Although effective, current conduits are limited by their inability to aid in pumping blood into the pulmonary circulation. In this report, we propose an innovative and versatile design strategy for a tissue engineered pulsatile conduit (TEPC) to aid circulation through the pulmonary system by producing contractile force. Several design strategies were tested for production of a functional TEPC. Ultimately, we found that porcine extracellular matrix (ECM)-based engineered heart tissue (EHT) composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary cardiac fibroblasts (HCF) wrapped around decellularized human umbilical artery (HUA) made an efficacious basal TEPC. Importantly, the TEPCs showed effective electrical and mechanical function. Initial pressure readings from our TEPC in vitro (0.68 mmHg) displayed efficient electrical conductivity enabling them to follow electrical pacing up to a 2 Hz frequency. This work represents a proof of principle study for our current TEPC design strategy. Refinement and optimization of this promising TEPC design will lay the groundwork for testing the construct's therapeutic potential in the future. Together this work represents a progressive step toward developing an improved treatment for SVD patients.Statement of significanceSingle Ventricle Cardiac defects (SVD) are a form of congenital disorder with a morbid prognosis without surgical intervention. These patients are treated through the Fontan procedure which requires vascular conduits to complete. Fontan conduits have been traditionally made from stable or biodegradable materials with no pumping activity. Here, we propose a tissue engineered pulsatile conduit (TEPC) for use in Fontan circulation to alleviate excess strain in SVD patients. In contrast to previous strategies for making a pulsatile Fontan conduit, we employ a modular design strategy that allows for the optimization of each component individually to make a standalone tissue. This work sets the foundation for an in vitro, trainable human induced pluripotent stem cell based TEPC.Graphical abstractImage, graphical abstract
  • Differential expression of genes involved in the acute innate immune
           response to intracortical microelectrodes
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Hillary W. Bedell, Nicholas J Schaub, Jeffrey R. Capadona, Evon S. EreifejHigher order tasks in development for brain-computer interfacing applications require the invasiveness of intracortical microelectrodes. Unfortunately, the resulting inflammatory response contributes to the decline of detectable neural signal. The major components of the neuroinflammatory response to microelectrodes have been well-documented with histological imaging, leading to the identification of broad pathways of interest for its inhibition such as oxidative stress and innate immunity. To understand how to mitigate the neuroinflammatory response, a more precise understanding is required. Advancements in genotyping have led the development of new tools for developing temporal gene expression profiles. Therefore, we have meticulously characterized the gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes. A time course of differential acute expression of genes of the innate immune response were compared to naïve sham mice, identifying significant changes following implantation. Differential gene expression analysis revealed 22 genes that could inform future therapeutic targets. Particular emphasis is placed on the largest changes in gene expression occurring 24 h post-implantation, and in genes that are involved in multiple innate immune sets including Itgam, Cd14, and Irak4.Statement of SignificanceCurrent understanding of the cellular response contributing to the failure of intracortical microelectrodes has been limited to the evaluation of cellular presence around the electrode. Minimal research investigating gene expression profiles of these cells has left a knowledge gap identifying their phenotype. This manuscript represents the first robust investigation of the changes in gene expression levels specific to the innate immune response following intracortical microelectrode implantation. To understand the role of the complement system in response to implanted probes, we performed gene expression profiling over acute time points from implanted subjects and compared them to no-surgery controls. This manuscript provides valuable insights into inflammatory mechanisms at the tissue-probe interface, thus having a high impact on those using intracortical microelectrodes to study and treat neurological diseases and injuries.Graphical abstractImage, graphical abstract
  • Degradation behavior, cytotoxicity, hemolysis, and antibacterial
           properties of electro-deposited Zn–Cu metal foams as potential
           biodegradable bone implants
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Xian Tong, Zimu Shi, Linchao Xu, Jixing Lin, Dechuang Zhang, Kun Wang, Yuncang Li, Cuie WenZinc (Zn) alloys have attracted much attention for biomedical applications due to their biodegradability, biocompatibility, and biological functionalities. Zn alloy foams have high potential to be used as regenerative medical implants by virtue of their porous structure, which allows new bone tissue ingrowth, their low elastic modulus approximating that of natural bone, and their biodegradation, which eliminates the need for follow-up surgery to remove the implants after bone tissue healing. In this context, a biodegradable Zn–Cu foam was fabricated by electrochemical deposition on a foamed Cu template and given a subsequent diffusion heat treatment. The microstructure, mechanical properties, degradation behavior, toxicity, hemolysis percentages, and antibacterial effects of the Zn–Cu foams were assessed for biomedical applications. The Zn–Cu foams exhibited a yield strength of ~12.1 MPa, a plateau strength of 16.8 MPa, and a strain over 50% under compression tests. The corrosion rate of the Zn–Cu foams measured by electrochemical polarization testing was 0.18 mm/y. The Zn–Cu foams showed good blood compatibility with a hemolysis percentage of less than 5%. Cytotoxicity assessment indicated that a 100% concentration of the Zn–Cu foam extract showed clear cytotoxicity against MC3T3-E1 osteoblast cells, but a 12.5% concentration of the extract showed> 90% cell viability. Moreover, the Zn–Cu foams showed good antibacterial effects.Statement of significanceThis work reportsa biodegradable Zn–Cu foam with high mechanical strength and ductility, suitable degradation rate, good antibacterial capacity, and good hemolysis property and biocompatibility. The Zn–Cu foam exhibited a yield strength of ~12.1 MPa, a plateau strength of 16.8 MPa, and a strain over 50% under compression tests. The corrosion rate of the Zn–Cu foam measured by electrochemical polarization testing was 0.18 mm/y in Hanks’ Solutions. The Zn–Cu foam showed good blood compatibility with a hemolysis percentage of less than 5%. Cytotoxicity assessment indicated that a 12.5% concentration of the foam extract showed> 90% cell viability. Moreover, the Zn–Cu foam showed good antibacterial effects against S. aureus.Graphical abstractImage, graphical abstract
  • Deconstructing tissue engineered trachea: Assessing the role of synthetic
           scaffolds, segmental replacement and cell seeding on graft performance
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Sayali Dharmadhikari, Lumei Liu, Kimberly Shontz, Matthew Wiet, Audrey White, Andrew Goins, Himani Akula, Jed Johnson, Susan D. Reynolds, Christopher K. Breuer, Tendy ChiangThe ideal construct for tracheal replacement remains elusive in the management of long segment airway defects. Tissue engineered tracheal grafts (TETG) have been limited by the development of graft stenosis or collapse, infection, or lack of an epithelial lining. We applied a mouse model of orthotopic airway surgery to assess the impact of three critical barriers encountered in clinical applications: the scaffold, the extent of intervention, and the impact of cell seeding and characterized their impact on graft performance. First, synthetic tracheal scaffolds electrospun from polyethylene terephthalate / polyurethane (PET/PU) were orthotopically implanted in anterior tracheal defects of C57BL/6 mice. Scaffolds demonstrated complete coverage with ciliated respiratory epithelium by 2 weeks. Epithelial migration was accompanied by macrophage infiltration which persisted at long term (>6 weeks) time points. We then assessed the impact of segmental tracheal implantation using syngeneic trachea as a surrogate for the ideal tracheal replacement. Graft recovery involved local upregulation of epithelial progenitor populations and there was no evidence of graft stenosis or necrosis. Implantation of electrospun synthetic tracheal scaffold for segmental replacement resulted in respiratory distress and required euthanasia at an early time point. There was limited epithelial coverage of the scaffold with and without seeded bone marrow-derived mononuclear cells (BM-MNCs). We conclude that synthetic scaffolds support re-epithelialization in orthotopic patch implantation, syngeneic graft integration occurs with focal repair mechanisms, however epithelialization in segmental synthetic scaffolds is limited and is not influenced by cell seeding.Statement of significanceThe life-threatening nature of long-segment tracheal defects has led to clinical use of tissue engineered tracheal grafts in the last decade for cases of compassionate use. However, the ideal tracheal reconstruction using tissue-engineered tracheal grafts (TETG) has not been clarified. We addressed the core challenges in tissue engineered tracheal replacement (re-epithelialization and graft patency) by defining the role of cell seeding with autologous bone marrow-derived mononuclear cells, the mechanism of respiratory epithelialization and proliferation, and the role of the inflammatory immune response in regeneration. This research will facilitate comprehensive understanding of cellular regeneration and neotissue formation on TETG, which will permit targeted therapies for accelerating re-epithelialization and attenuating stenosis in tissue engineered airway replacement.Graphical abstractImage, graphical abstract
  • Protein adsorption measurements on low fouling and ultralow fouling
           surfaces: A critical comparison of surface characterization techniques
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Mohammadhasan Hedayati, David Faulón Marruecos, Diego Krapf, Joel L. Kaar, Matt J. KipperUltralow protein fouling behavior is a common target for new high-performance materials. Ultralow fouling is often defined based on the amount of irreversibly adsorbed protein (< 5 ng cm−2) measured by a surface ensemble averaging method. However, protein adsorption at solid interfaces is a dynamic process involving multiple steps, which may include adsorption, desorption, and irreversible protein denaturation. In order to better optimize the performance of antifouling surfaces, it is imperative to fully understand how proteins interact with surfaces, including kinetics of adsorption and desorption, conformation, stability, and amount of adsorbed proteins. Defining ultralow fouling surfaces based on a measurement at or near the limit of detection of a surface-averaged measurement may not capture all of this behavior. Single-molecule microscopy techniques can resolve individual protein-surface interactions with high temporal and spatial resolution. This information can be used to tune the properties of surfaces to better resist protein adsorption. In this work, we demonstrate how combining surface plasmon resonance, X-ray photoelectron spectroscopy, atomic force microscopy, and single-molecule localization microscopy provides a more complete picture of protein adsorption on low fouling and ultralow fouling polyelectrolyte multilayer and polymer brush surfaces, over different regimes of protein concentration. In this case, comparing the surfaces using surface plasmon resonance alone is insufficient to rank their resistance to protein adsorption. Our results suggest a revision of the accepted definition of ultralow fouling surfaces is timely: with the advent of time-resolved studies of protein adsorption kinetics at the single-molecule level, it is neither necessary nor sufficient to rely on a surface averaging techniques to qualify ultralow fouling surfaces. Since protein adsorption is a dynamic process, understanding how surface properties affect the kinetics of protein adsorption will enable the design of future generations of advanced antifouling materials.Statement of significanceThe design of ultralow fouling surfaces is often optimized based on a single surface-averaging technique measuring the amount of irreversibly adsorbed protein. This work provides a critical comparison of alternative techniques for evaluating protein adsorption on low fouling and ultralow fouling surfaces, and demonstrates how additional information about the dynamics of protein-surface interactions at the interface can be obtained by application of single-molecule microscopy. This approach could be used to better elucidate mechanisms of protein resistance and design principles for advanced ultralow fouling materials.Graphical abstractImage, graphical abstract
  • Integration of polarized spatial frequency domain imaging (pSFDI) with a
           biaxial mechanical testing system for quantification of load-dependent
           collagen architecture in soft collagenous tissues
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Samuel V. Jett, Luke T. Hudson, Ryan Baumwart, Bradley N. Bohnstedt, Arshid Mir, Harold M. Burkhart, Gerhard A. Holzapfel, Yi Wu, Chung-Hao LeeCollagen fiber networks provide the structural strength of tissues, such as tendons, skin and arteries. Quantifying the fiber architecture in response to mechanical loads is essential towards a better understanding of the tissue-level mechanical behaviors, especially in assessing disease-driven functional changes. To enable novel investigations into these load-dependent fiber structures, a polarized spatial frequency domain imaging (pSFDI) device was developed and, for the first time, integrated with a biaxial mechanical testing system. The integrated instrument is capable of a wide-field quantification of the fiber orientation and the degree of optical anisotropy (DOA), representing the local degree of fiber alignment. The opto-mechanical instrument''s performance was assessed through uniaxial loading on tendon tissues with known collagen fiber microstructures. Our results revealed that the bulk fiber orientation angle of the tendon tissue changed minimally with loading (median ± 0.5*IQR of 52.7° ± 3.3° and 51.9° ± 3.3° under 0 and 3% longitudinal strains, respectively), whereas on a micro-scale, the fibers became better aligned with the direction of loading: the DOA (mean ± SD) increased from 0.149 ± 0.032 to 0.198 ± 0.056 under 0 and 3% longitudinal strains, respectively, p 
  • A new framework for characterization of poroelastic materials using
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Mohammad Hadi Esteki, Ali Akbar Alemrajabi, Chloe M. Hall, Graham K. Sheridan, Mojtaba Azadi, Emad MoeendarbaryTo characterize a poroelastic material, typically an indenter is pressed onto the surface of the material with a ramp of a finite approach velocity followed by a hold where the indenter displacement is kept constant. This leads to deformation of the porous matrix, pressurization of the interstitial fluid and relaxation due to redistribution of fluid through the pores. In most studies the poroelastic properties, including elastic modulus, Poisson ratio and poroelastic diffusion coefficient, are extracted by assuming an instantaneous step indentation. However, exerting step like indentation is not experimentally possible and usually a ramp indentation with a finite approach velocity is applied. Moreover, the poroelastic relaxation time highly depends on the approach velocity in addition to the poroelastic diffusion coefficient and the contact area. Here, we extensively studied the effect of indentation velocity using finite element simulations which has enabled the formulation of a new framework based on a master curve that incorporates the finite rise time. To verify our novel framework, the poroelastic properties of two types of hydrogels were extracted experimentally using indentation tests at both macro and micro scales. Our new framework that is based on consideration of finite approach velocity is experimentally easy to implement and provides a more accurate estimation of poroelastic properties.Statement of significanceHydrogels, tissues and living cells are constituted of a sponge-like porous elastic matrix bathed in an interstitial fluid. It has been shown that these materials behave according to the theory of ‘poroelasticity’ when mechanically stimulated in a way similar to that experienced in organs within the body. In this theory, the rate at which the fluid-filled sponge can be deformed is limited by how fast interstitial fluid can redistribute within the sponge in response to deformation. Here, we simulated indentation experiments at different rates and formulated a new framework that inherently captures the effects of stimulation speed on the mechanical response of poroelastic materials. We validated our framework by conducting experiments at different length-scales on agarose and polyacrylamide hydrogels.Graphical abstractImage, graphical abstract
  • Characterization of chemoelastic effects in arteries using digital volume
           correlation and optical coherence tomography
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Víctor A. Acosta Santamaría, María Flechas García, Jérôme Molimard, Stéphane AvrilUnderstanding stress-strain relationships in arteries is important for fundamental investigations in mechanobiology. Here we demonstrate the essential role of chemoelasticity in determining the mechanical properties of arterial tissues. Stepwise stress-relaxation uniaxial tensile tests were carried out on samples of porcine thoracic aortas immersed in a hyperosmotic solution. The tissue deformations were tracked using optical coherence tomography (OCT) during the tensile tests and digital volume correlation (DVC) was used to obtain measurements of depth-resolved strains across the whole thickness of the tested aortas. The hyperosmotic solution exacerbated chemoelastic effects, and we were able to measure different manifestations of these chemoelastic effects: swelling of the media inducing a modification of its optical properties, and existence of a transverse tensile strain. For the first time ever to our best knowledge, 3D strains induced by chemoelastic effects in soft tissues were quantified thanks to the OCT-DVC method. Without doubt, chemoelasticity plays an essential role in arterial mechanobiology in vivo and future work should focus on characterizing chemoelastic effects in arterial walls under physiological and disease conditions.Statement of significanceChemoelasticity, coupling osmotic phenomena and mechanical stresses, is essential in soft tissue mechanobiology. For the first time ever, we measure and analyze 3D strain fields induced by these chemoelastic effects thanks to the unique combination of OCT imaging and digital volume correlation.Graphical abstractImage, graphical abstract
  • Capturing instructive cues of tissue microenvironment by silica
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Sze Wing Tang, Wai Yuen, Ishdeep Kaur, Stella W. Pang, Nicolas H. Voelcker, Yun Wah LamCells in tissues are enveloped by an instructive niche made of the extracellular matrix. These instructive niches contain three general types of information: topographical, biochemical and mechanical. While the combined effects of these three factors are widely studied, the functions of each individual one has not been systematically characterised, because it is impossible to alter a single factor in a tissue microenvironment without simultaneously affecting the other two. Silica BioReplication (SBR) is a process that converts biological samples into silica, faithfully preserving the original topography at the nano-scale. We explored the use of this technique to generate inorganic replicas of intact mammalian tissues, including tendon, cartilage, skeletal muscle and spinal cord. Scanning electron and atomic force microscopy showed that the resulting replicas accurately preserved the three-dimensional ultrastructure of each tissue, while all biochemical components were eradicated by calcination. Such properties allowed the uncoupling the topographical information of a tissue microenvironment from its biochemical and mechanical components. Here, we showed that human mesenchymal stem cells (MSC) cultured on the replicas of different tissues displayed vastly different morphology and focal adhesions, suggesting that the topography of the tissue microenvironment captured by SBR could profoundly affect MSC biology. MSC cultured on tendon replica elongated and expressed tenocytes marker, while MSC on the spinal cord replica developed into spheroids that resembled neurospheres, in morphology and in the expression of neurosphere markers, and could be further differentiated into neuron-like cells. This study reveals the significance of topographical cues in a cell niche, as tissue-specific topography was sufficient in initiating and directing differentiation of MSC, despite the absence of any biochemical signals. SBR is a convenient and versatile method for capturing this topographical information, facilitating the functional characterisation of cell niches.Statement of significanceVarious studies have shown that three major factors, topographical, biochemical and mechanical, in a tissue microenvironment (TME) are essential for cellular homeostasis and functions. Current experimental models are too simplistic to represent the complexity of the TME, hindering the detailed understanding of its functions. In particular, the importance each factor in a tissue microenvironment have not been individually characterised, because it is challenging to alter one of these factors without simultaneously affecting the other two. Silica bioreplication (SBR) is a process that converts biological samples into silica replicas with high structural fidelity. SBR is a convenient and versatile method for capturing this topographical information on to a biologically inert material, allowing the functional characterisation of the architecture of a TME.Graphical abstractImage, graphical abstract
  • A detailed mechanical and microstructural analysis of ovine tricuspid
           valve leaflets
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): William D. Meador, Mrudang Mathur, Gabriella P. Sugerman, Tomasz Jazwiec, Marcin Malinowski, Matthew R. Bersi, Tomasz A. Timek, Manuel K. RauschThe tricuspid valve ensures unidirectional blood flow from the right atrium to the right ventricle. The three tricuspid leaflets operate within a dynamic stress environment of shear, bending, tensile, and compressive forces, which is cyclically repeated nearly three billion times in a lifetime. Ostensibly, the microstructural and mechanical properties of the tricuspid leaflets have mechanobiologically evolved to optimally support their function under those forces. Yet, how the tricuspid leaflet microstructure determines its mechanical properties and whether this relationship differs between the three leaflets is unknown. Here we perform a microstructural and mechanical analysis in matched ovine tricuspid leaflet samples. We found that the microstructure and mechanical properties vary among the three tricuspid leaflets in sheep. Specifically, we found that tricuspid leaflet composition, collagen orientation, and valve cell nuclear morphology are spatially heterogeneous and vary across leaflet type. Furthermore, under biaxial tension, the leaflets’ mechanical behaviors exhibited unequal degrees of mechanical anisotropy. Most importantly, we found that the septal leaflet was stiffer in the radial direction and not the circumferential direction as with the other two leaflets. The differences we observed in leaflet microstructure coincide with the varying biaxial mechanics among leaflets. Our results demonstrate the structure-function relationship for each leaflet in the tricuspid valve. We anticipate our results to be vital toward developing more accurate, leaflet-specific tricuspid valve computational models. Furthermore, our results may be clinically important, informing differential surgical treatments of the tricuspid valve leaflets. Finally, the identified structure-function relationships may provide insight into the homeostatic and remodeling potential of valvular cells in altered mechanical environments, such as in diseased or repaired tricuspid valves.Statement of significanceOur work is significant as we investigated the structure-function relationship of ovine tricuspid valve leaflets. This is important as tricuspid valves fail frequently and our current approach to repairing them is suboptimal. Specifically, we related the distribution of structural and cellular elements, such as collagen, glycosaminoglycans, and cell nuclei, to each leaflet’s mechanical properties. We found that leaflets have different structures and that their mechanics differ. This may, in the future, inform leaflet-specific treatment strategies and help optimize surgical outcomes.Graphical abstractGraphical abstract for this article
  • Biomechanical and microstructural characterisation of the porcine stomach
           wall: Location- and layer-dependent investigations
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Melanie Bauer, Enrique Morales-Orcajo, Lisa Klemm, Robert Seydewitz, Victoria Fiebach, Tobias Siebert, Markus BölThe mechanical properties of the stomach wall help to explain its function of storing, mixing, and emptying in health and disease. However, much remains unknown about its mechanical properties, especially regarding regional heterogeneities and wall microstructure. Consequently, the present study aimed to assess regional differences in the mechanical properties and microstructure of the stomach wall. In general, the stomach wall and the different tissue layers exhibited a nonlinear stress-stretch relationship. Regional differences were found in the mechanical response and the microstructure. The highest stresses of the entire stomach wall in longitudinal direction were found in the corpus (201.5 kPa), where food is ground followed by the antrum (73.1 kPa) and the fundus (26.6 kPa). In contrast, the maximum stresses in circumferential direction were 39.7 kPa, 26.2 kPa, and 15.7 kPa for the antrum, fundus, and corpus, respectively. Independent of the fibre orientation and with respect to the biaxial loading direction, partially clear anisotropic responses were detected in the intact wall and the muscular layer. In contrast, the innermost mucosal layer featured isotropic mechanical characteristics. Pronounced layers of circumferential and longitudinal muscle fibres were found in the fundus only, whereas corpus and antrum contained almost exclusively circumferential orientated muscle fibres. This specific stomach structure mirrors functional differences in the fundus as well as corpus and antrum. Within this study, the load transfer mechanisms, connected with these wavy layers but also in total with the stomach wall’s microstructure, are discussed.Statement of significanceThis article examines for the first time the layer-specific mechanical and histological properties of the stomach wall attending to the location of the sample. Moreover, both mechanical behaviour and microstructure were explicitly match identifying the heterogeneous characteristics of the stomach. On the one hand, the results of this study contribute to the understanding of stomach mechanics and thus to their functional understanding of stomach motility. On the other hand, they are relevant to the fields of constitutive formulation of stomach tissue, whole stomach mechanics, and stomach-derived scaffolds i.e., tissue-engineering grafts.Graphical abstractGraphical abstract for this article
  • Interfacial toughening effect of suture structures
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Zengqian Liu, Zhefeng Zhang, Robert O. RitchieSuture interfaces are one of the most common architectural designs in natural material-systems and are critical for ensuring multiple functionalities by providing flexibility while maintaining connectivity. Despite intensive studies on the mechanical role of suture structures, there is still a lack of understanding on the fracture mechanics of suture interfaces in terms of their interactions with impinging cracks. Here we reveal an interfacial toughening effect of suture structures by means of “excluding” cracks away from interfaces based on a dimensionless micro-mechanical model for single-leveled and hierarchical suture interfaces with triangular-shaped suture teeth. The effective stress-intensity driving forces for crack deflection along, versus penetration through, an interface at first impingement and on subsequent kinking are formulated and compared with the corresponding resistances. Quantitative criteria are established for discerning the cracking modes and fracture resistance of suture interfaces with their dependences on sutural tooth sharpness and interfacial toughness clarified. Additionally, the effects of structural hierarchy are elucidated through a consideration of hierarchical suture interfaces with fractal-like geometries. This study may offer guidance for designing bioinspired suture structures, especially for toughening materials where interfaces are a key weakness.Statement of significanceSuture interfaces are one of the most common architectural material designs in biological systems, and are found in a wide range of species including armadillo osteoderms, boxfish armor, pangolin scales and insect cuticles. They are designed to provide flexibility while maintaining connectivity. Despite many studies on the mechanical role of suture structures, there is still little understanding of their role in terms of interactions with impinging cracks. Here we reveal an interfacial toughening effect of suture structures by means of “excluding” cracks away from interfaces based on a dimensionless micro-mechanical model for single-leveled and hierarchical suture interfaces with triangular-shaped suture teeth. Quantitative criteria are established for discerning the cracking mode and fracture resistance of the interfaces with their dependences on sutural tooth sharpness and interfacial toughness clarified.Graphical abstractImage, graphical abstract
  • Peptide science: A “rule model” for new generations of
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Hannah R. Reese, Calvin C. Shanahan, Caroline Proulx, Stefano MenegattiPeptides have been heavily investigated for their biocompatible and bioactive properties. Though a wide array of functionalities can be introduced by varying the amino acid sequence or by structural constraints, properties such as proteolytic stability, catalytic activity, and phase behavior in solution are difficult or impossible to impart upon naturally occurring α-L-peptides. To this end, sequence-controlled peptidomimetics exhibit new folds, morphologies, and chemical modifications that create new structures and functions. The study of these new classes of polymers, especially α-peptoids, has been highly influenced by the analysis, computational, and design techniques developed for peptides. This review examines techniques to determine primary, secondary, and tertiary structure of peptides, and how they have been adapted to investigate peptoid structure. Computational models developed for peptides have been modified to predict the morphologies of peptoids and have increased in accuracy in recent years. The combination of in vitro and in silico techniques have led to secondary and tertiary structure design principles that mirror those for peptides. We then examine several important developments in peptoid applications inspired by peptides such as pharmaceuticals, catalysis, and protein-binding. A brief survey of alternative backbone structures and research investigating these peptidomimetics shows how the advancement of peptide and peptoid science has influenced the growth of numerous fields of study. As peptide, peptoid, and other peptidomimetic studies continue to advance, we will expect to see higher throughput structural analyses, greater computational accuracy and functionality, and wider application space that can improve human health, solve environmental challenges, and meet industrial needs.Statement of significanceMany historical, chemical, and functional relations draw a thread connecting peptides to their recent cognates, the “peptidomimetics”. This review presents a comprehensive survey of this field by highlighting the width and relevance of these familial connections. In the first section, we examine the experimental and computational techniques originally developed for peptides and their morphing into a broader analytical and predictive toolbox. The second section presents an excursus of the structures and properties of prominent peptidomimetics, and how the expansion of the chemical and structural diversity has returned new exciting properties. The third section presents an overview of technological applications and new families of peptidomimetics. As the field grows, new compounds emerge with clear potential in medicine and advanced manufacturing.Graphical abstractGraphical abstract for this article
  • Targeting strategies for superparamagnetic iron oxide nanoparticles in
           cancer therapy
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Defu Zhi, Ting Yang, Jian Yang, Shuang Fu, Shubiao ZhangAmong various nanoparticles, superparamagnetic iron oxide nanoparticles (SPIONs) have been increasingly studied for their excellent superparamagnetism, magnetic heating properties, and enhanced magnetic resonance imaging (MRI). The conjugation of SPIONs with drugs to obtain delivery nanosystems has several advantages including magnetic targeted functionalization, in vivo imaging, magnetic thermotherapy, and combined delivery of anticancer agents. To further increase the targeting efficiency of drugs through a delivery nanosystem based on SPIONs, additional targeting moieties including transferrin, antibodies, aptamers, hyaluronic acid, folate, and targeting peptides are coated onto the surface of SPIONs. Therefore, this review summarizes the latest progresses in the conjugation of targeting molecules and drug delivery nanosystems based on SPIONs, especially focusing on their performances to develop efficient targeted drug delivery systems for tumor therapy.Statement of significanceSome magnetic nanoparticle-based nanocarriers loaded with drugs were evaluated in patients and did not produce convincing results, leading to termination of clinical development in phase II/III. An alternative strategy for drug delivery systems based on SPIONs is the conjugation of these systems with targeting segments such as transferrin, antibodies, aptamers, hyaluronic acid, folate, and targeting peptides. These targeting moieties can be recognized by specific integrin/receptors that are overexpressed specifically on the tumor cell surface, resulting in minimizing dosage and reducing off-target effects. This review focuses on magnetic nanoparticle-based nonviral drug delivery systems with targeting moieties to deliver anticancer drugs, with an aim to provide suggestions on the development of SPIONs through discussion.Graphical abstractImage, graphical abstract
  • The use of bioactive matrices in regenerative therapies for traumatic
           brain injury
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Hui X. Tan, Mark P. Del Borgo, Marie-Isabel Aguilar, John S. Forsythe, Juliet M. Taylor, Peter J. CrackFunctional deficits due to neuronal loss are a common theme across multiple neuropathologies, including traumatic brain injury (TBI). Apart from mitigating cell death, another approach to treating brain injuries involves re-establishing the neural circuitry at the lesion site by utilizing exogeneous and/or endogenous stem cells to achieve functional recovery. While there has been limited success, the emergence of new bioactive matrices that promote neural repair introduces new perspectives on the development of regenerative therapies for TBI. This review briefly discusses current development on cell-based therapies and the use of bioactive matrices, hydrogels in particular, when incorporated in regenerative therapies. Desirable characteristics of bioactive matrices that have been shown to augment neural repair in TBI models were identified and further discussed. Understanding the relative outcomes of newly developed biomaterials implanted in vivo can better guide the development of biomaterials as a therapeutic strategy, for biomaterial-based cellular therapies are still in their nascent stages. Nonetheless, the value of bioactive matrices as a treatment for acute brain injuries should be appreciated and further developed.Statement of significanceCell-based therapies have received attention as an alternative therapeutic strategy to improve clinical outcome post-traumatic brain injury but have achieved limited success. Whilst the incorporation of newly developed biomaterials in regenerative therapies has shown promise in augmenting neural repair, studies have revealed new hurdles which must be overcome to improve their therapeutic efficacy. This review discusses the recent development of cell-based therapies with a specific focus on the use of bioactive matrices in the form of hydrogels, to complement cell transplantation within the injured brain. Moreover, this review consolidates in vivo animal studies that demonstrate relative functional outcome upon the implantation of different biomaterials to highlight their desirable traits to guide their development for regenerative therapies in traumatic brain injury.Graphical Image, graphical abstract
  • Mechanical, corrosion, and biocompatibility properties of Mg-Zr-Sr-Sc
           alloys for biodegradable implant applications
    • Abstract: Publication date: 15 January 2020Source: Acta Biomaterialia, Volume 102Author(s): Khurram Munir, Jixing Lin, Cuie Wen, Paul F.A. Wright, Yuncang LiMagnesium (Mg) and its alloys are considered promising biodegradable implant materials because of their strength and natural degradation in the human body. However, the high corrosion rate of pure Mg in the physiological environment leads to rapid degradation before adequate bone healing. This mismatch between bone healing and the degradation of Mg implants supports the development of new Mg alloys with the addition of other suitable alloying elements in order to achieve simultaneously high corrosion resistance and desirable mechanical properties. This study systematically investigates the microstructure, mechanical properties, corrosion behavior, and biocompatibility of Mg-based alloys with the addition of different concentrations of scandium (Sc), i.e., Mg-0.6Zr-0.5Sr-xSc (x = 0.5, 1, 2, 3 wt.%). Results indicated that high concentration of Sc in strontium (Sr)-containing Mg alloys can alter their microstructures by suppressing the intermetallic phases along the grain boundaries and improve the corrosion resistance by forming chemically stable Sc oxide layers on the surfaces of the Mg alloys. Cytotoxicity assessment revealed that the Sc containing Mg alloys did not significantly alter the viability of human osteoblast-like SaOS2 cells. This study highlights the advantages of using Sc as an alloying element to simultaneously tune Mg alloys with higher strength and slower degradation.Statement of significanceRare earth elements such as scandium (Sc) with both a high solid-solubility and strong affinity towards oxygen can improve the mechanical and corrosion properties of magnesium (Mg) alloys. However, the feasibility of Sc-containing Mg alloys as biodegradable implant materials is scarcely reported. This study investigates the effects of different Sc concentrations on the mechanical, corrosion, and biocompatibility properties of Mg-Zr-Sr-Sc alloys. Our findings indicated that the addition of Sc significantly improves the mechanical and corrosion properties of Mg-Zr-Sr alloys. Moreover, in vitro cytotoxicity assessment of the Mg-Zr-Sr-Sc alloys did not show any adverse effects on the viability of osteoblast-like cells.Graphical abstractImage, graphical abstract
  • Neither cortical nor trabecular: An unusual type of bone in the
           heavy-load-bearing lower pharyngeal jaw of the black drum (Pogonias
    • Abstract: Publication date: Available online 7 January 2020Source: Acta BiomaterialiaAuthor(s): Efrat Ziv, Joshua Milgram, Jonathan Davis, Ana Soares, Fabian Wilde, Paul Zaslansky, Ron ShaharDurophagous fish consume a diet based primarily on hard-shelled animals, mainly mollusks. In order to successfully perform this task, they are equipped with an extra set of jaws located in their throat called pharyngeal jaws.Here we present the results of a study of the structure of the bony material of the exceptionally powerful lower pharyngeal jaws (LPJs) of the black drum Pogonias cromis which generate the highest biting forces documented in bony fishes. In particular, we studied the two long and slender struts that support the entire dental plate and teeth of the LPJ, in order to determine how this structure withstands the huge stresses it encounters repetitively and for long periods of time.We describe the hierarchical structure of the struts of lower pharyngeal jaw of P. cromis at a wide range of length scales, and show how it is adapted to successfully achieve its high mechanical performance. In particular, we show that the bone material of the strut is neither cortical nor cancellous, and although it is highly porous, its complex and layered three-dimensional arrangement of thick lamellae sheets, which are inter-connected by thin plates, is perfectly tailored to withstand extremely large but directionally-consistent forces.Statement of significanceThe diet of some fish consists of hard food, like mollusks and shells. In order to accomplish the task of cracking this type of food, they have an extra set of bony jaws located in their throat, called pharyngeal jaws. Here we describe the hierarchical structural elements of these jaws which allow them to withstand huge forces repeatedly over long periods of time. Surprisingly, the structure is very porous, but its architectural design is superbly adapted to handle consistently-oriented forces. This structural motif defines a new bony material which is neither cortical nor cancellous.Graphical abstractImage, graphical abstract
  • The geometrical structure of interfaces in dental enamel: A FIB-STEM
    • Abstract: Publication date: Available online 7 January 2020Source: Acta BiomaterialiaAuthor(s): Jasmin Koldehoff, Michael V. Swain, Gerold A. SchneiderIn this study a high resolution structural analysis revealed that enamel prisms are surrounded by an interface that is discontinuous with frequent mineral to mineral contact separated by gaps. This contact manifests either by crystallites bridging the boundary between prismatic and interprismatic enamel or continuous crystallites curving and bridging the interprismatic enamel to the prisms. The geometrical resolution of this TEM investigation of the interfaces is ≤ 2 nm as a basis for micromechanical models. Within this resolution, contrary to existing structural descriptions of dental enamel structure in materials science literature, here the crystallites themselves are shown to be either in direct contact with each other, sometimes even fusing together, or are separated by gaps. Image analysis revealed that on average only 57 ± 15% of the interface consists of points of no contact between crystallites. This work reveals structural features of dental enamel that contribute important understanding to both the architecture and mechanical properties of this biological material. A new structural model is proposed and the implications for the mechanical properties of dental enamel are discussed.Graphical abstractImage, graphical abstract
  • Revealing the molecular origins of fibrin's elastomeric properties by in
           situ X-ray scattering
    • Abstract: Publication date: Available online 7 January 2020Source: Acta BiomaterialiaAuthor(s): Bart E. Vos, Cristina Martinez-Torres, Federica Burla, John W. Weisel, Gijsje H. KoenderinkFibrin is an elastomeric protein forming highly extensible fiber networks that provide the scaffold of blood clots. Here we reveal the molecular mechanisms that explain the large extensibility of fibrin networks by performing in situ small angle X-ray scattering measurements while applying a shear deformation. We simultaneously measure shear-induced alignment of the fibers and changes in their axially ordered molecular packing structure. We show that fibrin networks exhibit distinct structural responses that set in consecutively as the shear strain is increased. They exhibit an entropic response at small strains (25% strain) and finally changes in the fiber packing structure at high strain (>100%). Stretching reduces the fiber packing order and slightly increases the axial periodicity, indicative of molecular unfolding. However, the axial periodicity changes only by 0.7%, much less than the 80% length increase of the fibers, suggesting that fiber elongation mainly stems from uncoiling of the natively disordered αC-peptide linkers that laterally bond the molecules. Upon removal of the load, the network structure returns to the original isotropic state, but the fiber structure becomes more ordered and adopts a smaller packing periodicity compared to the original state. We conclude that the hierarchical packing structure of fibrin fibers, with built-in disorder, makes the fibers extensible and allows for mechanical annealing. Our results provide a basis for interpreting the molecular basis of haemostatic and thrombotic disorders associated with clotting and provide inspiration to design resilient bio-mimicking materials.Significance statementFibrin provides structural integrity to blood clots and is also widely used as a scaffold for tissue engineering. To fulfill its biological functions, fibrin networks have to be simultaneously compliant like skin and resilient against rupture. In this paper, we unravel the structural origin underlying this remarkable mechanical behavior. To this end, we performed in situ measurements of fibrin structure across multiple length scales by combining X-ray scattering with shear rheology. Our findings show that fibrin sustains large strains by undergoing a sequence of structural changes on different scales with increasing strain levels. This demonstrates aspects of an important biomaterial's structure and its mechanical function, and serves as an example in the design of biomimicking materials.Graphical abstractImage, graphical abstract
  • Vascularization of self-assembled peptide scaffolds for spinal cord injury
    • Abstract: Publication date: Available online 3 January 2020Source: Acta BiomaterialiaAuthor(s): Kiet A. Tran, Paul P. Partyk, Ying Jin, Julien Bouyer, Itzhak Fischer, Peter A. GalieThe disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury contributes to inflammation and glial scarring that inhibits axon growth and diminishes the effectiveness of conduits transplanted to the injury site to promote this growth. The purpose of this study is to evaluate whether scaffolds containing microvessels that exhibit BSCB integrity reduce inflammation and scar formation at the injury site and lead to increased axon growth. For these studies, a self-assembling peptide scaffold, RADA-16I, is used due to its established permissiveness to axon growth and ability to support vascularization. Immunocytochemistry and permeability transport assays verify the formation of tight-junction containing microvessels within the scaffold. Peptide scaffolds seeded with different concentrations of microvascular cells are then injected into a spinal contusion injury in rats to evaluate how microvessels affect axon growth and neurovascular interaction. The effect of the vascularized scaffold on inflammation and scar formation is evaluated by quantifying histological sections stained with ED-1 and GFAP, respectively. Our results indicate that the peptide scaffolds containing microvessels reduce inflammation and glial scar formation and increase the density of axons growing into the injury/transplant site. These results demonstrate the potential benefit of scaffold vascularization to treat spinal cord injury.Statement of SignificanceThis study evaluates the benefit of transplanting microvascular cells within a self-assembling peptide scaffold, RADA-16I, that has shown promise for facilitating regeneration in the central nervous system in previous studies. Our results indicate that vasculature featuring tight junctions that give rise to the blood-spinal cord barrier can be formed within the peptide scaffold both in vitro and in a rat model of a subacute contusion spinal cord injury. Histological analysis indicates that the presence of the microvessels encourages axon infiltration into the site of injury and reduces the area of astrocyte activation and inflammation. Overall, these results demonstrate the potential of vascularizing scaffolds for the repair of spinal cord injury.Graphical abstractImage, graphical abstract
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