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Publisher: John Wiley and Sons   (Total: 1583 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 55, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 44, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 143, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 11, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 25, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 49, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 253, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 29, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 129, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 31, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 250, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 118, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 157)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 212, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 43, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 93, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 44, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 67, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 138, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 13, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 215, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 49, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 28, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 14)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 3, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 13, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 43, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 22, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 17, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 386, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 66, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 3, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 8, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 136, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 18, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 34, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Advanced Healthcare Materials
  [SJR: 2.396]   [H-I: 29]   [13 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 2192-2659
   Published by John Wiley and Sons Homepage  [1583 journals]
  • Desmoplastic Reaction in 3D-Pancreatic Cancer Tissues Suppresses Molecular
           Permeability
    • Authors: Michiya Matsusaki; Misaki Komeda, Simona Mura, Hiroyoshi Y. Tanaka, Mitsunobu R. Kano, Patrick Couvreur, Mitsuru Akashi
      Abstract: The survival rate of pancreatic ductal adenocarcinoma is still the lowest among all types of cancers, primarily as a consequence of an important desmoplastic reaction. Although the presence of thick stromal tissues in pancreatic tumors has been reported, in vivo animal studies do not enable a clear understanding of the crosstalk between cancer cells and fibroblasts. Accordingly, this paper reports the design and characterization of an in vitro pancreatic cancer–stromal 3D-tissue model, which enhances the understanding of the interactions between cancer cells and fibroblasts and their influence on the secretion of extracellular matrix (ECM). 3D-tissue models comprising fibroblasts and pancreatic cancer cells (MiaPaCa-2 cell line) or colon cancer cells (HT29 cell line, used as a control) show decreased molecular permeability with increased cancer cell ratios. The 3D-MiaPaCa-2 tissues display an increase in the secretion of collagen as a function of the cancer cell ratio, whereas 3D-HT29 tissues do not show a significant difference. Notably, the secretion of ECM proteins from single fibroblasts in 3D-tissue models containing 90% MiaPaCa-2 cells is ten times higher than that under 10% cancer cell conditions. In vitro pancreatic cancer 3D-tissues will be a valuable tool to obtain information on the interactions between cancer and stromal cells.The design and characterization of in vitro pancreatic cancer–stromal 3D-tissues are reported, which enhance the current understanding of the interactions between cancer cells and fibroblasts and characterize the influence on the secretion of extracellular matrix (ECM). The 3D-pancreatic cancer tissues display a decrease in molecular permeability with increasing secretion of ECM proteins through cancer–stromal cell interactions.
      PubDate: 2017-04-27T19:04:09.476451-05:
      DOI: 10.1002/adhm.201700057
       
  • Bioresorbable Fe–Mn and Fe–Mn–HA Materials for Orthopedic
           Implantation: Enhancing Degradation through Porosity Control
    • Authors: Michael Heiden; Eric Nauman, Lia Stanciu
      Abstract: Resorbable, porous iron–manganese–hydroxyapatite biocomposites with suitable degradation rates for orthopedic applications are prepared using salt-leaching for the first time. These transient biomaterials have the potential to replace inert, permanent implants that can suffer from long-term complications, or have to be surgically removed, leaving an unfavorable void. Fe30Mn-10HA materials are newly developed to address inadequate resorption rates of degradable materials proposed for orthopedic environments in the past. In this study, controllable porosities with 300 µm diameter pores are introduced into Fe30Mn alloys and Fe30Mn-10HA composites, which enhance tissue ingrowth. For the composites, a Ca2Mn7O14 phase generated within the Fe30Mn matrix during the sintering process greatly increases degradability. The combination of this second phase and added porosity is found to contribute to increased bone-like apatite layer formation, mouse bone marrow mesenchymal stem cell attachment, and reduction of detrimental oxide layer flaking. Remarkably, after thirty days in vitro, there is a significant increase in degradation up to 0.82 ± 0.04 mm per year for 30 wt% porous Fe30Mn-10HA biocomposites, compared to 0.02 ± 0.00 mm per year for traditional nonporous Fe30Mn, thereby increasing the viability of these materials for future clinical studies.A significant problem with permanent implants is long-term complications and second surgeries. Here, the authors construct resorbable, iron–manganese–hydroxyapatite biocomposites that demonstrate high degradability. The development of a second Ca2Mn7O14 phase, paired with tailorable porosity generated by NaCl-leaching facilitates enhanced apatite layer formation, mouse bone marrow mesenchymal stem cell attachment, reduction of detrimental oxide layer flaking, and more clinically ideal degradation rates.
      PubDate: 2017-04-27T18:37:15.962816-05:
      DOI: 10.1002/adhm.201700120
       
  • Arginine-Rich Peptide-Based mRNA Nanocomplexes Efficiently Instigate
           Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the
           Peptide
    • Authors: Vimal K. Udhayakumar; Ans De Beuckelaer, Joanne McCaffrey, Cian M. McCrudden, Jonathan L. Kirschman, Daryll Vanover, Lien Van Hoecke, Kenny Roose, Kim Deswarte, Bruno G. De Geest, Stefan Lienenklaus, Philip J. Santangelo, Johan Grooten, Helen O. McCarthy, Stefaan De Koker
      Abstract: To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.T-cell immunity elicited by mRNA vaccines is heavily influenced by the delivery system. Cell penetrating peptide containing amphipathic RALA motifs condenses mRNA into nanocomplexes that efficiently translocate their mRNA cargo from endocytic vesicles to the cytosol. Through unique immune activation and enhanced expression, nucleoside modified mRNA complexed with RALA peptide induces potent antigen specific cytolytic T cells in vivo.
      PubDate: 2017-04-24T06:23:49.083063-05:
      DOI: 10.1002/adhm.201601412
       
  • Multilayer Nanofilms via Inkjet Printing for Stabilizing Growth Factor and
           Designing Desired Cell Developments
    • Authors: Moonhyun Choi; Hee Ho Park, Daheui Choi, Uiyoung Han, Tai Hyun Park, Hwankyu Lee, Juhyun Park, Jinkee Hong
      Abstract: Biologically versatile basic fibroblast growth factor (bFGF), well known for roles of signaling molecules between cells and regulating various cellular processes, has been proven to utilize specific functionalities. However, the remarkable functions are inclinable to dwindle with decrease of bFGFs' activity. In nanoscale, developing thin films with intrinsic characteristics of building molecules can facilitate handling various materials for desired purposes. Fabricating nanofilm and handling sensitive materials without detriment to activity via highly productive manufacturing are significant for practical uses in the field of biomedical applications. Herein, a multilayered nanofilm fabricating system is developed by inkjet printing to incorporate bFGF successfully. It is demonstrated that water mixed with glycerol as biological ink maintains stability of bFGFs through simulation and experimental study. With highly stable bFGFs, the proliferation of human dermal fibroblast is enhanced and the undifferentiated state of induced pluripotent stem cell is maintained by the controlled release of bFGF.Nanofilm incorporating basic fibroblast growth factors (bFGFs) are fabricated using inkjet printing and layer-by-layer assembly. During fabrication process, activity of bFGFs is highly stabilized by mixture of glycerol and water (3:7). The bFGFs released from nanofilm have an effect on a various kinds of cells, such as proliferation of human dermal fibroblast or differentiation of induced pluripotent stem cell.
      PubDate: 2017-04-24T02:30:48.004491-05:
      DOI: 10.1002/adhm.201700216
       
  • Modulation of Heterotypic and Homotypic Cell–Cell Interactions via
           Zwitterionic Lipid Masks
    • Authors: Matthew Park; Wongu Youn, Doyeon Kim, Eun Hyea Ko, Beom Jin Kim, Sung Min Kang, Kyungtae Kang, Insung S. Choi
      Abstract: Since the pioneering work by Whitesides, innumerable platforms that aim to spatio-selectively seed cells and control the degree of cell–cell interactions in vitro have been developed. These methods, however, have generally been technically and methodologically complex, or demanded stringent materials and conditions. In this work, we introduce zwitterionic lipids as patternable, cell-repellant masks for selectively seeding cells. The lipid masks are easily removed with a routine washing step under physiological conditions (37 °C, pH 7.4), and are used to create patterned cocultures, as well as to conduct cell migration studies. We demonstrate, via patterned cocultures of NIH 3T3 fibroblasts and HeLa cells, that HeLa cells proliferate far more aggressively than NIH 3T3 cells, regardless of initial population sizes. We also show that fibronectin-coated substrates induce cell movement akin to collective migration in NIH 3T3 fibroblasts, while the cells cultured on unmodified substrates migrate independently. Our lipid mask platform offers a rapid and highly biocompatible means of selectively seeding cells, and acts as a versatile tool for the study of cell–cell interactions.Easily removable, cell-repellant masks are developed based on zwitterioinic lipids to spatio-selectively seed cells for the study of cell–cell interactions. Prior fabrication methods have often required restrictive conditions or technically complex procedures, but this lipid-based strategy offers a simple and highly biocompatible means of restricting cell adhesion to specified areas, allowing for studies on heterotypic cocultures and collective migration.
      PubDate: 2017-04-21T01:58:07.55423-05:0
      DOI: 10.1002/adhm.201700063
       
  • Rod-Shaped Neural Units for Aligned 3D Neural Network Connection
    • Authors: Midori Kato-Negishi; Hiroaki Onoe, Akane Ito, Shoji Takeuchi
      Abstract: This paper proposes neural tissue units with aligned nerve fibers (called rod-shaped neural units) that connect neural networks with aligned neurons. To make the proposed units, 3D fiber-shaped neural tissues covered with a calcium alginate hydrogel layer are prepared with a microfluidic system and are cut in an accurate and reproducible manner. These units have aligned nerve fibers inside the hydrogel layer and connectable points on both ends. By connecting the units with a poly(dimethylsiloxane) guide, 3D neural tissues can be constructed and maintained for more than two weeks of culture. In addition, neural networks can be formed between the different neural units via synaptic connections. Experimental results indicate that the proposed rod-shaped neural units are effective tools for the construction of spatially complex connections with aligned nerve fibers in vitro.Assembly of four cortical units—fabricated microfiber-shaped neural tissues with cortical cells. Each unit has an insulated region covered with a thin alginate hydrogel layer to prevent the encapsulated neural tissues from connecting to surrounding cells within the regions; the edges of the unit are connectable, with the spherical ends functioning as glue to connect with other units.
      PubDate: 2017-04-21T01:53:13.730985-05:
      DOI: 10.1002/adhm.201700143
       
  • Mass Production of Cell-Laden Calcium Alginate Particles with Centrifugal
           Force
    • Authors: Yuya Morimoto; Maiko Onuki, Shoji Takeuchi
      Abstract: This paper describes a centrifuge-based device for oil-free and mass production of calcium-alginate (Ca-alginate) particles. The device is composed of four components: a tank with a glass capillary for forming sodium alginate droplets, a collecting bath with calcium chloride (CaCl2) solution, a waste liquid box, and a bypass channel bridged between the collecting bath and the waste liquid box. When the device is centrifuged, extra CaCl2 solution in the collecting bath is delivered to the waste liquid box to maintain the appropriate liquid level of CaCl2 solution for the production of monodisperse Ca-alginate particles. The proposed device enables oil-free production of over 45 000 uniformly sized Ca-alginate particles in a single 240 s process, whereas using the conventional method with only a glass capillary, ≈1000 particles are formed within the same processing time. Because of the high biocompatibility of the oil-free process, the device is applicable to cell encapsulation in Ca-alginate particles with high cell viability, as well as the formation of a macroscopic 3D cellular structure using Ca-alginate particles covered with cells as assembly modules. These results suggest that the device can be a useful tool for preparing experimental platforms in biomedical and tissue engineering fields.This paper describes a centrifuge-based device for oil-free and mass production of cell-laden calcium-alginate (Ca-alginate) particles: Ca-alginate particles encapsulating cells and Ca-alginate particles covered with cells. These results suggest that the device is a useful tool for easily and efficiently preparing experimental platforms in biomedical and tissue engineering fields owing to the high degree of biocompatibility of the oil-free process.
      PubDate: 2017-04-20T07:31:48.520562-05:
      DOI: 10.1002/adhm.201601375
       
  • Transparent and Gas-Permeable Liquid Marbles for Culturing and Drug
           Sensitivity Test of Tumor Spheroids
    • Authors: Hualin Li; Peng Liu, Guneet Kaur, Xi Yao, Mengsu Yang
      Abstract: Transparent nanoparticle-based liquid marbles with high gas-permeability are prepared to culture tumor spheroids in 3D without the need of supplementary growth factor. The culturing process of spheroids from a population of cancer cells or a single cell in the transparent liquid marbles can be optically recorded continuously. Compared to monolayer cells and spheroids generated in multiwell plate, tumor spheroids cultured in the liquid marbles show enhanced viability under the treatment of chemotherapeutic drugs and small interfering RNA.Transparent nanoparticle-based liquid marbles for culturing tumor spheroids in 3D are prepared and the formation of spheroids from a population of cancer cells or a single cell in the transparent liquid marbles can be optically recorded continuously. Tumor spheroids cultured in the liquid marbles show enhanced viability under the treatment of chemotherapeutic drugs and small interfering RNA.
      PubDate: 2017-04-20T07:31:26.695803-05:
      DOI: 10.1002/adhm.201700185
       
  • Panitumumab-Conjugated Pt-Drug Nanomedicine for Enhanced Efficacy of
           Combination Targeted Chemotherapy against Colorectal Cancer
    • Authors: Ming-Hsien Tsai; Chao-Hsuan Pan, Cheng-Liang Peng, Ming-Jium Shieh
      Abstract: Targeted combination chemotherapy (TCT) has recently been used to increase the induction of tumor cell death. In particular, the combination of Panitumumab and the platinum (Pt)-derived chemotherapeutic drug Oxaliplatin is clinically effective against KRAS and BRAF wild-type colorectal cancer (CRC) cells that overexpress epidermal growth factor receptors, and significantly greater efficacy is observed than with either drug alone. However, low accumulation of Pt drug in tumor sites prevents achievement of ideal efficacy. To develop an alternative drug therapy that achieves the ideal efficacy of TCT, the novel nanomedicine NANOPt-Pan using self-assembled dichloro(1,2-diaminocyclohexane)Pt(II)-modified Panitumumab is generated. Treatments with NANOPt-Pan lead to significant accumulation of Pt drug and Panitumumab in tumors, reflecting enhanced permeability and retention effect, active targeting, and sustained circulation of the Pt drug in the blood. In addition, NANOPt-Pan has excellent in vivo anti-CRC efficacy. These data indicate that NANOPt-Pan has high potential as a candidate nanomedicine for CRC.NANOPt-Pan self-assembles from dichloro(1,2-diaminocyclohexane)Pt(II)-modified Panitumumab and efficiently accumulates in tumors due to enhanced permeability and retention effect following intravenous injections. NANOPt-Pan actively binds and inactivates epidermal growth factor receptor. Subsequently, NANOPt-Pan is transported to lysosomes via endocytosis and is degraded. Consequently, Pt drug is released and reaches its action site.
      PubDate: 2017-04-18T04:51:38.944361-05:
      DOI: 10.1002/adhm.201700111
       
  • Hierarchical Micro/Nanofibrous Bioscaffolds for Structural Tissue
           Regeneration
    • Authors: Yun Xu; Wenguo Cui, Yanxia Zhang, Pinghui Zhou, Yong Gu, Xiaofeng Shen, Bin Li, Liang Chen
      Abstract: Various biomimetic scaffolds with hierarchical micro/nanostructures are designed to closely mimic native extracellular matrix network and to guide cell behavior to promote structural tissue generation. However, it remains a challenge to fabricate hierarchical micro/nanoscaled fibrous scaffolds with different functional components that endow the scaffolds with both biochemical and physical features to exert different biological roles during the process of tissue healing. In this study, a biomimetic designed micro/nanoscaled scaffold with integrated hierarchical dual fibrillar components is fabricated in order to repair dura mater and prevent the formation of epidural scars via collagen molecule self-assembly, electrospinning, and biological interface crosslinking strategies. The fabricated biomimetic scaffolds display micro/nanofibers staggered hierarchical architecture with good mechanical properties and biocompatibility, and it has a more profound effect on attachment, proliferation, and differentiation of fibroblasts. Using a rabbit duraplasty model in vivo, the authors find that dural defects repaired with hierarchical micro/nanoscaled scaffold form a continuous neodura tissue similar to native dura mater; furthermore, the number of scar tissues decreases significantly in the laminectomy sites compared with conventional electrospun microfibrous scaffold. Taken together, these data suggest that the hierarchical micro/nanoscaled fibrous scaffolds with dual fibrillar components may act as a “true” dural substitutes for dual repair.A biomimetic micro/nanoscaffold with integrated hierarchical dual fibrillar components is fabricated via collagen self-assembly, electrospinning, and biological interface crosslinking strategies. Hierarchical micro/nanoscaled fibrous scaffolds can not only induce the formation of new tissue of dura mater, but also mitigate the formation of spinal epidural scar fibrosis through scaffold medicated component modulation for epidural tissue structural remodeling.
      PubDate: 2017-04-13T10:53:21.603577-05:
      DOI: 10.1002/adhm.201601457
       
  • Spatiotemporal Evolution of the Wound Repairing Process in a 3D Human
           Dermis Equivalent
    • Authors: Bernadette Lombardi; Costantino Casale, Giorgia Imparato, Francesco Urciuolo, Paolo Antonio Netti
      Abstract: Several skin equivalent models have been developed to investigate in vitro the re-epithelialization process occurring during wound healing. Although these models recapitulate closure dynamics of epithelial cells, they fail to capture how a wounded connective tissue rebuilds its 3D architecture until the evolution in a scar. Here, the in vitro tissue repair dynamics of a connective tissue is replicated by using a 3D human dermis equivalent (3D-HDE) model composed of fibroblasts embedded in their own extracellular matrix (ECM). After inducing a physical damage, 3D-HDE undergoes a series of cellular and extracellular events quite similar to those occurring in the native dermis. In particular, fibroblasts differentiation toward myofibroblasts phenotype and neosynthesis of hyaluronic acid, fibronectin, and collagen during the repair process are assessed. Moreover, tissue reorganization after physical damage is investigated by measuring the diameter of bundles and the orientation of fibers of the newly formed ECM network. Finally, the ultimate formation of a scar-like tissue as physiological consequence of the repair and closure process is demonstrated. Taking together, the results highlight that the presence of cell-assembled and responsive stromal components enables quantitative and qualitative in vitro evaluation of the processes involved in scarring during wound healing.In this work, a 3D human dermis equivalent able to replicate the ECM-dynamics featuring the human dermis is fabricated. Such a model is used to replicate an acute wound and prove the possibility to follow in vitro the wound closure process by monitoring the assembly of collagen, hyaluronic acid, and fibronectin.
      PubDate: 2017-04-13T10:52:13.994312-05:
      DOI: 10.1002/adhm.201601422
       
  • Methotraxate-Loaded Hybrid Nanoconstructs Target Vascular Lesions and
           Inhibit Atherosclerosis Progression in ApoE−/− Mice
    • Authors: Cinzia Stigliano; Maricela R. Ramirez, Jaykrishna V. Singh, Santosh Aryal, Jaehong Key, Elvin Blanco, Paolo Decuzzi
      Abstract: Atherosclerosis is an inflammatory disorder characterized by the progressive thickening of blood vessel walls eventually resulting in acute vascular syndromes. Here, intravenously injectable hybrid nanoconstructs are synthesized for tempering immune cell inflammation locally and systemically. Lipid and polymer chains are nanoprecipitated to form 100 nm spherical polymeric nanoconstructs (SPNs), loaded with methotrexate (MTX) and subsequently labeled with Cu64 and fluorescent probes for combined nuclear/optical imaging. Upon engulfment into macrophages, MTX SPNs intracellularly release their anti-inflammatory cargo significantly lowering the production of proinflammatory cytokine (interleukin 6 and tumor necrosis factor α) already at 0.06 mg mL−1 of MTX. In ApoE−/− mice, fed with high-fat diet up to 17 weeks, nuclear and optical imaging demonstrates specific accumulation of SPNs within lipid-rich plaques along the arterial tree. Histological analyses confirm SPN uptake into macrophages residing within atherosclerotic plaques. A 4-week treatment with biweekly administration of MTX SPNs is sufficient to reduce the plaque burden in ApoE−/− mice by 50%, kept on high-fat diet for 10 weeks. Systemic delivery of MTX to macrophages via multifunctional, hybrid nanoconstructs constitutes an effective strategy to inhibit atherosclerosis progression and induce, potentially, the resorption of vascular lesions.Systemically injected spherical polymeric nanoconstructs, loaded with methotrexate and labeled with 64Cu(DOTA), accumulate in atherosclerotic plaques and reduce disease burden by almost 50% as compared to free drug treatments.
      PubDate: 2017-04-12T07:46:18.308336-05:
      DOI: 10.1002/adhm.201601286
       
  • Self-Assembled Carbon Dot Nanosphere: A Robust, Near-Infrared
           Light-Responsive, and Vein Injectable Photosensitizer
    • Authors: Qingyan Jia; Jiechao Ge, Weimin Liu, Liang Guo, Xiuli Zheng, Shiqing Chen, Mingxing Chen, Sha Liu, Liping Zhang, Mengqi Wang, Hongyan Zhang, Pengfei Wang
      Abstract: Self-assembly “activated” carbon dot photosensitizer: a robust, NIR-light responsive, and vein injectable carbon dot nanosphere (CDNS) photosensitizer with 1O2 quantum yield of 0.45 under 671 nm laser irradiation has been developed through self-assembly using individual CD as building units. This study develops the biomedical applications of CD, highlights the self-assembly for designing well-defined CD-based photosensitizers, and promotes future explorations of this CDNS photosensitizer in nanomedical and clinical applications.Self-assembly “activated” carbon dot (CD) photosensitizer: a robust, NIR-light responsive, and vein injectable CD nanosphere (CDNS) photosensitizer has been developed through self-assembly using individual CD as building units. This study develops the biomedical applications of CD, highlights the self-assembly for designing well-defined CD-based PSs, and promotes future explorations of this CDNS photosensitizer in nanomedical and clinical applications.
      PubDate: 2017-04-06T07:46:46.725581-05:
      DOI: 10.1002/adhm.201601419
       
  • Toward a Single-Dose Vaccination Strategy with Self-Encapsulating PLGA
           Microspheres
    • Authors: Brittany A. Bailey; Lukasz J. Ochyl, Steven P. Schwendeman, James J. Moon
      Abstract: Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely examined for vaccine applications due to their attractive features of biocompatibility, biodegradability, ability to be internalized by antigen-presenting cells, and long-term antigen release. However, one of the major challenges for PLGA particle vaccines is the potential for antigen instability and loss of antigenicity and immunogenicity. To address this challenge, we have developed a new method of “self-healing” encapsulation in PLGA microspheres, where pre-made PLGA microspheres are loaded with protein antigens under aqueous conditions with minimal impact on their antigenicity and immunogenicity. In this report, we show that mice immunized with self-encapsulating PLGA microspheres in a prime-boost regimen generated significantly enhanced antigen-specific CD8α+ T cell and antibody responses, compared with mice immunized with free, soluble protein admixed with calcium phosphate gel, a widely used adjuvant. Furthermore, a single-dose of microspheres designed for >40 day sustained antigen release elicited robust cellular and humoral immune responses as efficiently as the prime-boost vaccinations with calcium phosphate gel. Overall, these results suggest excellent potential of our self-encapsulating PLGA microspheres as a vaccine platform for multiple-dose as well as single-dose vaccinations.A “self-encapsulating” procedure is developed that maintains antigenicity and immunogenicity of protein antigens during the preparation of poly(lactic-co-glycolic acid) microspheres. A single-dose immunization with microspheres designed for >40 day antigen release elicits robust cellular and humoral immune responses in mice as efficiently as the prime-boost immunizations with a routinely used adjuvant, suggesting great vaccine potential for these “self-encapsulating” particles.
      PubDate: 2017-04-03T07:50:50.271446-05:
      DOI: 10.1002/adhm.201601418
       
  • Graphene Multielectrode Arrays as a Versatile Tool for Extracellular
           Measurements
    • Authors: Dmitry Kireev; Silke Seyock, Johannes Lewen, Vanessa Maybeck, Bernhard Wolfrum, Andreas Offenhäusser
      Abstract: Graphene multielectrode arrays (GMEAs) presented in this work are used for cardio and neuronal extracellular recordings. The advantages of the graphene as a part of the multielectrode arrays are numerous: from a general flexibility and biocompatibility to the unique electronic properties of graphene. The devices used for extensive in vitro studies of a cardiac-like cell line and cortical neuronal networks show excellent ability to extracellularly detect action potentials with signal to noise ratios in the range of 45 ± 22 for HL-1 cells and 48 ± 26 for spontaneous bursting/spiking neuronal activity. Complex neuronal bursting activity patterns as well as a variety of characteristic shapes of HL-1 action potentials are recorded with the GMEAs. This paper illustrates that the potential applications of the GMEAs in biological and medical research are still numerous and diverse.Graphene multielectrode arrays (GMEAS), reported in this work exhibit excellent ability to record electrophysiological signals. Cardiac-like cell activity as well as complex neuronal activity can be recorded with the arrays of graphene-based electrodes. Low noise performance, the corresponding large signal to noise ratio, and excellent long term in vitro stability place the GMEAs at the forefront of electrophysiological tools.
      PubDate: 2017-04-03T07:45:58.740131-05:
      DOI: 10.1002/adhm.201601433
       
  • Spherical Polyelectrolyte Brushes as a Novel Platform for Paramagnetic
           Relaxation Enhancement and Passive Tumor Targeting
    • Authors: Qin Zhu; Zhenyu Yuan, Weiqiao Qian, Yuanyuan Li, Zhiqiang Qiu, Weijun Tang, Jie Wang, Yun Ding, Aiguo Hu
      Abstract: A novel platform for the development of highly efficient magnetic resonance imaging (MRI) contrast agents has been demonstrated. New contrast agents are designed and produced through electrostatic self-assembly of cationic gadolinium(III) complexes onto anionic spherical polyelectrolyte brushes (SPB). The structurally well-defined SPB are composed of polystyrene core and polyacrylic acid brush layer, where numerous binding sites and confined microenvironments are available for the embedment of the gadolinium(III) contrast agents. Both in vitro and in vivo experiments show excellent biocompatibility and relaxometric performance of these SPB-based gadolinium hybrid materials. The enhanced relaxivity value is up to 86.2 mM−1 s−1 per Gd, a remarkably high record value at 1.5 T magnetic field. In vivo imaging displays a prolonged blood circulation time and massive accumulation of the contrast agents at the tumor region due to the enhanced permeability and retention effect. The SPB-based gadolinium hybrid materials not only broaden the horizons of new MRI contrast agents, but also have a great potential for tumor diagnosis.A novel platform for the development of highly efficient magnetic resonance imaging (MRI) contrast agents is demonstrated, by electrostatic self-assembly of cationic Gd complexes on spherical polyelectrolyte brushes. Both in vitro and in vivo experiments indicate excellent performance. It not only broadens the horizons of new MRI contrast agents, but also has a great potential for tumor diagnosis.
      PubDate: 2017-04-03T07:40:37.527334-05:
      DOI: 10.1002/adhm.201700071
       
  • Hydrogel Based Biosensors for In Vitro Dia of Biochemicals, Proteins, and
           Genes
    • Authors: Il Young Jung; Ji Su Kim, Bo Ram Choi, Kyuri Lee, Hyukjin Lee
      Abstract: Hydrogel-based biosensors have drawn considerable attention due to their various advantages over conventional detection systems. Recent studies have shown that hydrogel biosensors can be excellent alternative systems to detect a wide range of biomolecules, including small biochemicals, pathogenic proteins, and disease specific genes. Due to the excellent physical properties of hydrogels such as the high water content and stimuli-responsive behavior of cross-linked network structures, this system can offer substantial improvement for the design of novel detection systems for various diagnostic applications. The other main advantage of hydrogels is the role of biomimetic three-dimensional (3D) matrix immobilizing enzymes and aptamers within the detection systems, which enhances their stability. This provides ideal reaction conditions for enzymes and aptamers to interact with substrates within the aqueous environment of the hydrogel. In this review, we have highlighted various novel detection approaches utilizing the outstanding properties of the hydrogel. This review summarizes the recent progress of hydrogel-based biosensors and discusses their future perspectives and clinical limitations to overcome.Hydrogel-based biosensors have received much attention due to their distinctive advantages over conventional diagnostic platforms. The intrinsic properties of the hydrogel such as high water content and porous network structure provide an ideal condition for the detection of various biochemicals, proteins, and genes. This review highlights novel detection approaches using hydrogel based biosensors and their future potential in diagnostic applications.
      PubDate: 2017-03-31T14:45:43.608861-05:
      DOI: 10.1002/adhm.201601475
       
  • Bioinspired Collagen Scaffolds in Cranial Bone Regeneration: From Bedside
           to Bench
    • Abstract: Calvarial defects are common reconstructive dilemmas secondary to a variety of etiologies including traumatic brain injury, cerebrovascular disease, oncologic resection, and congenital anomalies. Reconstruction of the calvarium is generally undertaken for the purposes of cerebral protection, contour restoration for psychosocial well-being, and normalization of neurological dysfunction frequently found in patients with massive cranial defects. Current methods for reconstruction using autologous grafts, allogeneic grafts, or alloplastic materials have significant drawbacks that are unique to each material. The combination of wide medical relevance and the need for a better clinical solution render defects of the cranial skeleton an ideal target for development of regenerative strategies focused on calvarial bone. With the improved understanding of the instructive properties of tissue-specific extracellular matrices and the advent of precise nanoscale modulation in materials science, strategies in regenerative medicine have shifted in paradigm. Previously considered to be simple carriers of stem cells and growth factors, increasing evidence exists for differential materials directing lineage specific differentiation of progenitor cells and tissue regeneration. In this work, we review the clinical challenges for calvarial reconstruction, the anatomy and physiology of bone, and extracellular matrix-inspired, collagen-based materials that have been tested for in vivo cranial defect healing.In this review all of the current extracellular matrix-inspired, collagen-based materials reported in the literature with in vivo success in cranial defect healing in relationship to the clinical indications and challenges of cranial defect reconstruction are summarized. Future multi-disciplinary strategies in translating innovative materials to clinical medicine is discussed.
       
  • The Role of Titanium Surface Nanostructuring on Preosteoblast Morphology,
           Adhesion, and Migration
    • Abstract: Surface structuring of titanium-based implants is known to modulate the behavior of adherent cells, but the influence of different nanotopographies is poorly understood. The aim is to investigate preosteoblast proliferation, adhesion, morphology, and migration on surfaces with similar surface chemistry but distinct nanotopographical features. Sonochemical treatment and anodic oxidation are employed to fabricate disordered, mesoporous titania (TMS) and ordered titania nanotubular (TNT) topographies on titanium, respectively. Morphological evaluation reveals that cells are polygonal and well-spread on TMS, but display an elongated, fibroblast-like morphology on TNT surfaces, while they are much flatter on glass. Both nanostructured surfaces impair cell adhesion, but TMS is more favorable for cell growth due to its support of cell attachment and spreading in contrast to TNT. A quantitative wound healing assay in combination with live-cell imaging reveals that cell migration on TMS surfaces has a more collective character than on other surfaces, probably due to a closer proximity between neighboring migrating cells on TMS. The results indicate distinctly different cell adhesion and migration on ordered and disordered titania nanotopographies, providing important information that can be used in optimizing titanium-based scaffold design to foster bone tissue growth and repair while allowing for the encapsulation of drugs into porous titania layer.Different nanotopologies are generated on the surface of titanium implants by ultrasound treatment (left) and by anodic oxidation (right). The structural differences influence morphology and migration behavior of preosteoblastic cells growing on these surfaces. A quantitative wound healing assay in combination with live-cell imaging reveals more collective cell migration behavior on the disordered mesoporous surfaces generated by sonochemistry (left).
       
  • Development of a Hypoxic Radiosensitizer-Prodrug Liposome Delivery DNA
           Repair Inhibitor Dbait Combination with Radiotherapy for Glioma Therapy
    • Abstract: Gliomas are highly radioresistant tumors, mainly due to hypoxia in the core region of the gliomas and efficient DNA double-strand break repair. However, the design of a radiosensitizer incorporating the two above mechanisms is difficult and has rarely been reported. Thus, this study develops a hypoxic radiosensitizer-prodrug liposome (MLP) to deliver the DNA repair inhibitor Dbait (MLP/Dbait) to achieve the simultaneous entry of radiosensitizers with two different mechanisms into the glioma. MLP/Dbait effectively sensitizes glioma cells to X-ray radiotherapy (RT). Histological and microscopic examinations of dissected brain tissue confirm that MLP effectively delivers Dbait into the glioma. Furthermore, the combination of MLP/Dbait with RT significantly inhibits growth of the glioma, as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a Dbait delivery system to enhance the effect of RT on glioma, owing to the synergistic effects of the two different radiosensitizers.A hypoxic radiosensitizer-prodrug liposome (MLP) is developed to deliver the DNA repair inhibitor Dbait (MLP/Dbait) to achieve the simultaneous entry of radiosensitizers with two different mechanisms into the glioma. The combination of MLP/Dbait with radiotherapy significantly inhibits growth of the glioma.
       
  • Cancer Therapy: Injectable Supramolecular Hydrogels as Delivery Agents of
           Bcl-2 Conversion Gene for the Effective Shrinkage of Therapeutic
           Resistance Tumors (Adv. Healthcare Mater. 11/2017)
    • Abstract: In article number 1700159, Zibiao Li, Xian Jun Loh, Yun-Long Wu, and co-workers design injectable MPEG-PCL-PEI/α-CD based supramolecular hydrogels that possess good sustained release ability of Bcl-2 conversion genes in form of polyplex, to effectively inhibit in vivo tumor growth. This long term “enemy to friend” strategy will benefit various applications, including on-demand gene delivery and personalized medicine.
       
  • Tissue Engineering: Engineered 3D Cardiac Fibrotic Tissue to Study
           Fibrotic Remodeling (Adv. Healthcare Mater. 11/2017)
    • Abstract: Ali Khademhosseini and co-workers describe an engineered 3D fibrotic heart tissue, which is created by fabricating physiologically relevant cardiac tissues with native-like mechanical properties in article number 1601434. Upon exogenous stimulation with profibrotic transforming growth factor beta-1, these tissues reveal fibrogenic changes, such as collagen production, myofibroblast activation, and electrophysiological disturbances.
       
  • Angiogenesis: Affinity-Immobilization of VEGF on Laminin Porous Sponge
           Enhances Angiogenesis in the Ischemic Brain (Adv. Healthcare Mater.
           11/2017)
    • Abstract: Itsuki Ajioka and co-workers report a laminin-sponge (purple) with affinity-immobilized VEGF (yellow), which is an angiogenic growth factor. Neovascularization from existing blood vessels (red) in ischemic brain can potentially prevent the excess death of neurons (cyan) and improve functional recovery. The angiogenic activity of this sponge in vivo in a mouse stroke model is demonstrated in article number 1700183.
       
  • Masthead: (Adv. Healthcare Mater. 11/2017)
    •  
  • Contents: (Adv. Healthcare Mater. 11/2017)
    •  
  • Advanced Materials for Health Monitoring with Skin-Based Wearable Devices
    • Abstract: Skin-based wearable devices have a great potential that could result in a revolutionary approach to health monitoring and diagnosing disease. With continued innovation and intensive attention to the materials and fabrication technologies, development of these healthcare devices is progressively encouraged. This article gives a concise, although admittedly non-exhaustive, didactic review of some of the main concepts and approaches related to recent advances and developments in the scope of skin-based wearable devices (e.g. temperature, strain, biomarker-analysis werable devices, etc.), with an emphasis on emerging materials and fabrication techniques in the relevant fields. To give a comprehensive statement, part of the review presents and discusses different aspects of these advanced materials, such as the sensitivity, biocompatibility and durability as well as the major approaches proposed for enhancing their chemical and physical properties. A complementary section of the review linking these advanced materials with wearable device technologies is particularly specified. Some of the strong and weak points in development of each wearable material/device are highlighted and criticized. Several ideas regarding further improvement of skin-based wearable devices are also discussed.Concepts and approaches in skin-based wearable devices that can serve for health monitoring and diagnosing disease, with an emphasis on emerging materials and fabrication techniques in the relevant fields, are reviewed and discussed.
       
  • Simple Protein Modification Using Zwitterionic Polymer to Mitigate the
           Bioactivity Loss of Conjugated Insulin
    • Abstract: Polymer–protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer–protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non-site specific way, or a more complex site-specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB–insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB–insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB–insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB–insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one-step coupling reaction without complex site-specific linkage technique. The synthesized PCB–insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms.A significant problem with polymer–protein conjugation is the loss of the bioactivity. Here the authors report the finding when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through conventional coupling chemistry, the resulting PCB–insulin conjugate well maintains its in vitro bioactivity. Combined with the advantage of improved pharmacokinetics, the obtained PCB–insulin shows a significant increase of pharmacological activity of lowering blood glucose compared with native insulin.
       
  • An Engineered Cell-Instructive Stroma for the Fabrication of a Novel Full
           Thickness Human Cervix Equivalent In Vitro
    • Abstract: There is a growing interest for developing organotypic cervical models by using primary cervical cells that are able to reproduce the physiological relevant stromal microenvironment and the distinctive histology of the native cervical epithelium. Here for the first time it is reported the production of an organotypic cervical model featured by a scaffold-free stromal tissue resembling the extracellular matrix (ECM) composition and organization of the native counterpart as well as a completely well-differentiated epithelium. To reach this aim, human cervical microtissue precursors have been produced, characterized, and used as functional building units to fabricate a cell-synthesized cervical stroma equivalent by means of a bottom-up approach. Immunotypization, and molecular and morphological analyses reveal the extent of fundamental epithelial biomarkers and the presence of collagen and noncollagenous molecules, demonstrating that the natural tissue architecture and biological characteristics of cervical tissues are reproduced. The results of this study suggest that the bottom-up technology used to produce these 3D human cervical equivalents provides a fully functional organotypic cervical model that may be used as a valuable tool to investigate the epithelial-stromal interactions as well as for testing new therapeutics in vitro.In this work a bottom-up tissue engineering strategy is developed to obtain an engineered cell-instructive stroma by using human cervical microtissue precursors as functional building units. Starting from such 3D cervical stromal equivalent, a novel full thickness human cervical equivalent has been realized capable of expressing fundamental in vivo like functional characteristics.
       
  • Atomic Layer Deposition of a Silver Nanolayer on Advanced Titanium
           Orthopedic Implants Inhibits Bacterial Colonization and Supports
           Vascularized de Novo Bone Ingrowth
    • Abstract: Joint replacement surgery is associated with significant morbidity and mortality following infection with either methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis. These organisms have strong biofilm-forming capability in deep wounds and on prosthetic surfaces, with 103–104 microbes resulting in clinically significant infections. To inhibit biofilm formation, we developed 3D titanium structures using selective laser melting and then coated them with a silver nanolayer using atomic layer deposition. On bare titanium scaffolds, S. epidermidis growth was slow but on silver-coated implants there were significant further reductions in both bacterial recovery (p < 0.0001) and biofilm formation (p < 0.001). MRSA growth was similarly slow on bare titanium scaffolds and not further affected by silver coating. Ultrastructural examination and viability assays using either human bone or endothelial cells, demonstrated strong adherence and growth on titanium-only or silver-coated implants. Histological, X-ray computed microtomographic, and ultrastructural analyses revealed that silver-coated titanium scaffolds implanted into 2.5 mm defects in rat tibia promoted robust vascularization and conspicuous bone ingrowth. We conclude that nanolayer silver of titanium implants significantly reduces pathogenic biofilm formation in vitro, facilitates vascularization and osseointegration in vivo making this a promising technique for clinical orthopedic applications.Atomic layer deposition is used to coat the surface of titanium foams with a silver nanolayer, resulting in 2-log fold reduction of Staphylococcus epidermidis growth. Osteogenic cells, fibroblasts, and endothelium grow on these scaffolds in vitro. After implantation into rat tibia, vascular casting and scanning electron microscopy analysis (Etoc) reveal conspicuous bone ingrowth and numerous mature blood vessels on the struts.
       
  • 3D-Printed Multidrug-Eluting Stent from Graphene-Nanoplatelet-Doped
           Biodegradable Polymer Composite
    • Abstract: Patients with percutaneous coronary intervention generally receive either bare metal stents or drug-eluting stents to restore the normal blood flow. However, due to the lack of stent production with an individual patient in mind, the same level of effectiveness may not be possible in treating two different clinical scenarios. This study introduces for the first time the feasibility of a patient-specific stenting process constructed from direct 3D segmentation of medical images using direct 3D printing of biodegradable polymer–graphene composite with dual drug incorporation. A biodegradable polymer–carbon composite is prepared doped with graphene nanoplatelets to achieve controlled release of combinatorics as anticoagulation and antirestenosis agents. This study develops a technology prototyped for personalized stenting. An in silico analysis is performed to optimize the stent design for printing and its prediction of sustainability under force exerted by coronary artery or blood flow. A holistic approach covering in silico to in situ–in vivo establishes the structural integrity of the polymer composite, its mechanical properties, drug loading and release control, prototyping, functional activity, safety, and feasibility of placement in coronary artery of swine.The feasibility of a patient-specific stenting process constructed from computed tomographic images is introduced. A biodegradable polymer–carbon composite is prepared, doped with graphene nanoplatelets to achieve controlled release of combinatorics as anticoagulation and antirestenosis agents. A technology prototyped for personalized stenting is developed.
       
  • Microfluidic Encapsulation of Prickly Zinc-Doped Copper Oxide
           Nanoparticles with VD1142 Modified Spermine Acetalated Dextran for
           Efficient Cancer Therapy
    • Abstract: Structural features of nanoparticles have recently been explored for different types of applications. To explore specific particles as nanomedicine and physically destroy cancer is interesting, which might avoid many obstacles in cancer treatment, for example, drug resistance. However, one key element and technical challenge of those systems is to selectively target them to cancer cells. As a proof-of-concept, Prickly zinc-doped copper oxide (Zn–CuO) nanoparticles (Prickly NPs) have been synthesized, and subsequently encapsulated in a pH-responsive polymer; and the surface has been modified with a novel synthesized ligand, 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl] benzenesulfonamide (VD1142). The Prickly NPs exhibit very effective cancer cell antiproliferative capability. Moreover, the polymer encapsulation shields the Prickly NPs from unspecific nanopiercing and, most importantly, VD1142 endows the engineered NPs to specifically target to the carbonic anhydrase IX, a transmembrane protein overexpressed in a wide variety of cancer tumors. Intracellularly, the Prickly NPs disintegrate into small pieces that upon endosomal escape cause severe damage to the endoplasmic reticulum and mitochondria of the cells. The engineered Prickly NP is promising in efficient and targeted cancer treatment and it opens new avenue in nanomedication.Prickly Zn–CuO nanoparticles are engineered and encapsulated in spermine modified acetalated dextran nanomatrix, and further conjugated with VD1142 for enhancing the targeting and antiproliferative effect in carbonic anhydrase IX expressing cancer cells. The cell death is mainly induced by direct nanopiercing and destruction of the intracellular organelles, which offers several advantages and overcomes the traditional obstacles in drug based systems.
       
  • Stable Titania Nanostructures on Stainless Steel Coronary Stent Surface
           for Enhanced Corrosion Resistance and Endothelialization
    • Abstract: Stainless steel (SS) coronary stents continue to present risk of in-stent restenosis that impact its long term safety and efficacy. The present work focuses on developing a drug-free and polymer-less surface on coronary stents by utilizing a titania (TiO2) nanotexturing approach through hydrothermal processing, that will offer improved stent performance in vivo. Mechanically stable and durable nanotextured coatings are obtained on SS stents that also offer good corrosion resistance. In vitro vascular cell (endothelial and smooth muscle cells) studies on surface modified SS show preferential rapid endothelialization with enhanced nitric oxide production and reduce smooth muscle cell proliferation, in comparison to unmodified SS. In vivo evaluation of the nanotextured stents after subcutaneous implantation in rabbits show reduced irritability and minimal localized inflammatory response. These beneficial effects suggest that the stable, easily scalable titania nanosurface modification strategy on coronary stent surfaces can be a much cheaper alternative to drug eluting stents in addressing in-stent restenosis.Stable and well adherent titania nanostructures formed on stainless steel stent surface by a simple thermochemical technique provide improved features such as corrosion resistance, coating stability, minimal ion leaching, and preferential vascular cell response, in comparison to bare metal stents.
       
  • Construction of Small-Diameter Vascular Graft by Shape-Memory and
           Self-Rolling Bacterial Cellulose Membrane
    • Abstract: Bacterial cellulose (BC) membranes with shape-memory properties allow the rapid preparation of artificial small-diameter blood vessels when combined with microfluidics-based patterning with multiple types of cells. Lyophilization of a wet multilayered rolled BC tube endows it with memory to recover its tubular shape after unrolling. The unrolling of the BC tube yields a flat membrane, and subsequent patterning with endothelial cells, smooth muscle cells, and fibroblast cells is carried out by microfluidics. The cell-laden BC membrane is then rerolled into a multilayered tube. The different cells constituting multiple layers on the tubular wall can imitate blood vessels in vitro. The BC tubes (2 mm) without cell modification, when implanted into the carotid artery of a rabbit, maintain thrombus-free patency 21 d after implantation. This study provides a novel strategy for the rapid construction of multilayered small-diameter BC tubes which may be further developed for potential applications as artificial blood vessels.A method for the rapid preparation of artificial small-diameter vascular structures from bacterial cellulose (BC) membranes with self-rolling and tubular shape-memory properties is described. By combining the shape-memory BC membrane and microfluidics, multilayered cell-laden tubular BC structures mimicking blood vessels can be produced for long-term thrombosis-free implantation in the rabbit carotid artery.
       
  • High-Throughput Screening of Vascular Endothelium-Destructive or
           Protective Microenvironments: Cooperative Actions of Extracellular Matrix
           Composition, Stiffness, and Structure
    • Abstract: Pathological modification of the subendothelial extracellular matrix (ECM) has closely been associated with endothelial activation and subsequent cardiovascular disease progression. To understand regulatory mechanisms of these matrix modifications, the majority of previous efforts have focused on the modulation of either chemical composition or matrix stiffness on 2D smooth surfaces without simultaneously probing their cooperative effects on endothelium function on in vivo like 3D fibrous matrices. To this end, a high-throughput, combinatorial microarray platform on 2D and 3D hydrogel settings to resemble the compositions, stiffness, and structure of healthy and diseased subendothelial ECM has been established, and further their respective and combined effects on endothelial attachment, proliferation, inflammation, and junctional integrity have been investigated. For the first time, the results demonstrate that 3D fibrous structure resembling native ECM is a critical endothelium-protective microenvironmental factor by maintaining the stable, quiescent endothelium with strong resistance to proinflammatory stimuli. It is also revealed that matrix stiffening, in concert with chemical compositions resembling diseased ECM, particularly collagen III, could aggravate activation of nuclear factor kappa B, disruption of endothelium integrity, and susceptibility to proinflammatory stimuli. This study elucidates cooperative effects of various microenvironmental factors on endothelial activation and sheds light on new in vitro model for cardiovascular diseases.A high-throughput, cellular microarrays platform is established on 2D and 3D hydrogel settings to resemble the compositions, stiffness, and structure of healthy and diseased subendothelial extracellular matrix. The findings reveal a significant, as well as complex, interplay between matrix composition, stiffness, and structure exists in the regulation of both healthy and pathological endothelium.
       
  • Bridging the Knowledge of Different Worlds to Understand the Big Picture
           of Cancer Nanomedicines
    • Abstract: Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.Nanomedicine is emerging as effective therapeutic strategy for cancer therapy. As cancer nanomedicines are at the interface of diverse fields along with complexities lying in nanomedicines and cancer, demanding for an multidisciplinary efforts to advance the understanding and development of cancer-specific nanomedicines are needed to meet the current challenges in translating them into the clinic.
       
  • Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High
           Sensitive X-Ray Computed Tomography Imaging Agent for Diagnosis of Renal
           Dysfunctions
    • Abstract: Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (≈24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (≈0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy.Graphene oxide and Ag nanoparticle nanocoposites are prepared as enhanced contrast agent of computed tomography (CT) imaging in the presence of simvastatin, which exhibit excellent performance for in vivo CT imaging of the lung, liver, and renal perfusion, and intuitively diagnose the disease of the right renal in renal dysfunction mice.
       
  • Cyanine based Nanoprobes for Cancer Theranostics
    • Abstract: Cyanine dyes are greatly accredited in the development of non-invasive therapy that can “see” and “treat” tumor cells via imaging, photothermal and photodynamic treatment. However, these dyes suffer from poor pharmacokinetics inducing severe toxicity to normal cells, insufficient accumulation in tumor regions and rapid photobleaching when delivered in free forms. Nanoparticles engineered to encapsulate these compounds and delivering them into tumor regions have increased rapidly, however, so far, these nanoparticles (NPs) have not proved to be so effective to circumvent existing challenges. Newly designed multifunctional smart nanocarriers that can improve phototherapeutic properties of these dyes, co-encapsulate multiple potent therapeutic compounds, and simultaneously overcome limitations related to tumor recurrence, metastases, limited intracellular uptake, and tumor hypoxia have potential to revolutionize modern paradigm of cancer therapy. Such cyanine based multifunctional nanocarriers integrating imaging and therapy in a single platform can effectively produce better clinical outcomes in cancer treatment. This review briefly summarizes recent advancements of cyanine nanoprobes that are currently used as imaging/phototherapeutic agents in unimodal/bimodal/trimodal cancer theranostics. Finally, we conclude this review by addressing challenges of pre-existing therapeutic systems and designs adopted to overcome them with a brief insight assimilating future perspective of emerging cyanine-based NPs in cancer theranostics.Cyanines are well-established dyes that are remarkably safe and have been widely exploited for photothermal therapy, photodynamic therapy, and fluorescent imaging. Cyanine based nanoprobes are mostly designed to improve photostability, optical property, tumor accumulation, and targeting to malignant tumors essential for cancer treatment. It is believed that the future of cancer theranostics is in safe hands of cyanine nanoprobes.
       
  • ‘Printability' of Candidate Biomaterials for Extrusion Based 3D
           Printing: State-of-the-Art
    • Abstract: Regenerative medicine has been highlighted as one of the UK's 8 ‘Great Technologies' with the potential to revolutionize patient care in the 21st Century. Over the last decade, the concept of ‘3D bioprinting' has emerged, which allows the precise deposition of cell laden bioinks with the aim of engineering complex, functional tissues. For 3D printing to be used clinically, there is the need to produce advanced functional biomaterials, a new generation of bioinks with suitable cell culture and high shape/print fidelity, to match or exceed the physical, chemical and biological properties of human tissue. With the rapid increase in knowledge associated with biomaterials, cell-scaffold interactions and the ability to biofunctionalize/decorate bioinks with cell recognition sequences, it is important to keep in mind the ‘printability' of these novel materials. In this illustrated review, we define and refine the concept of ‘printability' and review seminal and contemporary studies to highlight the current ‘state of play' in the field with a focus on bioink composition and concentration, manipulation of nozzle parameters and rheological properties.3D bioprinting has the potential to replicate complex tissue architecture and biomanufacture physiologically relevant multicellular constructs on demand. Advanced functional biomaterials, a new generation of bioinks with suitable biocompatibility and high shape/print fidelity, when combined with the appropriate cell source have the potential to match or exceed the physical, chemical and biological properties of human tissue. Successful clinical translation would revolutionize patient care.
       
  • Dendritic Mesoporous Silica Nanoparticles for pH-Stimuli-Responsive Drug
           Delivery of TNF-Alpha
    • Abstract: Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells. Half-maximal effective concentration (EC50) for loaded TNF-α is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-α-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-α from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects.Dendritic mesoporous silica nanoparticles are used to encapsulate the highly toxic antitumor drug TNF-α. Efficiency of the employed system is tested in 2D and 3D tumor cell cultures. Encapsulation in mesoporous silica nanoparticles is a promising approach to enhance delivery and efficacy of antitumor drugs is demonstrated, while minimizing adverse side effects.
       
  • Understanding the Effect of Surface Chemistry of Mesoporous Silica
           Nanorods on Their Vaccine Adjuvant Potency
    • Abstract: Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with NH2 and C18 groups to investigate the influence of surface functional groups (OH, NH2, and C18) on their adjuvant efficacy. It is found that compared to OH and NH2 groups, the hydrophobic C18 modification significantly enhances antigen uptake by antigen presenting cells and endosomal–lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-γ level and antibody response in immunized mice. Moreover, bare MSNR and MSNRNH2 exhibit T-helper 2 biased immune response, while MSNRC18 shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines.The surface chemistry of mesoporous silica nanorods (MSNR) shows significant impact on their adjuvant potency. Compared to pristine MSNR with OH surface group, highly hydrophobic C18 functionalization displays significantly enhanced both humoral and cellular mediated immune response, while NH2 modification only moderately improves humoral immunity. These findings may provide useful guidance for the rational design of effective silica based vaccines.
       
  • Wet-AMD on a Chip: Modeling Outer Blood-Retinal Barrier In Vitro
    • Abstract: Choroidal neovascularization (CNV) in the retinal pigment epithelium (RPE)–choroid complex constituting outer blood retinal barrier (oBRB) is a critical pathological step in various ophthalmic diseases, which results in blindness, such as wet type age-related macula degeneration. Current in vitro experimental models using petri dishes or transwell are unable to study CNV morphogenesis. Here, a unique organotypic eye-on-a-chip model is described that mimics the RPE–choroid complex in vitro. This model consists of an RPE monolayer and adjacent perfusable blood vessel network, which is supporting barrier function of oBRB. The intact barrier function of the RPE-choroid complex is reconstituted while maintaining important structural features. Further, this model can successfully mimic the pathogenesis of CNV especially in terms of morphogenesis, which is penetrating angiogenic sprouts from pre-existing choroidal vessels that result in breakdown of RPE monolayer. The alleviation of the pathological angiogenesis can be modeled with bevacizumab, a clinical drug for CNV treatment. It is believed that this model can be used to aid in the development of advanced in vitro eye drug evaluation in conjunction with animal models.On-chip model of wet type age-related macular degeneration (AMD) that causes severe vision loss in the elderly is described. A process that destructs integrity of retinal pigment epithelium by angiogenesis of choroid vessel, a main pathological process of wet-AMD called choroidal neovascularization (CNV), is reconstituted on a microfluidic platform. Inhibitory effect of a therapeutic antiangiogenic compound on CNV is demonstrated.
       
  • Review of Flexible Temperature Sensing Networks for Wearable Physiological
           Monitoring
    • Abstract: Physiological temperature varies temporally and spatially. Accurate and real-time detection of localized temperature changes in biological tissues regardless of large deformation is crucial to understand thermal principle of homeostasis, to assess sophisticated health conditions, and further to offer possibilities of building a smart healthcare and medical system. Additionally, continuous temperature mapping in flexible and stretchable formats opens up many other potential areas, such as artificially electronic skins and reflection of emotional changes. This review exploits a comprehensive investigation onto recent advances in flexible temperature sensors, stretchable sensor networks, and platforms constructed in soft and compliant formats for wearable physiological monitoring. The most recent examples of flexible temperature sensors are first discussed regarding to their materials, structures, electrical and mechanical properties; temperature sensing network technologies in new materials and structural designs are then presented based on platforms comprised of multiple physical sensors and stretchable electronics. Finally, wearable applications of the sensing network are described, such as detection of human activities, monitoring of health conditions, and emotion-related bodily sensations. Conclusions are made with emphasis on critical issues and new trends in the field of wearable temperature sensor network technologies.Accurate and real-time detection of localized temperature changes in biological tissues regardless of large deformation is crucial to understand thermal principle of homeostasis and to assess sophisticated health conditions. This review exploits recent advances in flexible temperature sensors, stretchable sensor networks, and platforms constructed in soft and compliant formats for wearable physiological monitoring.
       
  • Biomimetic Model of Tumor Microenvironment on Microfluidic Platform
    • Abstract: The “Tumor microenvironment” (TME) is a complex, interacting system of the tumor and its surrounding environment. The TME has drawn more attention recently in attempts to overcome current drug resistance and the recurrence of cancer by understanding the cancer and its microenvironment systematically, beyond past reductionist approaches. However, a lack of experimental tools to dissect the intricate interactions has hampered in-depth research into the TME. Here, a biomimetic TME model using a microfluidic platform is presented, which enables the interaction between TME constituents to be studied in a comprehensive manner. Paracrine interactions of cocultured tumor cell lines (SK-OV-3, MKN-74, and SW620) with primary fibroblasts show marked morphological changes in the tumor cells, depending on the type of tumor cells, and, importantly, the composition of the extracellular matrix. Furthermore, this model allows direct observation of angiogenesis induced by the tumor–stroma interaction. Finally, reconstituting simultaneous angiogenesis and lymphangiogenesis induced by the tumor-stromal interaction with TME mimicking extrinsic factors is enabled. It is believed that the in vitro biomimetic model and the experimental concepts described will help to shed light on the complex biology of the TME.A biomimetic tumor microenvironment model that mimics simultaneous angiogenesis and lymphangiogenesis toward tumor mass is created in microfluidic platform. Tumor–stromal mixture induces natural morphogenesis of endothelial cells to migrate through 3D fibrin matrix and interacts directly with the tumor cells. This model can potentially be used not only in drug evaluation but also in studying complex tumor microenvironment systematically.
       
  • 3D Bioprinting Human Induced Pluripotent Stem Cell Constructs for In Situ
           Cell Proliferation and Successive Multilineage Differentiation
    • Abstract: The ability to create 3D tissues from induced pluripotent stem cells (iPSCs) is poised to revolutionize stem cell research and regenerative medicine, including individualized, patient-specific stem cell-based treatments. There are, however, few examples of tissue engineering using iPSCs. Their culture and differentiation is predominantly planar for monolayer cell support or induction of self-organizing embryoids (EBs) and organoids. Bioprinting iPSCs with advanced biomaterials promises to augment efforts to develop 3D tissues, ideally comprising direct-write printing of cells for encapsulation, proliferation, and differentiation. Here, such a method, employing a clinically amenable polysaccharide-based bioink, is described as the first example of bioprinting human iPSCs for in situ expansion and sequential differentiation. Specifically, There are extrusion printed the bioink including iPSCs, alginate (Al; 5% weight/volume [w/v]), carboxymethyl-chitosan (5% w/v), and agarose (Ag; 1.5% w/v), crosslinked the bioink in calcium chloride for a stable and porous construct, proliferated the iPSCs within the construct and differentiated the same iPSCs into either EBs comprising cells of three germ lineages—endoderm, ectoderm, and mesoderm, or more homogeneous neural tissues containing functional migrating neurons and neuroglia. This defined, scalable, and versatile platform is envisaged being useful in iPSC research and translation for pharmaceuticals development and regenerative medicine.Human tissues are generated by 3D bioprinting human induced pluripotent stem cells that proliferate and differentiate to form renewable 3D tissues. 3D tissues comprise cells of the three germ lineages—endoderm, ectoderm, and mesoderm, demonstrating the capacity to form all cells and tissues of the body, or more homogeneous neural tissues containing functional (including migrating) neurons and supporting neuroglia.
       
  • Deconvoluting the Bioactivity of Calcium Phosphate-Based Bone Graft
           Substitutes: Strategies to Understand the Role of Individual Material
           Properties
    • Abstract: Calcium phosphate (CaP)-based ceramics are the most widely applied synthetic biomaterials for repair and regeneration of damaged and diseased bone. CaP bioactivity is regulated by a set of largely intertwined physico-chemical and structural properties, such as the surface microstructure, surface energy, porosity, chemical composition, crystallinity and stiffness. Unravelling the role of each individual property in the interaction between the biomaterial and the biological system is a prerequisite for evolving from a trial-and-error approach to a design-driven approach in the development of new functional biomaterials. This progress report critically reviews various strategies developed to decouple the roles of the individual material properties in the biological performance of CaP ceramics. It furthermore emphasizes on the importance of a comprehensive and adequate material characterization that is needed to enhance our knowledge of the property-function relationship of biomaterials used in bone regeneration, and in regenerative medicine in general.Calcium phosphate ceramics are the most widely applied synthetic bone graft substitutes. Their biological performance is regulated by a set of largely intertwined material properties. To evolve from a production process-driven to a design-driven development of these biomaterials, it is necessary to unravel the role of each individual property in their interaction with a biological system. For this, strategies to decouple the effects of the individual properties are required.
       
  • Dual Cross-Linked Biofunctional and Self-Healing Networks to Generate
           User-Defined Modular Gradient Hydrogel Constructs
    • Abstract: Gradient hydrogels have been developed to mimic the spatiotemporal differences of multiple gradient cues in tissues. Current approaches used to generate such hydrogels are restricted to a single gradient shape and distribution. Here, a hydrogel is designed that includes two chemical cross-linking networks, biofunctional, and self-healing networks, enabling the customizable formation of modular gradient hydrogel construct with various gradient distributions and flexible shapes. The biofunctional networks are formed via Michael addition between the acrylates of oxidized acrylated hyaluronic acid (OAHA) and the dithiol of matrix metalloproteinase (MMP)-sensitive cross-linker and RGD peptides. The self-healing networks are formed via dynamic Schiff base reaction between N-carboxyethyl chitosan (CEC) and OAHA, which drives the modular gradient units to self-heal into an integral modular gradient hydrogel. The CEC-OAHA-MMP hydrogel exhibits excellent flowability at 37 °C under shear stress, enabling its injection to generate gradient distributions and shapes. Furthermore, encapsulated sarcoma cells respond to the gradient cues of RGD peptides and MMP-sensitive cross-linkers in the hydrogel. With these superior properties, the dual cross-linked CEC-OAHA-MMP hydrogel holds significant potential for generating customizable gradient hydrogel constructs, to study and guide cellular responses to their microenvironment such as in tumor mimicking, tissue engineering, and stem cell differentiation and morphogenesis.A user-defined modular gradient hydrogel system is developed by using dual cross-linked biofunctional and self-healing networks. The modular gradient hydrogel construct can be generated with various gradient distributions and flexible shapes as defined by users. The encapsulated cells are responsive to the gradient cues in the hydrogel construct, which holds potential to study cellular responses to their tissue microenvironment.
       
  • Bioprinted Osteogenic and Vasculogenic Patterns for Engineering 3D Bone
           Tissue
    • Abstract: Fabricating 3D large-scale bone tissue constructs with functional vasculature has been a particular challenge in engineering tissues suitable for repairing large bone defects. To address this challenge, an extrusion-based direct-writing bioprinting strategy is utilized to fabricate microstructured bone-like tissue constructs containing a perfusable vascular lumen. The bioprinted constructs are used as biomimetic in vitro matrices to co-culture human umbilical vein endothelial cells and bone marrow derived human mesenchymal stem cells in a naturally derived hydrogel. To form the perfusable blood vessel inside the bioprinted construct, a central cylinder with 5% gelatin methacryloyl (GelMA) hydrogel at low methacryloyl substitution (GelMALOW ) was printed. We also develop cell-laden cylinder elements made of GelMA hydrogel loaded with silicate nanoplatelets to induce osteogenesis, and synthesized hydrogel formulations with chemically conjugated vascular endothelial growth factor to promote vascular spreading. It was found that the engineered construct is able to support cell survival and proliferation during maturation in vitro. Additionally, the whole construct demonstrates high structural stability during the in vitro culture for 21 days. This method enables the local control of physical and chemical microniches and the establishment of gradients in the bioprinted constructs.The authors develop a strategy for engineering vascularized bone tissue through bioprinting using cell-laden gelatin methacryloyl (GelMA) hydrogels. The authors bioprint human umbilical vein endothelial cells laden fiber for blood vessel formation surrounded by GelMA fibers containing human mesenchymal stem cells for bone generation. The vascular vessel enables continuous perfusion and supports in vitro bone tissue formation and maturation.
       
  • Taxane-Grafted Metal-Oxide Nanoparticles as a New Theranostic Tool against
           Cancer: The Promising Example of Docetaxel-Functionalized Titanate
           Nanotubes on Prostate Tumors
    • Abstract: The combination of anticancer drugs and metal oxide nanoparticles is of great interest in cancer nanomedicine. Here, the development of a new nanohybrid, titanate nanotube–docetaxel (TiONts–DTX) is reported, the two parts of which are conjugated by covalent linkages. Unlike most nanoparticles currently being developed for biomedical purposes, TiONts present a needle-shaped morphology. The surface of TiONts is linked with 3-aminopropyl triethoxysilane and with a hetero-bifunctional polymer (polyethylene glycol) to create well-dispersed and biocompatible nanovectors. The prefunctionalized surface of this scaffold has valuable attachments to graft therapeutic agents (DTX in our case) as well as chelating agents (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to monitor the nanohybrids. To evaluate drug efficacy, in vitro tests have demonstrated that the association between TiONts and DTX shows cytotoxic activity against a hormone-refractory prostate cancer cell line (22Rv1) whereas TiONts without DTX do not. Finally, the first in vivo tests with intratumoral injections show that more than 70% of TiONts nanovectors are retained within the tumor for at least 7 d. Moreover, tumor growth in mice receiving TiONts–DTX is significantly slower than that in mice receiving free DTX. This nanohybrid can thus become a promising new tool in biomedicine to fight against prostate cancer.A new docetaxel-nanocarrier based on titanate nanotubes (TiONts) is synthesized step-by-step. Attention is paid to the elaboration of functionalized-TiONts nanohybrids in order to control the surface properties by chemical functionalization. Their efficacy is evaluated using in vitro and in vivo prostate cancer models. TiONts which combine a chemotherapeutic agent and a macrocyclic chelator appear to be an effective theranostic platform.
       
  • Peptide-Functionalized Fluorescent Particles for In Situ Detection of
           Nitric Oxide via Peroxynitrite-Mediated Nitration
    • Abstract: Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half-life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio-inspired peptide-based NO sensor is developed, which detects NO-derived oxidants, predominately peroxynitrite-mediated nitration of tyrosine residues. It is demonstrated that these peptide-based NO sensors can detect peroxynitrite-mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide-conjugated fluorescent particle immunoassay, peroxynitrite-mediated nitration activity with a detection limit of ≈100 × 10−9m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell-based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.Peptide-conjugated fluorescent particles are developed as biosensors to detect nitric oxide (NO) based on 3-nitrotyrosine labelling. The biosensors successfully detect NO release from endothelial cells under shear stress with a sensitivity exceeding that of standard assays. The biosensors provide an integrated measure of NO in the vicinity of the fluorescent particle, thereby allowing spatiotemporal localization of NO production within biological systems.
       
  • Self-Assembled Nanoparticles from Phenolic Derivatives for Cancer Therapy
    • Abstract: Therapeutic nanoparticles hold clinical promise for cancer treatment by avoiding limitations of conventional pharmaceuticals. Herein, a facile and rapid method is introduced to assemble poly(ethylene glycol) (PEG)-modified Pt prodrug nanocomplexes through metal-polyphenol complexation and combined with emulsification, which results in ≈100 nm diameter nanoparticles (PtP NPs) that exhibit high drug loading (0.15 fg Pt per nanoparticle) and low fouling properties. The PtP NPs are characterized for potential use as cancer therapeutics. Mass cytometry is used to quantify uptake of the nanoparticles and the drug concentration in individual cells in vitro. The PtP NPs have long circulation times, with an elimination half-life of ≈18 h in healthy mice. The in vivo antitumor activity of the PtP NPs is systematically investigated in a human prostate cancer xenograft mouse model. Mice treated with the PtP NPs demonstrate four times better inhibition of tumor growth than either free prodrug or cisplatin. This study presents a promising strategy to prepare therapeutic nanoparticles for biomedical applications.A polyphenol-based therapeutic nanoparticle system for cancer therapy is prepared by self-assembly and emulsion templating. The nanoparticles have a long blood half-life, accumulate in tumors in vivo, and exhibit better inhibition of tumor growth than either free prodrug or cisplatin.
       
  • Microcarriers with Synthetic Hydrogel Surfaces for Stem Cell Expansion
    • Abstract: Microcarriers are scalable support surfaces for cell growth that enable high levels of expansion, and are particularly relevant for expansion of human mesenchymal stem cells (hMSCs). The goal of this study is to develop a poly(ethylene glycol) (PEG)-based microcarrier coating for hMSC expansion. Commercially available microcarriers do not offer customizability of microcarrier surface properties, including elastic modulus and surface cell adhesion ligands. The lab has previously demonstrated that tuning these material properties on PEG-based hydrogels can modulate important cellular growth characteristics, such as cell attachment and expansion, which are important in microcarrier-based culture. Eosin-Y is adsorbed to polystyrene microcarriers and used as a photoinitiator for thiol-ene polymerization under visible light. Resultant PEG coatings are over 100 µm thick and localized to microcarrier surfaces. This thickness is relevant for cells to react to mechanical properties of the hydrogel coating, and coated microcarriers support hMSC attachment and expansion. hMSC expansion is highly favorable on coated microcarriers in serum-free media, with doubling times under 25 h in the growth phase, and retained osteogenic and adipogenic differentiation capacity after culture on microcarriers. These microcarriers with defined, synthetic coatings enable tailorable surfaces for cell expansion that may be suitable for a variety of biomanufacturing applications.A hydrogel coating platform for microcarriers based on interfacial polymerization is developed, enabling mesenchymal stem cell (MSC) culture and expansion. The coating system is robust, and MSCs maintain functionality in both serum-containing and serum-free media after expansion. The platform is amenable to customization for biomanufacturing applications.
       
  • Detection of Avian Influenza Virus from Cloacal Swabs Using a Disposable
           Well Gate FET Sensor
    • Abstract: Current methods to detect avian influenza viruses (AIV) are time consuming and lo inw sensitivity, necessitating a faster and more sensitive sensor for on-site epidemic detection in poultry farms and urban population centers. This study reports a field effect transistor (FET) based AIV sensor that detects nucleoproteins (NP) within 30 minutes, down to an LOD of 103 EID50 mL−1 from a live animal cloacal swab. Previously reported FET sensors for AIV detection have not targeted NPs, an internal protein shared across multiple strains, due to the difficulty of field-effect sensing in a highly ionic lysis buffer. The AIV sensor overcomes the sensitivity limit with an FET-based platform enhanced with a disposable well gate (DWG) that is readily replaceable after each measurement. In a single procedure, the virus-containing sample is immersed in a lysis buffer mixture to expose NPs to the DWG surface. In comparison with commercial AIV rapid kits, the AIV sensor is proved to be highly sensitive, fast, and compact, proving its potential effectiveness as a portable biosensor.A field effect transistor avian influenza virus (AIV) sensor with a disposable well gate that detects nucleoproteins within 30 minutes from a cloacal swab of a live host animal. T is reported in this studyhe AIV sensor exhibits an LOD of 103 EID50 mL−1, outperforming a commercially available rapid kit by one order and proving its potential effectiveness as a point-of-care virus sensor.
       
  • Topography-Guided Control of Local Migratory Behaviors and Protein
           Expression of Cancer Cells
    • Abstract: In vivo cancer cell migration and invasion are directed by biophysical guidance mechanisms such as pre-existing microtracks and basement membrane extracellular matrices. Here, this paper reports the correlation of the local migratory behavior of cancer cells and the biochemical signal expression using the topography that can guide or inhibit cell behaviors. To this end, the local apparent migration and the protein expression level are investigated with respect to the topographical feature size (flat, nanoline, and microline) and orientation (microline, microconcentric, and microradial) with the collectively migrating (A431) and individually migrating (MDA-MB-231 and U-87-MG) cancer cells. The results show that the migration and the protein expression of focal adhesion kinase, rho-associated protein kinase, and extracellular signal-regulated kinase are localized in the periphery of cell colony. Furthermore, the inhibition of migratory behavior at the periphery recues the protein expression, while the guidance of migration enhances the aforementioned protein expression. The results may imply the employ of biophysical inhibitory factors can help to control invasiveness of cancer cells during the progression state.Migration behaviors of cancer cells on various topographies are described. The migratory behaviors of cancer cells in colony are controlled by the topographical guidance or hindrance. Cells at front of the colony display most activated behavior for migration. The expression of the proteins involved in the migratory behaviors is localized in the periphery of the cell colony.
       
  • Highly Luminescent Folate-Functionalized Au22 Nanoclusters for Bioimaging
    • Abstract: Gold nanoclusters are emerging as new materials for biomedical applications because of promises offered by their ultrasmall size and excellent biocompatibility. Here, the synthesis and optical and biological characterizations of a highly luminescent folate-functionalized Au22 cluster (Au22-FA) are reported. The Au22-FA clusters are synthesized by functionalizing the surface of Au22(SG)18 clusters, where SG is glutathione, with benzyl chloroformate and folate. The functionalized clusters are highly water-soluble and exhibit remarkably bright luminescence with a quantum yield of 42%, significantly higher than any other water-soluble gold clusters protected with thiolate ligands. The folate groups conjugated to the gold cluster give rise to additional luminescence enhancement by energy transfer sensitization. The brightness of Au22-FA is found to be 4.77 mM−1 cm−1, nearly 8-fold brighter than that of Au22(SG)18. Further biological characterizations have revealed that the Au22-FA clusters are well-suited for bioimaging. The Au22-FA clusters exhibit excellent photostability and low toxicity; nearly 80% cell viability at 1000 ppm of the cluster. Additionally, the Au22-FA clusters show target specificity to folate-receptor positive cells. Finally, the time-course in vivo luminescence images of intravenous-injected mice show that the Au22-FA clusters are renal-clearable, leaving only 8% of them remained in the body after 24 h post-injection.Folate-functionalized Au22 nanoclusters show the highest luminescence quantum yield of 42% among other water-soluble gold nanoclusters protected with thiolate ligands. The brightness is enhanced by 8-fold via the rigidification of the surface shell and energy transfer sensitization from the photoexcited folate. The highly luminescent gold clusters with excellent biocompatibility and active targeting ability are well-suited to targeted bioimaging.
       
  • Broad Spectrum Macromolecular Antimicrobials with Biofilm Disruption
           Capability and In Vivo Efficacy
    • Abstract: In this study, antimicrobial polymers are synthesized by the organocatalytic ring-opening polymerization of an eight-membered heterocyclic carbonate monomer that is subsequently quaternized with methyl iodide. These polymers demonstrate activity against clinically relevant Gram-positive Staphylococcus epidermidis and Staphylococcus aureus, Gram-negative Escherichia coli and Pseudomonas aeruginosa, and fungus Candida albicans with fast killing kinetics. Importantly, the polymer efficiently inhibits biofilm growth and lyses existing biofilm, leading to a reduction in biomass and cell viability. In addition, the macromolecular antimicrobial is less likely to induce resistance as it acts via a membrane-lytic mechanism. The polymer is not cytotoxic toward mammalian cells with LD50 of 99.0 ± 11.6 mg kg−1 in mice through i.v. injection. In an S. aureus blood stream infection mouse model, the polymer removes bacteria from the blood more rapidly than the antibiotic Augmentin. At the effective dose, the polymer treatment does not damage liver and kidney tissues or functions. In addition, blood electrolyte balance remains unchanged after the treatment. The low cost of starting materials, ease of synthesis, nontoxicity, broad spectrum activity with fast killing kinetics, and in vivo antimicrobial activity make these macromolecular antimicrobials ideal candidates for prevention of sepsis and treatment of infections.Biodegradable eight membered polycarbonates that exhibit broad spectrum antimicrobial activity are synthesized by organocatalytic ring-opening polymerization. These materials are nonhemolytic and nontoxic with the ability to lyse individual microbes or biofilm via membrane lytic mechanism. In a blood stream infection mouse model, the polymer, injected intravenously, removes bacteria from the blood more rapidly than the antibiotic Augmentin without causing toxicity.
       
  • Multifunctional Liposomes for Image-Guided Intratumoral Chemo-Phototherapy
    • Abstract: Intratumoral (IT) drug injections reduce systemic toxicity, but delivered volumes and distribution can be inconsistent. To improve IT delivery paradigms, porphyrin–phospholipid (PoP) liposomes are passively loaded with three hydrophilic cargos: sulforhodamine B, a fluorophore; gadolinium-gadopentetic acid, a magnetic resonance (MR) agent; and oxaliplatin, a colorectal cancer chemotherapeutic. Liposome composition is optimized so that cargo is retained in serum and storage, but is released in less than 1 min with exposure to near infrared light. Light-triggered release occurs with PoP-induced photooxidation of unsaturated lipids and all cargos release concurrently. In subcutaneous murine colorectal tumors, drainage of released cargo is delayed when laser treatment occurs 24 h after IT injection, at doses orders of magnitude lower than systemic ones. Delayed light-triggering results in substantial tumor shrinkage relative to controls a week following treatment, although regrowth occurs subsequently. MR imaging reveals that over this time frame, pools of liposomes within the tumor migrate to adjacent regions, possibly leading to altered spatial distribution during triggered drug release. Although further characterization of cargo loading and release is required, this proof-of-principle study suggests that multimodal theranostic IT delivery approaches hold potential to both guide injections and interpret outcomes, in particular when combined with chemo-phototherapy.Porphyrin–phospholipid (PoP) liposomes are developed to load three hydrophilic cargo: a fluorophore for tracking cargo release; a magnetic resonance imaging agent for monitoring tumor distribution; and a chemotherapeutic. PoP liposomes rapidly release all cargos concurrently under near infrared light. Intratumoral injections are used to demonstrate chemo-phototherapy under image guidance.
       
  • Engineered 3D Cardiac Fibrotic Tissue to Study Fibrotic Remodeling
    • Abstract: Activation of cardiac fibroblasts into myofibroblasts is considered to play an essential role in cardiac remodeling and fibrosis. A limiting factor in studying this process is the spontaneous activation of cardiac fibroblasts when cultured on two-dimensional (2D) culture plates. In this study, a simplified three-dimensional (3D) hydrogel platform of contractile cardiac tissue, stimulated by transforming growth factor-β1 (TGF-β1), is presented to recapitulate a fibrogenic microenvironment. It is hypothesized that the quiescent state of cardiac fibroblasts can be maintained by mimicking the mechanical stiffness of native heart tissue. To test this hypothesis, a 3D cell culture model consisting of cardiomyocytes and cardiac fibroblasts encapsulated within a mechanically engineered gelatin methacryloyl hydrogel, is developed. The study shows that cardiac fibroblasts maintain their quiescent phenotype in mechanically tuned hydrogels. Additionally, treatment with a beta-adrenergic agonist increases beating frequency, demonstrating physiologic-like behavior of the heart constructs. Subsequently, quiescent cardiac fibroblasts within the constructs are activated by the exogenous addition of TGF-β1. The expression of fibrotic protein markers (and the functional changes in mechanical stiffness) in the fibrotic-like tissues are analyzed to validate the model. Overall, this 3D engineered culture model of contractile cardiac tissue enables controlled activation of cardiac fibroblasts, demonstrating the usability of this platform to study fibrotic remodeling.Engineered 3D cardiac fibrotic tissue is fabricated by using a cardiac cell-laden 3D hydrogel-platform which is used to create a physiologically relevant in vitro platform to control the activation of cardiac fibroblasts as they are induced into cardiac myofibroblasts. By the exogenous addition of a pro-fibrotic transforming growth factor-β1, the heart tissues reveal de novo expression of several cardiac fibrosis markers.
       
  • A Freeze-Concentration and Polyampholyte-Modified Liposome-Based
           Antigen-Delivery System for Effective Immunotherapy
    • Abstract: Immunotherapy is an exciting new approach to cancer treatment. The development of a novel freeze-concentration method is described that could be applicable in immunotherapy. The method involves freezing cells in the presence of pH-sensitive, polyampholyte-modified liposomes with encapsulated ovalbumin (OVA) as the antigen. In RAW 264.7 cells, compared to unfrozen, freeze-concentration of polyampholyte-modified liposomes encapsulating OVA resulted in efficient OVA uptake and also allowed its delivery to the cytosol. Efficient delivery of OVA to the cytosol was shown to be partly due to the pH-dependence of the polyampholyte-modified liposomes. Cytosolic OVA delivery also resulted in significant up-regulation of the major histocompatibility complex class I pathway through cross-stimulation, as well as an increase in the release of IL-1β, IL-6, and TNF-α. The results demonstrate that the combination of a simple freeze-concentration method and polyampholyte-modified liposomes might be useful in future immunotherapy applications.A freeze-concentration approach is presented for effective immunotherapy. Antigen internalization by cells is enhanced using a straightforward freezing technique. Moreover, a pH-sensitive polyampholyte-modified liposome is developed that enhances the cytoplasmic delivery of antigen when combined with the freeze-concentration method. The enhanced expression of MHC class I seen following the combination of freeze-concentration and polyampholyte-modified liposomes might be of benefit in immunotherapy.
       
  • A Ferroelectric Ceramic/Polymer Composite-Based Capacitive Electrode Array
           for In Vivo Recordings
    • Abstract: A new implantable capacitive electrode array for electrocorticography signal recording is developed with ferroelectric ceramic/polymer composite. This ultrathin and electrically safe capacitive electrode array is capable of attaching to the biological tissue conformably. The barium titanate/polyimide (BaTiO3/PI) nanocomposite with high dielectric constant is successfully synthesized and employed as the ultrathin dielectric layer of the capacitive BaTiO3/PI electrode array. The performance of the capacitive BaTiO3/PI electrode array is evaluated by electrical characterization and 3D finite-element modeling. In vivo, neural experiments on the visual cortex of rats show the reliability of the capacitive BaTiO3/PI electrode array. This work shows the potentials of capacitive BaTiO3/PI electrode array in the field of brain/computer interfaces.A new implantable capacitive electrode array for electrocorticography signal recording is developed with barium titanate/polyimide (BaTiO3/PI) nanocomposite. This ultrathin and electrically safe capacitive BaTiO3/PI electrode array is capable of attaching to the biological tissue conformably. In vivo neural experiments indicate its feasibility. This work shows the potentials of capacitive BaTiO3/PI electrode arrays in the field of brain/computer interfaces.
       
  • Damage, Healing, and Remodeling in Optogenetic Skeletal Muscle
           Bioactuators
    • Abstract: A deeper understanding of biological materials and the design principles that govern them, combined with the enabling technology of 3D printing, has given rise to the idea of “building with biology.” Using these materials and tools, bio-hybrid robots or bio-bots, which adaptively sense and respond to their environment, can be manufactured. Skeletal muscle bioactuators are developed to power these bio-bots, and an approach is presented to make them dynamically responsive to changing environmental loads and robustly resilient to induced damage. Specifically, since the predominant cause of skeletal muscle loss of function is mechanical damage, the underlying mechanisms of damage are investigated in vitro, and an in vivo inspired healing strategy is developed to counteract this damage. The protocol that is developed yields complete recovery of healthy tissue functionality within two days of damage, setting the stage for a more robust, resilient, and adaptive bioactuator technology than previously demonstrated. Understanding and exploiting the adaptive response behaviors inherent within biological systems in this manner is a crucial step forward in designing bio-hybrid machines that are broadly applicable to grand engineering challenges.Bio-hybrid robots, which harness the adaptive response behaviors of biological materials, need robust and resilient bioactuators to produce force and generation motion. Novel skeletal muscle bioactuators that are dynamically responsive to changing environmental loads and robustly resilient to induced damage are presented. An in vivo inspired healing strategy is used to accomplish accelerated recovery of healthy tissue functionality.
       
  • Induction of Chondrogenic Differentiation of Human Mesenchymal Stem Cells
           by Biomimetic Gold Nanoparticles with Tunable RGD Density
    • Abstract: Nanostructured materials have drawn a broad attention for their applications in biomedical fields. Ligand-modified nanomaterials can well mimic the dynamic extracellular matrix (ECM) microenvironments to regulate cell functions and fates. Herein, ECM mimetic gold nanoparticles (Au NPs) with tunable surface arginine-glycine-aspartate (RGD) density are designed and synthesized to induce the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). The biomimetic Au NPs with an average size of 40 nm shows good biocompatibility without affecting the cell proliferation in the studied concentration range. The RGD motifs on Au NPs surface facilitate cellular uptake of NPs into monolayer hMSCs through integrin-mediated endocytosis. The biomimetic NPs have a promotive effect on cartilaginous matrix production and marker gene expression in cell pellet culture, especially for the biomimetic Au NPs with high surface RGD density. This study provides a novel strategy for fabricating biomimetic NPs to regulate cell differentiation, which holds great potentials in tissue engineering and biomedical applications.Arginine-glycine-aspartate-modified gold nanoparticles (Au NPs) with tunable surface ligand density are developed to mimic the dynamic extracellular matrix. The biomimetic NPs have a promotive effect on cartilaginous matrix production and marker gene expression in cell pellet culture, especially for the biomimetic Au NPs with high surface RGD density.
       
  • Affinity-Immobilization of VEGF on Laminin Porous Sponge Enhances
           Angiogenesis in the Ischemic Brain
    • Abstract: Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue growth and repair. Proangiogenic therapy for stroke is promising for preventing excess neuron death and improving functional recovery. Vascular endothelial growth factor (VEGF) is a critical factor for angiogenesis by promoting the proliferation, the survival, and the migration of endothelial cells. Here, angiogenic biomaterials to support injured brain regeneration are developed. Porous laminin (LN)-rich sponge (LN-sponge), on which histidine-tagged VEGF (VEGF-Histag) is immobilized via affinity interaction is developed. In an in vivo mouse stroke model, transplanting VEGF-Histag-LN-sponge produces remarkably stronger angiogenic activity than transplanting LN-sponge with soluble VEGF. The findings indicate that using affinity interactions to immobilize VEGF is a practical approach for developing angiogenic biomaterials for regenerating the injured brain.Neovascularization from existing blood vessels, which is called angiogenesis, is essential for tissue growth and repair. Proangiogenic therapies for brain stroke can potentially prevent excess neuron death and improve functional recovery. The laminin-sponge with affinity-immobilized vascular endothelial growth factor, which is an angiogenic growth factor, is reported. The angiogenic activity of this sponge in vivo in a mouse stroke model is demonstrated.
       
  • Clickable Microgel Scaffolds as Platforms for 3D Cell Encapsulation
    • Abstract: While microporous scaffolds are increasingly used for regenerative medicine and tissue repair applications, the most common techniques to fabricate these scaffolds use templating or top-down fabrication approaches. Cytocompatible bottom-up assembly methods afford the opportunity to assemble microporous systems in the presence of cells and create complex polymer-cell composite systems in situ. Here, microgel building blocks with clickable surface groups are synthesized for the bottom-up fabrication of porous cell-laden scaffolds. The facile nature of assembly allows for human mesenchymal stem cells to be incorporated throughout the porous scaffold. Particles are designed with mean diameters of ≈10 and 100 µm, and assembled to create varied microenvironments. The resulting pore sizes and their distribution significantly alter cell morphology and cytoskeletal formation. This microgel-based system provides numerous tunable properties that can be used to control multiple aspects of cellular growth and development, as well as providing the ability to recapitulate various biological interfaces.Microgel “building blocks” are designed and assembled in the presence of cells to create polymer-cell composites. These materials have highly tunable mechanical and chemical properties, allowing for a highly versatile cell culture platform.
       
  • Highly Efficient Virus Rejection with Self-Organized Membranes Based on a
           Crosslinked Bicontinuous Cubic Liquid Crystal
    • Abstract: To remove viruses from water, the use of self-assembling liquid crystals is presented as a novel method for the synthesis of membranes with a regular pore size (below 1 nm) and controlled pore structures. Nanostructured bicontinuous cubic liquid-crystalline (LC) thin films are photopolymerized onto a polysulfone support layer. It is found that these membranes reject the virus, Qβ bacteriophage (≈20 nm diameter) by >99.9999%. Prepressurization of the membrane appears to enhance their virus rejection properties. This is the first example of nanostructured LC membranes that are used for virus rejection, for which they show great potential.Virus rejection by a liquid crystal membrane is realized for the first time using a self-assembling mesogen stabilized by crosslinking in an ordered bicontinuous cubic phase. This structure allows for the level of control over pore size distribution necessary for efficient rejection of small particles including viruses while allowing for permeation of water. Applying pressurization to the membrane prior to testing results in improved virus removal efficiency and water flux.
       
  • Injectable Supramolecular Hydrogels as Delivery Agents of Bcl-2 Conversion
           Gene for the Effective Shrinkage of Therapeutic Resistance Tumors
    • Abstract: Injectable hydrogels to deliver therapeutic genes in a minimally invasive manner and to achieve long term sustained release at tumor sites to minimize side effects are attractive for cancer therapy and precision medicine, but its rational design remains a challenge. In this report, an injectable supramolecular hydrogel system is designed based on the polypesudorotaxane formation between α-cyclodextrin (α-CD) and cationic methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(ethylene imine) (MPEG–PCL–PEI) copolymer, with the ability to form polyplexes with anionic plasmid DNA for effective sustained gene delivery. To be mentioned, the MPEG–PCL–PEI copolymers show similar pDNA binding ability, better gene transfection efficiency, lower cytotoxicity than nonviral gene transfection gold standard PEI (25 kDa), due to the formation of micelles and more stable polyplexes. More importantly, this MPEG–PCL–PEI/α-CD/pDNA supramolecular hydrogel shows a sustained release of pDNA in form of polyplex for up to 7 d. By taking these advantages, this supramolecular hydrogel system is applied as an injectable carrier for sustained Bcl-2 conversion gene release, in an in vivo rodent model of therapeutic resistant hepatocarcinoma with high expression of antiapoptotic Bcl-2 protein. This work represents the first time that injectable MPEG–PCL–PEI/α-CD supramolecular hydrogels possess good controllable release effect of Bcl-2 conversion genes in the form of polyplex to effectively inhibit in vivo tumor growth and this “enemy to friend” strategy will benefit various applications, including on-demand gene delivery and personalized medicine.An injectable supramolecular hydrogel is designed by using a cationic copolymer consisting hydrophilic methoxy-poly(ethylene glycol), biodegradable poly(ε-caprolactone), and cationic poly(ethylene imine) blocks. This minimally invasive hydrogel can achieve localized delivery of Bcl-2 conversion Nur77 gene in the form of polyplexes and exhibit sustained release of Nur77 gene to effectively inhibit the growth of therapeutic resistant tumor with high expression of Bcl-2 anti-apoptotic protein.
       
  • A Magnetically Actuated Microscaffold Containing Mesenchymal Stem Cells
           for Articular Cartilage Repair
    • Abstract: This study proposes a magnetically actuated microscaffold with the capability of targeted mesenchymal stem cell (MSC) delivery for articular cartilage regeneration. The microscaffold, as a 3D porous microbead, is divided into body and surface portions according to its materials and fabrication methods. The microscaffold body, which consists of poly(lactic-co-glycolic acid) (PLGA), is formed through water-in-oil-in-water emulsion templating, and its surface is coated with amine functionalized magnetic nanoparticles (MNPs) via amino bond formation. The porous PLGA structure of the microscaffold can assist in cell adhesion and migration, and the MNPs on the microscaffold can make it possible to steer using an electromagnetic actuation system that provides external magnetic fields for the 3D locomotion of the microscaffold. As a fundamental test of the magnetic response of the microscaffold, it is characterized in terms of the magnetization curve, velocity, and 3D locomotion of a single microscaffold. In addition, its function with a cargo of MSCs for cartilage regeneration is demonstrated from the proliferation, viability, and chondrogenic differentiation of D1 mouse MSCs that are cultured on the microscaffold. For the feasibility tests for cartilage repair, 2D/3D targeting of multiple microscaffolds with the MSCs is performed to demonstrate targeted stem cell delivery using the microscaffolds and their swarm motion.A magnetically actuated microscaffold is developed for targeted stem cell delivery. The microscaffold, which has a 3D porous microbead structure, supports mesenchymal stem cell adhesion and migration and is driven to a target site by external magnetic fields. Its function as a cell carrier through 2D/3D targeting tests using multiple microscaffolds containing D1 mouse mesenchymal stem cells is demonstrated.
       
  • Mechanotransduction and Growth Factor Signalling to Engineer Cellular
           Microenvironments
    • Abstract: Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing.The combination of physical stimuli and growth factor is essential to engineer advanced cellular microenvironments with impact in stem cell technologies, cancer research and regenerative medicine. This progress report discusses the role of properties such as stiffness, geometry, viscoelasticity and other dynamic properties as well as their combination with growth factor presentation in controlling (stem) cell behaviour.
       
  • Self-Targeting, Immune Transparent Plasma Protein Coated Nanocomplex for
           Noninvasive Photothermal Anticancer Therapy
    • Abstract: Cancer cells exhibit specific physiological differences compared to normal cells. Most surface membranes of cancer cells are characterized by high expression of given protein receptors, such as albumin, transferrin, and growth factors that are also present in the plasma of patients themselves, but are lacking on the surface of normal cells. These distinct features between cancer and normal cells can serve as a niche for developing specific treatment strategies. Near-infrared (NIR)-light-triggered therapy platforms are an interesting novel avenue for use in clinical nanomedicine. As a photothermal agent, conducting polymer nanoparticles, such as polypyrrole (PPy), of great NIR light photothermal effects and good biocompatibility, show promising applications in cancer treatments through the hyperthermia mechanism. Autologous plasma proteins coated PPy nanoparticles for hyperthermia therapy as a novel core technology platform to treat cancers through secreted protein acid and rich in cysteine targeting are developed here. This approach can provide unique features of specific targeting toward cancer cell surface markers and immune transparency to avoid recognition and attack by defense cells and achieve prolonged circulation half-life. This technology platform unveils new clinical options for treatment of cancer patients, supporting the emergence of innovative clinical products.The illustration shows that the developed nanocarriers are composed of plasma protein coated polypyrrole@polyethylenimine (PPy-PEI) nanoparticles (NP), referred to as the PPy-PEI-P nanocomplex (NC), with the self-targeting made possible through the cellular interactions between the cancer cell secreted protein acid and rich in cysteine and autologous plasma proteins and subsequent cancer cell killing allowed by the near-infrared-triggered hyperthermia effects.
       
  • Europium-Doped Cerium Oxide Nanoparticles Limit Reactive Oxygen Species
           Formation and Ameliorate Intestinal Ischemia–Reperfusion Injury
    • Abstract: Accumulating evidence suggests that ischemia–reperfusion-induced injury is associated with the formation of reactive oxygen species (ROS). This study demonstrates the therapeutic effectiveness of novel europium-doped cerium oxide nanoparticles (Eu-doped Ceria NPs) as ROS scavengers in a mouse model of intestinal ischemia–reperfusion-induced injury. An increased production of superoxide radicals is detected in the intestine throughout the ischemia stage and again after initiating reperfusion. These changes in superoxide radical formation are associated with the induction of inflammatory cytokines in the intestine. This study further shows that Eu-Ceria NPs exhibit superoxide scavenging activity in vitro. Importantly, administration of Eu-Ceria NPs into the intestinal lumen during the onset of ischemia effectively blocks superoxide accumulation, reduces the expression of IL-1b, and ameliorates the intestinal pathology. These results suggest that early increased production of ROS during the ischemia–reperfusion promotes intestinal pathology and that mucosal delivery of Eu-Ceria NPs may be a potential therapeutic approach to block ROS accumulation and ameliorate the severity of intestinal disease.Europium-doped cerium oxide nanoparticles (Eu-Cerium NPs) effectively block formation of reactive oxygen species (ROS). ROS are detected in live intestine in real-time using superoxide electrochemical biosensor.
      Authors demonstrate that early increase of ROS during ischemia–reperfusion promotes intestinal injury and that mucosal delivery of Eu-Ceria NPs can be a therapeutic approach to block ROS and reduce the severity of intestinal disease.
       
  • Metabolic Reprogramming of Macrophages Exposed to Silk,
           Poly(lactic-co-glycolic acid), and Silica Nanoparticles
    • Abstract: Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications. 1H NMR analysis of cell extracts and culture media is used to quantify the changes in the intracellular and extracellular metabolomes of macrophages in response to nanoparticle exposure. Increased glycolytic activity, an altered tricarboxylic acid cycle, and reduced ATP generation are consistent with a proinflammatory phenotype. Furthermore, amino acids possibly arising from autophagy, the creatine kinase/phosphocreatine system, and a few osmolytes and antioxidants emerge as important players in the metabolic reprogramming of macrophages exposed to nanoparticles. This metabolic signature is a common response to all nanoparticles tested; however, the direction and magnitude of some variations are clearly nanoparticle specific, indicating material-induced biological specificity. Overall, metabolic reprogramming of macrophages can be achieved with nanoparticle treatments, modulated through the choice of the material, and monitored using 1H NMR metabolomics.The changes in macrophage metabolism upon exposure to silk, poly(lactic-co-glycolic acid), or silica nanoparticles are revealed through NMR metabolomics. Main findings comprise increased glycolysis, altered tricarboxylic acid cycle, reduced ATP generation, activation of the creatine/phosphocreatine system, and changes in osmolytes and antioxidants. Metabolic reprogramming of macrophages can be achieved with nanoparticle treatments and monitored using NMR metabolomics.
       
  • Alpha-Tocopheryl Succinate-Conjugated G5 PAMAM Dendrimer Enables Effective
           Inhibition of Ulcerative Colitis
    • Abstract: Ulcerative colitis (UC) is a severe inflammatory disease in colon, however, the therapeutic efficacy of the standard-of-care in clinic for UC patients is unsatisfactory. To explore new drugs for effective and safe treatment of UC, alpha-tocopheryl succinate (α-TOS) is conjugated to generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer to construct a nanodevice of G5-NH-acetamide (Ac)-TOS. The inhibitory effects of the G5-NH-Ac-TOS on UC are evaluated in vivo in a dextran sulfate sodium induced UC mouse model, and its mechanisms are explored in vitro in lipopolysaccharide stimulated mouse peritoneal macrophages. The results indicate that the G5-NH-Ac-TOS exhibits greater inhibitive effects on UC than free α-TOS, through significant attenuation of the disease activity index and reduction of macrophage infiltration in the colon tissues. The protective mechanisms of the G5-NH-Ac-TOS are revealed to be related to inhibition of expression of nuclear translocation of NF-κB, phosphorylation of Akt, and reduction of reactive oxygen species production in the macrophages.Alpha-tocopheryl succinate (α-TOS) is conjugated to generation 5 (G5) poly(amidoamine) dendrimer to construct a nanodevice of G5-NH-acetamide (Ac)-TOS. After administrated to mice with ulcerative colitis, the G5-NH-Ac-TOS exhibits greater inhibitive effects on ulcerative colitis than free α-TOS.
       
  • Mechanical Adaptability of the MMP-Responsive Film Improves the
           Functionality of Endothelial Cell Monolayer
    • Abstract: Extracellular matrix and cells are inherent in coordinating and adapting to each other during all physiological and pathological processes. Synthetic materials, however, show rarely reciprocal and spatiotemporal responses to cells, and lacking self-adapting properties as well. Here, a mechanical adaptability based on the matrix metalloproteinase (MMPs) sensitive polyelectrolyte film is reported. Poly-lysine (PLL) and methacrylated hyaluronic acid (HA-MA) nanolayers are employed to build the thin film through the layer-by-layer assembly, and it is further crosslinked using MMP sensitive peptides, which endows the films with changeable mechanical properties in response to MMPs. It is demonstrated that stiffness of the (PLL/HA-MA) films increases with the crosslinking, and then decreases in response to a treatment of enzyme. Consequently, the crosslinked (PLL/HA-MA) films reveal effective growth of endothelial cells (ECs), leading to fast formation of EC monolayer. Importantly, significantly improved endothelial function of the EC monolayer, which is characterized by integrity, biomolecules release, expression of function related gene, and antithrombotic properties, is achieved along with the decrosslinking of the film because of EC-secreted MMPs. These results suggest that mechanical adaptability of substrate in Young's modulus plays a significant role in endothelial progression, which shows great application potential in tissue engineering, regenerative medicine, and organ-on-a-chip.Polyelectrolyte multilayer films with mechanical adaptability are prepared through matrix metalloproteinase (MMP)-sensitive peptide crosslinked (PLL/HA-MA) multilayer films. The stiffness of the substrates can be dynamically changed along with cell-secreted MMPs. Compared with substrates with static stiffness, such stiffness-adaptive substrates show the cell-controlled manner to benefit endothelial cell growth and consequent endothelial function of endothelial cell monolayer.
       
  • Bioinspired Pollen-Like Hierarchical Surface for Efficient Recognition of
           Target Cancer Cells
    • Abstract: The efficient recognition and isolation of rare cancer cells holds great promise for cancer diagnosis and prognosis. In nature, pollens exploit spiky structures to realize recognition and adhesion to stigma. Herein, a bioinspired pollen-like hierarchical surface is developed by replicating the assembly of pollen grains, and efficient and specific recognition to target cancer cells is achieved. The pollen-like surface is fabricated by combining filtering-assisted assembly and soft lithography-based replication of pollen grains of wild chrysanthemum. After modification with a capture agent specific to cancer cells, the pollen-like surface enables the capture of target cancer cells with high efficiency and specificity. In addition, the pollen-like surface not only assures high viability of captured cells but also performs well in cell mixture system and at low cell density. This study represents a good example of constructing cell recognition biointerfaces inspired by pollen–stigma adhesion.A pollen-like hierarchical surface is developed by combining a filtering-assisted assembly method and soft lithography. The as-prepared surface can enable the capture of target cancer cells with high efficiency and specificity after modification with recognition agent. The work represents a good example of constructing cell recognition biointerfaces inspired by pollen–stigma adhesion.
       
  • Extrusion Bioprinting of Shear-Thinning Gelatin Methacryloyl Bioinks
    • Abstract: Bioprinting is an emerging technique for the fabrication of 3D cell-laden constructs. However, the progress for generating a 3D complex physiological microenvironment has been hampered by a lack of advanced cell-responsive bioinks that enable bioprinting with high structural fidelity, particularly in the case of extrusion-based bioprinting. Herein, this paper reports a novel strategy to directly bioprint cell-laden gelatin methacryloyl (GelMA) constructs using bioinks of GelMA physical gels (GPGs) achieved through a simple cooling process. Attributed to their shear-thinning and self-healing properties, the GPG bioinks can retain the shape and form integral structures after deposition, allowing for subsequent UV crosslinking for permanent stabilization. This paper shows the structural fidelity by bioprinting various 3D structures that are typically challenging to fabricate using conventional bioinks under extrusion modes. Moreover, the use of the GPG bioinks enables direct bioprinting of highly porous and soft constructs at relatively low concentrations (down to 3%) of GelMA. It is also demonstrated that the bioprinted constructs not only permit cell survival but also enhance cell proliferation as well as spreading at lower concentrations of the GPG bioinks. It is believed that such a strategy of bioprinting will provide many opportunities in convenient fabrication of 3D cell-laden constructs for applications in tissue engineering, regenerative medicine, and pharmaceutical screening.A new strategy is developed that allows for direct bioprinting of 3D cell-laden pure gelatin methacryloyl (GelMA) constructs with high structural fidelity and enhanced bioactivity, by employing GelMA physical gels as the bioinks, achieved through a simple cooling process.
       
  • Electrospun Nanofibrous Silk Fibroin Membranes Containing Gelatin
           Nanospheres for Controlled Delivery of Biomolecules
    • Abstract: Development of novel and effective drug delivery systems for controlled release of bioactive molecules is of critical importance in the field of regenerative medicine. Here, oppositely charged gelatin nanospheres are incorporated into silk fibroin nanofibers through a colloidal electrospinning technique. A novel fibrous nano-in-nano drug delivery system is fabricated without the use of any organic solvent. The distribution of fluorescently labeled gelatin A and B nanospheres inside the nanofibers can be fine-tuned by simple adjustment of the weight ratio between the nanospheres and the relative feeding rate of core and shell solutions containing nanospheres by using single and coaxial nozzle electrospinning, respectively. Incorporation of vancomycin-loaded gelatin B nanospheres into the silk fibroin nanofibrous membranes results in a more sustained release of vancomycin, compared to the gelatin nanospheres free membranes. In addition, these membranes exhibit excellent and prolonged antibacterial effects against Staphylococcus aureus. Moreover, these membranes support the attachment, spreading, and proliferation of periodontal ligament cells. These results suggest that the beneficial properties of gelatin nanospheres can be exploited to improve the biological functionality of electrospun nanofibrous silk fibroin membranes.A nano-in-nano structured drug delivery system composed of oppositely charged gelatin A and B nanospheres inside silk fibroin nanofibers is developed for controlled delivery of biomolecules. The distribution of gelatin A and B nanospheres can be fine-tuned using electrospinning techniques. Incorporation of gelatin nanospheres is beneficial for sustained release of vancomycin with prolonged antibacterial effects and excellent cytocompatibility.
       
  • Drug “Pent-Up” in Hollow Magnetic Prussian Blue Nanoparticles for
           NIR-Induced Chemo-Photothermal Tumor Therapy with Trimodal Imaging
    • Abstract: The study reports a biocompatible smart drug delivery system based on a doxorubicin (DOX) blending phase-change material of 1-pentadecanol loaded hollow magnetic Prussian blue nanoparticles, resulting in HMNP-PB@Pent@DOX. The system possesses concentration-dependent high thermogenesis (>50 °C) when applying a near-infrared (NIR) laser irradiation only for 5 min. Furthermore, the system realizes near “zero release” of drug and is efficiently triggered by NIR for drug delivery in an “on” and “off” manner, thus inducing cell apoptosis in vitro and in vivo. Moreover, the system clearly indicates tumor site with trimodal imaging of magnetic resonance imaging, photoacoustic tomography imaging, and infrared thermal imaging. Furthermore, the system achieves efficient chemo-photothermal combined tumor therapy in vivo with 808 nm laser irradiation for 5 min at 1.2 W cm−2, revealing the good tumor inhibition effect comparing with those of chemotherapy or photothermal therapy alone. The system is also confirmed to be biocompatible in regard to the mortality rate.A biocompatible, trimodal imaging guided chemo-photothermal drug delivery system is fabricated with phase-change material of 1-pentadecanol filled hollow magnetic Prussian blue nanoparticles. The system realizes “on–off” and near “zero release” of drug and demonstrates great potential for synergistic tumor therapy. The study offers a promising theranostic nanoagent for chemo-photothermal combined tumor therapy in vivo.
       
  • Hollow Au–Cu Nanocomposite for Real-Time Tracing
           Photothermal/Antiangiogenic Therapy
    • Abstract: High absorption in the near-infrared (NIR) region is essential for a photoabsorbing agents to realize efficient photothermal therapy (PTT) for cancer. Here, a novel hollow Au–Cu nanocomposite (HGCNs) is developed, which displays a significantly enhanced NIR surface plasmon resonance absorption and photothermal transduction efficiency. Besides, fluorescent polymer dots poly(9,9-dioctylfluorene-2,7-diyl-co-benzothiadiazole) (PFBT) and chemotherapeutic mammalian target of rapamycin (mTOR) inhibitor agent rapamycin (RAPA) are attached onto the HGCNs (RAPA/PFBT-HGCNs) for real-time NIR fluorescence tracing and combined PTT/antiangiogenesis therapy. In particular, due to the fluorescence resonance energy transfer effect, RAPA/PFBT-HGCNs can act as NIR-activatable on/off probe system for real-time tracing of tumor tissues. A standard in vitro cellular uptake study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dual-staining study, and flow cytometry assay reveal that the RAPA/PFBT-HGCNs combined with NIR laser exhibit higher drug accumulation and cytotoxicity in both tumor cells and epithelial cells. Moreover, the margins of tumor and normal tissue can be accurately indicated by NIR-stimulated dequenched PFBT after 24 h intravenous administration. Further, tumor growth can be considerably hampered by the optimal formulation plus laser treatment with relatively lower side effects. Consequently, the work highlights the real-time tracing and enhanced PTT/antiangiogenesis therapy prospects of the established HGCNs with tremendous potential for treatment of cancer.A novel polymer dot poly(9,9-dioctylfluorene-2,7-diyl-co-benzothiadiazole) and mammalian target of rapamycin (mTOR) inhibitor rapamycin coloaded hollow Au–Cu nanocomposite is fabricated. The established dual agent loaded hollow Au–Cu nocomposite performs real-time near-infrared light fluorescence tracing and enhanced photothermal/antiangiogenesis therapy prospects, which can considerably hamper tumor growth with relatively lower side effects, thus realizing precise antitumor performance.
       
 
 
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