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Publisher: John Wiley and Sons   (Total: 1577 journals)

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Showing 1 - 200 of 1577 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: 61, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 49, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 142, 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: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, 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: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 3)
Addiction     Hybrid Journal   (Followers: 33, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, 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: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 251, 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: 5)
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: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, 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: 30, 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: 133, 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: 91, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 27, 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 Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 253, 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: 16, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 125, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, 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: 159)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 210, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 36, 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: 44, 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: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
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: 92, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, 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: 69, 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: 14, 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: 223, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 50, 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: 315, 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: 4, 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: 12, 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: 13, 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: 7, 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: 25, 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: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 399, 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: 68, 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: 5, 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: 9, 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: 15, 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: 37, 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: 135, 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: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 35, 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)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 221, SJR: 2.083, h-index: 125)

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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  [1577 journals]
  • The Potential of Liquid Marbles for Biomedical Applications: A Critical
    • Abstract: Liquid marbles (LM) are freestanding droplets covered by micro/nanoparticles with hydrophobic/hydrophilic properties, which can be manipulated as a soft solid. The phenomenon that generates these soft structures is regarded as a different method to generate a superhydrophobic behavior in the liquid/solid interface without modifying the surface. Several applications for the LM have been reported in very different fields, however the developments for biomedical applications are very recent. At first, the LM properties are reviewed, namely shell structure, LM shape, evaporation, floatability and robustness. The different strategies for LM manipulation are also described, which make use of magnetic, electrostatic and gravitational forces, ultraviolet and infrared radiation, and approaches that induce LM self-propulsion. Then, very distinctive applications for LM in the biomedical field are presented, namely for diagnostic assays, cell culture, drug screening and cryopreservation of mammalian cells. Finally, a critical outlook about the unexplored potential of LM for biomedical applications is presented, suggesting possible advances on this emergent scientific area.Liquid marbles (LM) are freestanding droplets and are regarded as a different method to generate superhydrophobic behavior in the liquid/solid interface. Here, it is reviewed the LM properties, several methods for LM manipulation and biomedical applications found for LM. Finally, a critical view of LM potential for biomedical applications is presented, suggesting some possible advances on this emergent field.
  • Multiplexed Optogenetic Stimulation of Neurons with Spectrum-Selective
           Upconversion Nanoparticles
    • Abstract: Optical modulation of nervous system becomes increasingly popular as the wide adoption of optogenetics. For these applications, upconversion materials hold great promise as novel photonic elements. This study describes an upconversion based strategy for combinatorial neural stimulation both in vitro and in vivo by using spectrum-selective upconversion nanoparticles (UCNPs). NaYF4 based UCNPs are used to absorb near-infrared (NIR) energy and to emit visible light for stimulating neurons expressing different channelrhodopsin (ChR) proteins. The emission spectrum of the UCNPs is selectively tuned by different doping strategy (Tm3+ or Er3+) to match the responsive wavelength of ChR2 or C1V1. When the UCNPs are packaged into a glass microoptrode, and placed close to or in direct contact with neurons expressing ChR2 or C1V1, the cells can be reliably activated by NIR illumination at single cell level as well as network level, which is characterized by patch-clamping and multielectrode-array recording in culture primary neurons. Furthermore, the UCNP-based optrode is implanted into the brain of live rodents to achieve all-optical remote activation of brain tissues in mammalian animals. It is believed that this proof-of-concept study opens up completely new applications of upconversion materials for regulating physiological functions, especially in neuroscience research.An upconversion-based technique is developed for combinatorial neural stimulation both in vitro and in vivo by using spectrum-selective upconversion nanoparticles (UCNPs). Differentially doped, NaYF4-based UCNPs are sealed in a biocompatible package and used to deliver visible light to neural tissues by absorbing remotely applied near infared energy for effective stimulation of neurons expressing various channelrhodopsin proteins.
  • Silicone-Based Adhesives with Highly Tunable Adhesion Force for
           Skin-Contact Applications
    • Abstract: A fundamental approach to fabricating silicone-based adhesives with highly tunable adhesion force for the skin-contact applications is presented. Liquid blends consisting of vinyl-multifunctional polydimethylsiloxane (V-PDMS), hydride-terminated PDMS (H-PDMS), and a tackifier composed of a silanol-terminated PDMS/MQ resin mixture and the MQ resin are used as the adhesive materials. The peel adhesion force of addition-cured adhesives on the skin is increased by increasing the H-PDMS molecular weights and the tackifier content, and decreasing the H-PDMS/V-PDMS ratio. There is an inverse relationship between the adhesion force and the Young's modulus. The low-modulus adhesives with a low H-PDMS/V-PDMS ratio exhibit enhanced adhesion properties. The low-modulus adhesives with the high MQ resin content show significantly enhanced adhesion properties. These adhesives exhibit a wide range of modulus (2–499 kPa), and their adhesion force (0.04–5.38 N) is superior to commercially available soft silicone adhesives (0.82–2.79 N). The strong adhesives (>≈2 N) provide sufficient adhesion for fixing the flexible electrocardiogram (ECG) device to the skin in most daily activity. The human ECG signals are successfully recorded in real time. These results suggest that the silicone-based adhesives should be useful as an atraumatic adhesive for the skin-contact applications.A fundamental approach to fabricating silicone-based adhesives with highly tunable adhesion is presented for the skin-contact applications. By adjusting the molecular weight of PDMSs and the concentration of PDMSs and MQ resin, the adhesion force of adhesives is highly controlled. The Young's modulus and silanol functionalities of the adhesives are the two main factors governing the adhesion to the skin.
  • Construction of Silica-Based Micro/Nanoplatforms for Ultrasound
           Theranostic Biomedicine
    • Abstract: Ultrasound (US)-based biomedicine has been extensively explored for its applications in both diagnostic imaging and disease therapy. The fast development of theranostic nanomedicine significantly promotes the development of US-based biomedicine. This progress report summarizes and discusses the recent developments of rational design and fabrication of silica-based micro/nanoparticles for versatile US-based biomedical applications. The synthetic strategies and surface-engineering approaches of silica-based micro/nanoparticles are initially discussed, followed by detailed introduction on their US-based theranostic applications. They have been extensively explored in contrast-enhanced US imaging, US-based multi-modality imaging, synergistic high-intensity focused US (HIFU) ablation, sonosensitizer-enhanced sonodynamic therapy (SDT), as well as US-triggered chemotherapy. Their biological effects and biosafety have been briefly discussed to guarantee further clinical translation. Based on the high biocompatibility, versatile composition/structure and high performance in US-based theranostic biomedicine, these silica-based theranostic agents are expected to pave a new way for achieving efficient US-based theranostics of disease by taking the specific advantages of material science, nanotechnology and US-based biomedicine.Recent development of the design and fabrication of silica-based micro/nanoparticles for versatile ultrasound (US)-based biomedical applications is summarized and discussed in this Progress Report. Synthetic strategies and surface-engineering approaches of silica-based micro/nanoparticles are initially discussed, followed by the comprehensive introduction on their broad applications in US-based theranostics. These silica-based micro/nanoparticles have been extensively explored in contrast-enhanced diagnostic US imaging, US-based multi-modality imaging, synergistic high-intensity focused ultrasound (HIFU) ablation, sonosensitizer-enhanced sonodynamic therapy (SDT), as well as US-triggered on-demand chemotherapy. The specific biological effects and biosafety of these silica-based micro/nanoparticles have been briefly discussed to guarantee their further clinical translation.
  • Bright AIE Nanoparticles with F127 Encapsulation for Deep-Tissue
           Three-Photon Intravital Brain Angiography
    • Abstract: Deep-tissue imaging is of great significance to biological applications. In this paper, a deep-red emissive luminogen 2,3-bis(4′-(diphenylamino)-[1,1′-biphenyl]-4-yl) fumaronitrile (TPATCN) with aggregation-induced emission (AIE) feature is prepared. TPATCN molecules were then encapsulated within a polymeric matrix of Pluronic F-127 to form nanoparticles (NPs). TPATCN NPs exhibit bright three-photon fluorescence (3PF) in deep-red region, together with high chemical stability, good photostability, and biocompatibility. They are further utilized for in vivo 3PF imaging of the brain vasculature of mice, under the excitation of a 1550 nm femtosecond laser. A vivid 3D reconstruction of the brain vasculature is then built with a penetration depth of 875 µm, which is the largest in ever reported 3PF imaging based on AIE NPs. After that, by collecting both of the 3PF and third-harmonic generation signals, multichannel nonlinear optical imaging of the brain blood vessels is further realized. These results will be helpful to study the structures and functions of the brain in the future.A type of aggregation-induced emission luminogen 2,3-bis(4′-(diphenylamino)-[1,1′-biphenyl]-4-yl) fumaronitrile (TPATCN) with deep-red emission and large Stokes shift is prepared. By the encapsulation of Pluronic F-127, TPATCN nanoparticles (NPs) are obtained. They exhibit bright three-photon fluorescence, good biocompatibility, and photostability. By intravenously injected with TPATCN NPs, the brain vasculature of a mouse is clearly and vividly imaged up to 875 µm.
  • Graphene Field-Effect Transistors for the Sensitive and Selective
           Detection of Escherichia coli Using Pyrene-Tagged DNA Aptamer
    • Abstract: This study reports biosensing using graphene field-effect transistors with the aid of pyrene-tagged DNA aptamers, which exhibit excellent selectivity, affinity, and stability for Escherichia coli (E. coli) detection. The aptamer is employed as the sensing probe due to its advantages such as high stability and high affinity toward small molecules and even whole cells. The change of the carrier density in the probe-modified graphene due to the attachment of E. coli is discussed theoretically for the first time and also verified experimentally. The conformational change of the aptamer due to the binding of E. coli brings the negatively charged E. coli close to the graphene surface, increasing the hole carrier density efficiently in graphene and achieving electrical detection. The binding of negatively charged E. coli induces holes in graphene, which are pumped into the graphene channel from the contact electrodes. The carrier mobility, which correlates the gate voltage to the electrical signal of the APG-FETs, is analyzed and optimized here. The excellent sensing performance such as low detection limit, high sensitivity, outstanding selectivity and stability of the graphene biosensor for E. coli detection paves the way to develop graphene biosensors for bacterial detection.The pyrene-tagged DNA aptamer-modified graphene field-effect transistor biosensors are demonstrated for Escherichia coli (E. coli) detection with high sensitivity, selectivity, and affinity. The change of the carrier density in the probe-modified graphene due to the attachment of E. coli is correlated with the electrical response of the graphene biosensors.
  • Edible Electrochemistry: Food Materials Based Electrochemical Sensors
    • Abstract: This study demonstrates the first example of completely food-based edible electrochemical sensors. The new edible composite electrodes consist of food materials and supplements serving as the edible conductor, corn, and olive oils as edible binders, vegetables as biocatalysts, and food-based packing sleeves. These edible composite electrodes are systematically characterized for their attractive electrochemical properties, such as potential window, capacitance, redox activity using various electrochemical techniques. The sensing performance of the edible carbon composite electrodes compares favorably with that of “traditional” carbon paste electrodes. Well defined voltammetric detection of catechol, uric acid, ascorbic acid, dopamine, and acetaminophen is demonstrated, including sensitive measurements in simulated saliva, gastric fluid, and intestinal fluid. Furthermore, successful biosensing applications are realized by incorporating a mushroom and horseradish vegetable tissues with edible carbon pastes for imparting biocatalytic activity toward the biosensing of phenolic and peroxide compounds. The attractive sensing performance of the new edible sensors indicates considerable promise for physiological monitoring applications and for developing edible and ingestible devices for diverse biomedical applications.This study first demonstrates the first example of edible electrochemical sensors made solely of food materials, offering digestive and innocuous platform. Various types of food materials are demonstrated and their electroanalytical behaviors are characterized. For biomedical monitoring applications, several (bio)markers are detected in artificial biofluids, indicating that the developed edible sensors can be expanded to monitor healthcare status following gastrointestinal tract.
  • Human Perinatal-Derived Biomaterials
    • Abstract: Human perinatal tissues have been used for over a century as allogeneic biomaterials. Due to their advantageous properties including angiogenecity, anti-inflammation, anti-microbial, and immune privilege, these tissues are being utilized for novel applications across wide-ranging medical disciplines. Given continued clinical success, increased adoption of perinatal tissues as a disruptive technology platform has allowed for significant penetration into the multi-billion dollar biologics market. Here, we review current progress and future applications of perinatal biomaterials, as well as associated regulatory issues.Biomaterials derived from human perinatal tissues have had widespread clinical success across multiple medical disciplines. This progress report provides an overview of their biological and mechanical properties as well as their current and future potential clinical applications. In addition, we review the current state of regulatory issues associated with perinatal biomaterial usage.
  • Integrin-Mediated Interactions Control Macrophage Polarization in 3D
    • Abstract: Adverse immune reactions prevent clinical translation of numerous implantable devices and materials. Although inflammation is an essential part of tissue regeneration, chronic inflammation ultimately leads to implant failure. In particular, macrophage polarity steers the microenvironment toward inflammation or wound healing via the induction of M1 and M2 macrophages, respectively. Here, this paper demonstrates that macrophage polarity within biomaterials can be controlled through integrin-mediated interactions between human monocytic THP-1 cells and collagen-derived matrix. Surface marker, gene expression, biochemical, and cytokine profiling consistently indicate that THP-1 cells within a biomaterial lacking cell attachment motifs yield proinflammatory M1 macrophages, whereas biomaterials with attachment sites in the presence of interleukin-4 (IL-4) induce an anti-inflammatory M2-like phenotype and propagate the effect of IL-4 in induction of M2-like macrophages. Importantly, integrin α2β1 plays a pivotal role as its inhibition blocks the induction of M2 macrophages. The influence of the microenvironment of the biomaterial over macrophage polarity is further confirmed by its ability to modulate the effect of IL-4 and lipopolysaccharide, which are potent inducers of M2 or M1 phenotypes, respectively. Thus, this study represents a novel, versatile, and effective strategy to steer macrophage polarity through integrin-mediated 3D microenvironment for biomaterial-based programming.Macrophage polarity steers the microenvironment toward inflammation or wound healing via the induction of M1 and M2 macrophages, respectively. However, active control over macrophage polarity has remained elusive. This study reveals that biomaterial-based integrin attachment can steer human monocytic cells differentiation into a specific macrophage lineage and thus has broad clinical implications.
  • An Accessible Organotypic Microvessel Model Using iPSC-Derived Endothelium
    • Abstract: While organotypic approaches promise increased relevance through the inclusion of increased complexity (e.g., 3D extracellular microenvironment, structure/function relationships, presence of multiple cell types), cell source is often overlooked. Induced pluripotent stem cell (iPSC)-derived cells are potentially more physiologically relevant than cell lines, while also being less variable than primary cells, and recent advances have made them commercially available at costs similar to cell lines. Here, the use of induced pluripotent stem cell-derived endothelium for the generation of a functional microvessel model is demonstrated. High precision structural and microenvironmental control afforded by the design approach synergizes with the advantages of iPSC to produce microvessels for modeling endothelial biology in vitro. iPSC microvessels show endothelial characteristics, exhibit barrier function, secrete angiogenic and inflammatory mediators, and respond to changes in the extracellular microenvironment by altering vessel phenotype. Importantly, when deployed in the investigation of neutrophils during innate immune recruitment, the presence of the iPSC endothelial vessel facilitates neutrophil extravasation and migration toward a chemotactic source. Relevant cell sources, such as iPSC, combine with organotypic models to open the way for improved and increasingly accessible in vitro tissue, disease, and patient-specific models.Improved cell sources, such as induced pluripotent stem cells (iPSCs), are critical complements to the increased relevance organotypic in vitro models provide. Coupling a robust 3D lumen microfabrication approach with iPSC-derived endothelium, a functional in vitro endothelial vessel is presented that provides structure, regulates barrier function, secretes cytokines, and is capable of supporting innate immune modeling.
  • Carbon Nanomaterials in Biological Studies and Biomedicine
    • Abstract: The “carbon nano-world” has made over the past few decades huge contributions in diverse scientific disciplines and technological advances. While dramatic advances have been widely publicized in using carbon nanomaterials such as fullerenes, carbon nanotubes, and graphene in materials sciences, nano-electronics, and photonics, their contributions to biology and biomedicine have been noteworthy as well. This Review focuses on the use of carbon nanotubes (CNTs), graphene, and carbon quantum dots [encompassing graphene quantum dots (GQDs) and carbon dots (C-dots)] in biologically oriented materials and applications. Examples of these remarkable nanomaterials in bio-sensing, cell- and tissue-imaging, regenerative medicine, and other applications are presented and discussed, emphasizing the significance of their unique properties and their future potential.Carbon nanomaterials are employed in diverse biological applications. This Review Article by Teradal and Jelinek highlights applications of carbon nanotubes, graphene, and carbon dots in biosensing, drug delivery, bioimaging, tissue engineering, and regenerative medicine. In particular, their unique physical properties and relative biocompatibility make carbon nanomaterials attractive vehicles for biological uses.
  • Liposome-Indocyanine Green Nanoprobes for Optical Labeling and Tracking of
           Human Mesenchymal Stem Cells Post-Transplantation In Vivo
    • Abstract: Direct labeling of human mesenchymal stem cells (hMSC) prior to transplantation provides a means to track cells after administration and it is a powerful tool for the assessment of new cell-based therapies. Biocompatible nanoprobes consisting of liposome-indocyanine green hybrid vesicles (liposome-ICG) are used to safely label hMSC. Labeled hMSC recapitulating a 3D cellular environment is transplanted as spheroids subcutaneously and intracranially in athymic nude mice. Cells emit a strong NIR signal used for tracking post-transplantation with the IVIS imaging system up to 2 weeks (subcutaneous) and 1 week (intracranial). The transplanted stem cells are imaged in situ after engraftment deep in the brain up to 1 week in living animals using optical imaging techniques and without the need to genetically modify the cells. This method is proposed for efficient, nontoxic direct cell labeling for the preclinical assessment of cell-based therapies and the design of clinical trials, and potentially for localization of the cell engraftment after transplantation into patients.Liposome-indocyanine green nanoscale vesicles are developed as biocompatible nanoprobes for long-lasting labeling of stem cells. The nanoprobes enable in vivo tracking using near-infrared fluorescence imaging at different tissue depths after transplantation, subcutaneously and in the brain. They are designed to be used as tools for in vivo monitoring of cell-based therapies with optical imaging modalities.
  • Tissue Engineering: Rod-Shaped Neural Units for Aligned 3D Neural Network
           Connection (Adv. Healthcare Mater. 15/2017)
    • Abstract: The cover shows a three-dimensional (3D) neural network formed by rod-shaped neural units, which are 3D fiber-shaped neural tissues with aligned nerve fibers, to connect neural networks with aligned neurons. Neural networks can be formed between the different neural units via synaptic connections as described by Shoji Takeuchi and co-workers in article number 1700143.
  • Neuronal Interfaces: Interactions of Neurons with Physical Environments
           (Adv. Healthcare Mater. 15/2017)
    • Abstract: In Progress Report 1700267, Orit Shefi and co-workers exploit studies of platforms generated with a range of physical topographies, from micro- down to nano- scale, that interact effectively with neurons, affecting differentiation, outgrowth and activity. Matching these specific needs may advance therapies and brain-machine interface applications.
  • Cell Alignment: Control of Cell Alignment and Morphology by Redesigning
           ECM-Mimetic Nanotopography on Multilayer Membranes (Adv. Healthcare Mater.
    • Abstract: Natural-based and biomimetic multilayer membranes, whose surface resembles the nanotopography of the native extracellular matrix, are able to induce cellular alignment along with the pattern direction. João F. Mano and co-workers use a simple layer-by-layer technology to produce such platforms, that can be a promising system to control cell behavior and to regenerate tissues, in article number 1601462.
  • Cell Culture: Clickable Microgel Scaffolds as Platforms for 3D Cell
           Encapsulation (Adv. Healthcare Mater. 15/2017)
    • Abstract: Clickable microgel scaffolds as platforms for 3D cell encapsulation are described in article number 1700254 by Kristi S. Anseth and co-workers. Microgel “building blocks” are designed and assembled in the presence of cells to create polymer-cell composites. Cell growth within the network can be controlled and directed by altering microgel size.
  • Masthead: (Adv. Healthcare Mater. 15/2017)
  • Contents: (Adv. Healthcare Mater. 15/2017)
  • Biomimetic Interfaces in Biomedical Devices
  • Materials for Microfluidic Immunoassays: A Review
    • Abstract: Conventional immunoassays suffer from at least one of these following limitations: long processing time, high costs, poor user-friendliness, technical complexity, poor sensitivity and specificity. Microfluidics, a technology characterized by the engineered manipulation of fluids in channels with characteristic lengthscale of tens of micrometers, has shown considerable promise for improving immunoassays that could overcome these limitations in medical diagnostics and biology research. The combination of microfluidics and immunoassay can detect biomarkers with faster assay time, reduced volumes of reagents, lower power requirements, and higher levels of integration and automation compared to traditional approaches. This review focuses on the materials-related aspects of the recent advances in microfluidics-based immunoassays for point-of-care (POC) diagnostics of biomarkers. We compare the materials for microfluidic chips fabrication in five aspects: fabrication, integration, function, modification and cost, and describe their advantages and drawbacks. In addition, we review materials for modifying antibodies to improve the performance of the reaction of immunoassay. We also review the state of the art in microfluidic immunoassays POC platforms, from the laboratory to routine clinical practice, and also commercial products in the market. Finally, we discuss the current challenges and future developments in microfluidic immunoassays.Microfluidic immunoassays for point-of-care diagnostics can detect biomarkers in a faster and easier way compared to traditional approaches. This Review reports on the materials-related aspects of the recent advances in microfluidic immunoassays including materials for chips fabrication and materials for improving the performance of immunoassays. Some clinical practice, and commercial products in the market have also been discussed.
  • Mechanotransduction and Growth Factor Signalling to Engineer Cellular
    • 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.
  • Rod-Shaped Neural Units for Aligned 3D Neural Network Connection
    • 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.
  • Modulation of Heterotypic and Homotypic Cell–Cell Interactions via
           Zwitterionic Lipid Masks
    • 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.
  • 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.
  • Cell Adhesion: The Role of Titanium Surface Nanostructuring on
           Preosteoblast Morphology, Adhesion, and Migration (Adv. Healthcare Mater.
    • Abstract: A kaleidoscope of surface properties guides a kaleidoscope of cell dynamic behavior and communication with a nanoarchitectured support. In article number 1601244, Peter Fratzl and co-workers focus on the impact of different titania nanotopography on osteo-progenitor cell adhesion, stress fiber formation and migration.
  • 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).
  • Control of Cell Alignment and Morphology by Redesigning ECM-Mimetic
           Nanotopography on Multilayer Membranes
    • Abstract: Inspired by native extracellular matrix (ECM) together with the multilevel architecture observed in nature, a material which topography recapitulates topographic features of the ECM and the internal architecture mimics the biological materials organization is engineered. The nanopatterned design along the XY plane is combined with a nanostructured organization along the Z axis on freestanding membranes prepared by layer-by-layer deposition of chitosan and chondroitin sulfate. Cellular behavior is monitored using two different mammalian cell lines, fibroblasts (L929) and myoblasts (C2C12), in order to perceive the response to topography. Viability, proliferation, and morphology of L929 are sensitively controlled by topography; also differentiation of C2C12 into myotubes is influenced by the presence of nanogrooves. This kind of nanopatterned structure has also been associated with strong cellular alignment. To the best of the knowledge, it is the first time that such a straightforward and inexpensive strategy is proposed to produce nanopatterned freestanding multilayer membranes. Controlling cellular alignment plays a critical role in many human tissues, such as muscles, nerves, or blood vessels, so these membranes can be potentially useful in specific tissue regeneration strategies.Flexible and freestanding biomimetic multilayer membranes, which topography resemble the nanofeatures of the extracellular matrix, are successfully developed using a friendly user layer-by-layer technology. The ability to crosslink with genipin as well as the presence of a patterned topography on the surface of the natural-based membranes provides a promising system to tailor cellular behavior including cell alignment and differentiation.
  • 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.
  • Bacterial Interactions with Immobilized Liquid Layers
    • Abstract: Bacterial interactions with surfaces are at the heart of many infection-related problems in healthcare. In this work, the interactions of clinically relevant bacteria with immobilized liquid (IL) layers on oil-infused polymers are investigated. Although oil-infused polymers reduce bacterial adhesion in all cases, complex interactions of the bacteria and liquid layer under orbital flow conditions are uncovered. The number of adherent Escherichia coli cells over multiple removal cycles increases in flow compared to static growth conditions, likely due to a disruption of the liquid layer continuity. Surprisingly, however, biofilm formation appears to remain low regardless of growth conditions. No incorporation of the bacteria into the layer is observed. Bacterial type is also found to affect the number of adherent cells, with more E. coli remaining attached under dynamic orbital flow than Staphylococcus aureus, Pseudomonas aeruginosa under identical conditions. Tests with mutant E. coli lacking flagella confirm that flagella play an important role in adhesion to these surfaces. The results presented here shed new light on the interaction of bacteria with IL layers, highlighting the fundamental differences between oil-infused and traditional solid interfaces, as well as providing important information for their eventual translation into materials that reduce bacterial adhesion in medical applications.The number of bacterial cells adherent on an immobilized liquid layer of silicone oil is significantly affected by the presence or absence of orbital flow, the species of bacteria, and the bacterial cell morphology. In all tested experimental conditions, however, immobilized liquid layers show superior resistance to irreversible bacterial adhesion compared to equivalent solid polydimethylsiloxane surfaces.
  • Small Subcompartmentalized Microreactors as Support for Hepatocytes
    • Abstract: Mimicking specific structural or functional aspects of cells is considered a promising approach to substitute for missing or lost cellular functions. However, the interaction of such artificial assemblies with their biological counterparts including the exploitation of the activity of the synthetic partner remains thus-far a rather unexplored avenue. Herein, the assembly of active microreactors with similar size to hepatocytes is reported. These microreactors are successfully cocultured with hepatocytes into bionic tissue for up to 10 d. Further, microreactors loaded with the liver enzyme catalase are effective in alleviating external pressure, induced by the addition of hydrogen peroxide, from such bionic tissue in an attempt to mimic the detoxification ability of hepatocytes. Taken together, the findings open up a different route in combining synthetic and biological entities for tissue engineering by using the former partner not only as structural support, but also to induce beneficial activity.Hepatic bionic tissue is assembled using hepatocytes and sub 10 µm sized core–shell or capsosome-based microreactors. Positive surface charge shows the best integration of the synthetic entities in the proliferating tissue. Upon stressing the bionic tissue with hydrogen peroxide, core–shell microreactors loaded with catalase can alleviate the pressure and improve the viability to the hepatocytes.
  • Selectively Inducing Cancer Cell Death by Intracellular Enzyme-Instructed
           Self-Assembly (EISA) of Dipeptide Derivatives
    • Abstract: Tight ligand-receptor binding, paradoxically, is a major root of drug resistance in cancer chemotherapy. To address this problem, instead of using conventional inhibitors or ligands, this paper focuses on the development of a novel process—enzyme-instructed self-assembly (EISA)—to kill cancer cells selectively. Here it is demonstrated that EISA as an intracellular process to generate nanofibrils of short peptides for selectively inhibiting cancer cell proliferation, including drug resistant ones. As the process that turns the non-self-assembling precursors into the self-assembling peptides upon the catalysis of carboxylesterases (CES), EISA occurs intracellularly to selectively inhibit a range of cancer cells that exhibit relatively high CES activities. More importantly, EISA inhibits drug resistant cancer cells (e.g., triple negative breast cancer cells (HCC1937) and platinum-resistant ovarian cells (SKOV3, A2780cis)). With the IC50 values of 28–80 and 25–44 µg mL−1 of l- and d-dipeptide precursors against cancer cells, respectively, EISA is innocuous to normal cells. Moreover, using coculture of cancer and normal cells, the selectivity of EISA is validated against cancer cells. Besides revealing that intracellular EISA cause apoptosis or necroptosis to kill the cancer cells, this work illustrates a new approach to amplify the enzymatic difference between cancer and normal cells and to expand the pool of drug candidates for potentially overcoming drug resistance in cancer therapy.A novel process—enzyme-instructed self-assembly (EISA)—to kill cancer cells selectively is reported. We designed two precursors that became self-assembling molecules upon the catalysis of carboxylesterases (CES)–a type of enzyme overexpressed in cancer cells. By amplifying the enzymatic difference between cancer and normal cells, this work provided a new approach for cancer therapy.
  • Desmoplastic Reaction in 3D-Pancreatic Cancer Tissues Suppresses Molecular
    • 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.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.
  • Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep
           Eutectic Solvent
    • Abstract: Transdermal delivery of peptides and other biological macromolecules is limited due to skin's inherent low permeability. Here, the authors report the use of a deep eutectic solvent, choline and geranate (CAGE), to enhance topical delivery of proteins such as bovine serum albumin (BSA, molecular weight: ≈66 kDa), ovalbumin (OVA, molecular weight: ≈45 kDa) and insulin (INS, molecular weight: 5.8 kDa). CAGE enhances permeation of BSA, OVA, and insulin into porcine skin ex vivo, penetrating deep into the epidermis and dermis. Studies using tritium-labeled BSA and fluorescein isothiocyanate labeled insulin show significantly enhanced delivery of proteins into and across porcine skin, penetrating the skin in a time-dependent manner. Fourier transform IR spectra of porcine stratum corneum (SC) samples before and after incubation in CAGE show a reduction in peak area attributed to SC lipid content, suggesting lipid extraction from the SC. Circular dichroism confirms that CAGE does not affect insulin's secondary conformation. In vivo studies in rats show that topical application of 10 U insulin dispersed in CAGE (25 U kg−1 insulin dose) leads to a highly significant 40% drop in blood glucose levels in 4 h that is relatively sustained for 12 h. Taken together, these studies demonstrate that CAGE is a promising vehicle for transdermal delivery of therapeutic proteins; specifically, as a noninvasive delivery alternative to injectable insulin for the treatment of diabetes.Choline and geranate (CAGE) significantly enhances transdermal protein delivery. CAGE acts as an effective material for transdermal drug delivery. Proteins simply dispersed in CAGE retain their secondary conformation and traverse through the skin to demonstrate significantly higher in vivo efficacy compared to proteins in buffer.
  • Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine
           Kinase Inhibitors in a Biomaterial Model of Glioblastoma
    • Abstract: 3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.This biomaterial tumor model recreates relevant features of the glioblastoma tumor microenvironment, and is used as a valuable tool in the mechanistic studies of tumor development and prediction of tyrosine kinase inhibitors efficacy. Experiments here highlight the importance of extracellular hyaluronic acid in inhibition efficiency of epidermal growth factor receptor by erlotinib.
  • Novel Cranial Implants of Yttria-Stabilized Zirconia as Acoustic Windows
           for Ultrasonic Brain Therapy
    • Abstract: Therapeutic ultrasound can induce changes in tissues by means of thermal and nonthermal effects. It is proposed for treatment of some brain pathologies such as Alzheimer's, Parkinson's, Huntington's diseases, and cancer. However, cranium highly absorbs ultrasound reducing transmission efficiency. There are clinical applications of transcranial focused ultrasound and implantable ultrasound transducers proposed to address this problem. In this paper, biocompatible materials are proposed for replacing part of the cranium (cranial implants) based on low porosity polycrystalline 8 mol% yttria-stabilized-zirconia (8YSZ) ceramics as acoustic windows for brain therapy. In order to assess the viability of 8YSZ implants to effectively transmit ultrasound, various 8YSZ ceramics with different porosity are tested; their acoustic properties are measured; and the results are validated using finite element models simulating wave propagation to brain tissue through 8YSZ windows. The ultrasound attenuation is found to be linearly dependent on ceramics' porosity. Results for the nearly pore-free case indicate that 8YSZ is highly effective in transmitting ultrasound, with overall maximum transmission efficiency of ≈81%, compared to near total absorption of cranial bone. These results suggest that 8YSZ polycrystals could be suitable acoustic windows for ultrasound brain therapy at 1 MHz.Biocompatible cranial implants for brain ultrasound therapy based on polycrystalline 8 mol% yttria-stabilized-zirconia (8YSZ) ceramics are presented. Therapeutic ultrasound is proposed for the treatment of some brain pathologies, but the cranium is an acoustic barrier for its adequate clinical application. 8YSZ ceramics are highly effective for transmitting ≈81% of ultrasound, compared to near total absorption of cranium.
  • Spatiotemporally Controlled Release of Rho-Inhibiting C3 Toxin from a
           Protein–DNA Hybrid Hydrogel for Targeted Inhibition of Osteoclast
           Formation and Activity
    • Abstract: In osteoporosis, bone structure can be improved by the introduction of therapeutic molecules inhibiting bone resorption by osteoclasts. Here, biocompatible hydrogels represent an excellent option for the delivery of pharmacologically active molecules to the bone tissue because of their biodegradability, injectability, and manifold functionalization capacity. The present study reports the preparation of a multifunctional hybrid hydrogel from chemically modified human serum albumin and rationally designed DNA building blocks. The hybrid hydrogel combines advantageous characteristics, including rapid gelation through DNA hybridization under physiological conditions and a self-healing and injectable nature with the possibility of specific loading and spatiotemporally controlled release of active proteins, making it an advanced biomaterial for the local treatment of bone diseases, for example, osteoporosis. The hydrogels are loaded with a recombinant Rho-inhibiting C3 toxin, C2IN-C3lim-G205C. This toxin selectively targets osteoclasts and inhibits Rho-signaling and, thereby, actin-dependent processes in these cells. Application of C2IN-C3lim-G205C toxin-loaded hydrogels effectively reduces osteoclast formation and resorption activity in vitro, as demonstrated by tartrate-resistant acid phosphatase staining and the pit resorption assay. Simultaneously, osteoblast activity, viability, and proliferation are unaffected, thus making C2IN-C3lim-G205C toxin-loaded hybrid hydrogels an attractive pharmacological system for spatial and selective modulation of osteoclast functions to reduce bone resorption.To achieve local and sustained delivery of therapeutic compounds in bone defects or weak bone, an appropriate carrier is crucial. Protein–DNA hybrid hydrogels represent an excellent option due to their biocompatibility, injectability, self-healing, and manifold functionalization capacity. Here, the hydrogels are loaded with a novel recombinant clostridial C3 toxin, C2IN-C3lim-G205C, which selectively inhibits Rho-signaling in osteoclasts potentially preventing bone resorption.
  • Freeze-Drying as a Novel Biofabrication Method for Achieving a Controlled
           Microarchitecture within Large, Complex Natural Biomaterial Scaffolds
    • Abstract: The biofabrication of large natural biomaterial scaffolds into complex 3D shapes which have a controlled microarchitecture remains a major challenge. Freeze-drying (or lyophilization) is a technique used to generate scaffolds in planar 3D geometries. Here we report the development of a new biofabrication process to form a collagen-based scaffold into a large, complex geometry which has a large height to width ratio, and a controlled porous microarchitecture. This biofabrication process is validated through the successful development of a heart valve shaped scaffold, fabricated from a collagen-glycosaminoglycan co-polymer. Notably, despite the significant challenges in using freeze-drying to create such a structure, the resultant scaffold has a uniform, homogenous pore architecture throughout. This is achieved through optimization of the freeze-drying mold and the freezing parameters. We believe this to be the first demonstration of using freeze-drying to create a large, complex scaffold geometry with a controlled, porous architecture for natural biomaterials. This study validates the potential of using freeze-drying for development of organ-specific scaffold geometries for tissue engineering applications, which up until now might not have been considered feasible.Biofabrication methods for natural materials are limited, especially where a specific geometry and microarchitecture is required for a particular application. Herein, a biofabrication technique using freeze-drying (lyophilization) is presented, which facilitates the formation of natural materials into large, complex geometries, while maintaining a controlled porous microarchitecture. This enables the use of natural materials for applications that up until now might not have been considered feasible.
  • Atomic Force Microscopy as a Tool to Assess the Specificity of Targeted
           Nanoparticles in Biological Models of High Complexity
    • Abstract: The ability to design nanoparticle delivery systems capable of selectively target their payloads to specific cell populations is still a major caveat in nanomedicine. One of the main hurdles is the fact that each nanoparticle formulation needs to be precisely tuned to match the specificities of the target cell and route of administration. In this work, molecular recognition force spectroscopy (MRFS) is presented as a tool to evaluate the specificity of neuron-targeted trimethyl chitosan nanoparticles to neuronal cell populations in biological samples of different complexity. The use of atomic force microscopy tips functionalized with targeted or non-targeted nanoparticles made it possible to assess the specific interaction of each formulation with determined cell surface receptors in a precise fashion. More importantly, the combination of MRFS with fluorescent microscopy allowed to probe the nanoparticles vectoring capacity in models of high complexity, such as primary mixed cultures, as well as specific subcellular regions in histological tissues. Overall, this work contributes for the establishment of MRFS as a powerful alternative technique to animal testing in vector design and opens new avenues for the development of advanced targeted nanomedicines.Evaluation of neuron-targeted trimethyl-chitosan nanoparticles specificity toward neuronal cell populations in samples of different complexity and biological relevance by molecular recognition force spectroscopy (MRFS). This work puts forward MRFS as a valuable tool for the design and characterization of new targeted formulations that will lead to the development of more robust and advanced nanomedicines.
  • Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related
           Biomedical Applications
    • Abstract: During the past few decades, supercritical fluid (SCF) has emerged as an effective alternative for many traditional pharmaceutical manufacturing processes. Operating active pharmaceutical ingredients (APIs) alone or in combination with various biodegradable polymeric carriers in high-pressure conditions provides enhanced features with respect to their physical properties such as bioavailability enhancement, is of relevance to the application of SCF in the pharmaceutical industry. Herein, recent advances in drug delivery systems manufactured using the SCF technology are reviewed. We provide a brief description of the history, principle, and various preparation methods involved in the SCF technology. Next, we aim to give a brief overview, which provides an emphasis and discussion of recent reports using supercritical carbon dioxide (SC-CO2) for fabrication of polymeric carriers, for applications in areas related to drug delivery, tissue engineering, bio-imaging, and other biomedical applications. We finally summarize with perspectives.The supercritical carbon dioxide technology utilizes carbon dioxide in its supercritical state as it is non-toxic, cost-effective, and environmental-friendly. This green technology produces polymeric carriers in various forms by altering critical conditions such as temperature and pressure during the fabrication process. We provide an overview of the history, principle, and preparation methods involving this versatile technology and its use in fabrication of polymeric carriers for applications in drug delivery and related biomedical areas.
  • Graphene Quantum Dots Downregulate Multiple Multidrug-Resistant Genes via
           Interacting with Their C-Rich Promoters
    • Abstract: Multidrug resistance (MDR) is the major factor in the failure of many forms of chemotherapy, mostly due to the increased efflux of anticancer drugs that mediated by ATP-binding cassette (ABC) transporters. Therefore, inhibiting ABC transporters is one of effective methods of overcoming MDR. However, high enrichment of ABC transporters in cells and their broad substrate spectra made to circumvent MDR are almost insurmountable by a single specific ABC transporter inhibitor. Here, this study demonstrates that graphene quantum dots (GQDs) could downregulate the expressions of P-glycoprotein, multidrug resistance protein MRP1, and breast cancer resistance protein genes via interacting with C-rich regions of their promoters. This is the first example that a single reagent could suppress multiple MDR genes, suggesting that it will be possible to target multiple ABC transporters simultaneously with a single reagent. The inhibitory ability of the GQDs to these drug-resistant genes is validated further by reversing the doxorubicin resistance of MCF-7/ADR cells. Notably, GQDs have superb chemical and physical properties, unique structure, low toxicity, and high biocompatibility; hence, their capability of inhibiting multiple drug-resistant genes holds great potential in cancer therapy.Graphene quantum dots (GQDs) downregulate multiple multidrug-resistant (MDR) genes via interacting with C-rich regions of their promoters. The inhibitory ability of the GQDs to MDR genes is validated by reversing doxorubicin resistance of MCF-7/ADR cells.
  • Protein Coating of DNA Nanostructures for Enhanced Stability and
    • Abstract: Fully addressable DNA nanostructures, especially DNA origami, possess huge potential to serve as inherently biocompatible and versatile molecular platforms. However, their use as delivery vehicles in therapeutics is compromised by their low stability and poor transfection rates. This study shows that DNA origami can be coated by precisely defined one-to-one protein-dendron conjugates to tackle the aforementioned issues. The dendron part of the conjugate serves as a cationic binding domain that attaches to the negatively charged DNA origami surface via electrostatic interactions. The protein is attached to dendron through cysteine-maleimide bond, making the modular approach highly versatile. This work demonstrates the coating using two different proteins: bovine serum albumin (BSA) and class II hydrophobin (HFBI). The results reveal that BSA-coating significantly improves the origami stability against endonucleases (DNase I) and enhances the transfection into human embryonic kidney (HEK293) cells. Importantly, it is observed that BSA-coating attenuates the activation of immune response in mouse primary splenocytes. Serum albumin is the most abundant protein in the blood with a long circulation half-life and has already found clinically approved applications in drug delivery. It is therefore envisioned that the proposed system can open up further opportunities to tune the properties of DNA nanostructures in biological environment, and enable their use in various delivery applications.DNA origami nanostructures can be coated with well-defined protein–dendron conjugates. Plain DNA origami nanostructures often suffer from poor delivery properties, stability, and immunogenicity in biological systems. Coating of the origami with inert proteins (e.g., serum albumin) can, however, alleviate these issues efficiently.
  • Monodispersed Bioactive Glass Nanoclusters with Ultralarge Pores and
           Intrinsic Exceptionally High miRNA Loading for Efficiently Enhancing Bone
    • Abstract: Bioactive glass nanoparticles (BGNs) have attracted much attention in drug delivery and bone tissue regeneration, due to the advantages including biodegradation, high bone-bonding bioactivity, and facile large-scale fabrication. However, the wide biomedical applications of BGNs such as efficient gene delivery are limited due to their poor pore structure and easy aggregation. Herein, for the first time, this study reports novel monodispersed bioactive glass nanoclusters (BGNCs) with ultralarge mesopores (10–30 nm) and excellent miRNA delivery for accelerating critical-sized bone regeneration. BGNCs with different size (100–500 nm) are fabricated by using a branched polyethylenimine as the structure director and catalyst. BGNCs show an excellent apatite-forming ability and high biocompatibility. Importantly, BGNCs demonstrate an almost 19 times higher miRNA loading than those of conventional BGNs. Additionally, BGNCs–miRNA nanocomplexes exhibit a significantly high antienzymolysis, enhance cellular uptake and miRNA transfection efficiency, overpassing BGNs and commercial Lipofectamine 3000. BGNCs-mediated miRNA delivery significantly improves the osteogenic differentiation of bone marrow stromal stem cells in vitro and efficiently enhances bone formation in vivo. BGNCs can be a highly efficient nonviral vector for various gene therapy applications. The study may provide a novel strategy to develop highly gene-activated bioactive nanomaterials for simultaneous tissue regeneration and disease therapy.Monodispersed bioactive glass nanoclusters (BGNCs) with ultra-large mesopores (10–30 nm) are developed for miRNA delivery to enhance bone regeneration. BGNCs demonstrated an ultrahigh miRNA loading and transfection efficiency, overpassing commercial lipofectamine. BGNCs-mediated miRNA delivery significantly improved osteogenic differentiation of bone marrow stromal stem cells in vitro and enhanced bone formation in vivo.
  • Newly Designed Silica-Containing Redox Nanoparticles for Oral Delivery of
           Novel TOP2 Catalytic Inhibitor for Treating Colon Cancer
    • Abstract: Although oral drug delivery is the most common route of drug administration, the conventional polymeric nanocarriers exhibit a low drug loading capacity and low stability in the gastrointestinal (GI) environments. In this study, a newly designed silica-containing redox nanoparticle (siRNP) with reactive oxygen species (ROS) scavenging capacity is developed as an ideal oral nanocarrier for a novel hydrophobic anticancer compound BNS-22 to treat colitis-associated colon cancer in vivo. Crosslinking of silica moieties significantly enhances the stability under acidic conditions and improves BNS-22 loading capacity of siRNP compared to the conventional redox nanoparticle. After oral administration to mice, BNS-22-loaded siRNP (BNS-22@siRNP) remarkably improves bioavailability and colonic tumor distribution of BNS-22. As the result, BNS-22@siRNP significantly inhibits the tumor progression in colitis-associated colon cancer mice compared to other control treatments. It is noteworthy that no systemic absorption of siRNP carrier is observed after oral administration. Interestingly, orally administered BNS-22@siRNP significantly suppresses the adverse effects of BNS-22 owing to its ROS scavenging capacity, and no other noticeable toxicities are observed in mice treated with BNS-22@siRNP although siRNP is localized in the GI tract. Our results indicate that siRNP is a promising oral drug nanocarrier for cancer therapy.Novel silica-containing redox nanoparticle (siRNP) is developed to enhance the stability and drug loading capacity with reactive oxygen species (ROS) scavenging activity. Oral administration of hydrophobic drug-loaded siRNP significantly improves drug bioavailability to inhibit the tumor growth in a mouse colon cancer model. By accumulating in gastrointestinal tract, ROS scavenging capacity of siRNP suppresses the systemic side effect of anticancer drug. siRNP is a promising candidate as novel nanotherapeutic and nanocarrier for a wide range of water-insoluble chemotherapeutic agents.
  • Controlled Exposure of Bioactive Growth Factor in 3D Amyloid Hydrogel for
           Stem Cells Differentiation
    • Abstract: Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering both in vitro and in vivo. A pH responsive self-assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage. Diffusion studies with fluorescence recovery after photobleaching and bulk release with the model protein fluorescein isothiocyanate-bovine serum albumin show that encapsulated protein molecules can be released in a sustained fashion from the hydrogel over a considerable period of time (30 d). Moreover, by modulating the porosity of the hydrogel by the simple addition of salt, the encapsulated protein molecules can be retained for a longer period of time within the hydrogel. Mesenchymal stem cells, when cultured in 3D amyloid hydrogels with growth factors fibroblast growth factor 8 and sonic hedgehog, show more neuron specific differentiation as compared to hydrogel alone. This higher differentiation potential of growth factor encapsulated amyloid hydrogels can be due to concomitant exposure of cells to biomechanical as well as biochemical cues during the course of differentiation. The present study suggests that amyloid based hydrogel can be exploited for controlled growth factor delivery as well as directed stem cell differentiation to neuron.Amyloid hydrogel for sustained growth factors delivery in tissue engineering applications. Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering applications both in vitro and in vivo. A pH responsive, self-assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage.
  • Mechanically Tunable Bioink for 3D Bioprinting of Human Cells
    • Abstract: This study introduces a thermogelling bioink based on carboxylated agarose (CA) for bioprinting of mechanically defined microenvironments mimicking natural tissues. In CA system, by adjusting the degree of carboxylation, the elastic modulus of printed gels can be tuned over several orders of magnitudes (5–230 Pa) while ensuring almost no change to the shear viscosity (10–17 mPa) of the bioink solution; thus enabling the fabrication of 3D structures made of different mechanical domains under identical printing parameters and low nozzle shear stress. Human mesenchymal stem cells printed using CA as a bioink show significantly higher survival (95%) in comparison to when printed using native agarose (62%), a commonly used thermogelling hydrogel for 3D-bioprinting applications. This work paves the way toward the printing of complex tissue-like structures composed of a range of mechanically discrete microdomains that could potentially reproduce natural mechanical aspects of functional tissues.Carboxylated agarose hydrogels with mechanical property independent of the bioink solution viscosity allow the high-viability 3D bioprinting of human mesenchymal stem cells. Furthermore, addition of collagen to the carboxylated agarose induces the proliferation of the human mesenchymal stem cells used in this study.
  • Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965
           Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid
           Metabolism in Ldlr−/− Mice
    • Abstract: The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV–GW–NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW–NPs) (≈18%). In addition, mice administered the Col IV–GW–NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.A new form of liver X receptor-based therapeutics based on the nanoparticles (NPs) decorated with collagen IV targeting ligands is generated. The NPs with optimal polyethylene glycol density can successfully reach atherosclerotic lesions and enhance therapeutic efficacy of GW3965 while maintaining hepatic lipid metabolism. This targeted NP system suggests a new modality for combating inflammation in advanced atherosclerosis.
  • Aspherical, Nanostructured Microparticles for Targeted Gene Delivery to
           Alveolar Macrophages
    • Abstract: Introducing novel shapes to particulate carrier systems adds unique features to modern drug and gene delivery. Depending on the route of administration, particle geometry can influence deposition and fate within biological environments. In this work, a template-assisted engineering technique is applied, providing full control of size and shape in the preparation of aspherical, nanostructured microparticles. Based on the interconnection of nanoparticles, stabilized by a functional layer-by-layer (LbL) coating, the resulting cylindrical micrometer architecture is especially qualified for pulmonary delivery. Designed as gene delivery system, plasmid-DNA (pCMV-luciferase) and branched polyethylenimine are used to reach both structural integrity of the carrier system and delivery of genes into the cells of interest. Due to their size, particles are exclusively taken up by phagocytes, which also adds a targeting effect to the introduced system. The luciferase expression is demonstrated in macrophages showing increasing levels over a time period of at least 7 d. Furthermore, it is shown for the first time that the expression is depending on the LbL design. From in vivo experiments, corresponding luciferase expression is observed in mice alveolar macrophages. Combining site specific transport with the possibility of genetically engineering immunocompetent phagocytes, the presented system offers promising potential to improve applications for cell-based immunotherapy.A novel aspherical, nanostructured microparticle for pulmonary gene delivery is fabricated utilizing a template-assisted engineering technique. Here, nanoparticles build up rod-like shaped structures in the micrometer size range, stabilized with plasmid-DNA and polyethylenimine. The carrier provides the introduction of genes into alveolar macrophages both in vitro and in vivo, qualifying the system for the genetic engineering of immunocompetent phagocytes.
  • Retardation of Antigen Release from DNA Hydrogel Using
           Cholesterol-Modified DNA for Increased Antigen-Specific Immune Response
    • Abstract: Our previous study indicates that cationization of an antigen is effective for sustained release of both immunostimulatory DNA containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides, or CpG DNA, and antigen from a DNA hydrogel. Another approach to sustained antigen release would increase the applicability and versatility of the system. In this study, a hydrophobic interaction-based sustained release system of ovalbumin (OVA), a model antigen, from immunostimulatory CpG DNA hydrogel is developed by the use of cholesterol-modified DNA and urea-denatured OVA (udOVA). Cholesterol-modified DNA forms a hydrogel, Dgel(chol), and induces IL-6 mRNA expression in mouse skin after intradermal injection, as DNA without cholesterol does. Cholesterol-modified DNA associated with OVA and denaturation of OVA using urea increases the interaction. The release of udOVA from Dgel(chol) is significantly slower than that from DNA hydrogel with no cholesterol, Dgel. Moreover, intratumoral injections of udOVA/Dgel(chol) significantly inhibit the growth of EG7-OVA tumors in mice. These results indicate that sustained release of antigen from Dgel can be achieved by the combination of urea denaturation and cholesterol modification, and retardation of antigen release is effective to induce antigen-specific cancer immunity.A hydrophobic interaction-based sustained release system of ovalbumin (OVA), a model antigen, from immunostimulatory cytosine-phosphate-guanine (CpG) DNA hydrogel is developed by the use of cholesterol-modified DNA and urea-denatured OVA, and this system efficiently inhibits tumor growth. This study further supports the importance of sustained release of both antigen and CpG DNA to induce antigen-specific immune responses.
  • Multifunctional Nanotube–Mucoadhesive Poly(methyl vinyl ether-co-maleic
           acid)@Hydroxypropyl Methylcellulose Acetate Succinate Composite for
           Site-Specific Oral Drug Delivery
    • Abstract: An advanced oral drug delivery system that can effectively deliver drugs with poor oral bioavailability is strongly desirable. Herein, a multifunctional nano-in-micro structured composite is developed by encapsulation of the mucoadhesive poly(methyl vinyl ether-co-maleic acid) modified halloysite nanotubes (HNTs) with the pH-responsive hydroxypropyl methylcellulose acetate succinate by the microfluidics to control the drug release, increase cell–particle interaction, and improve drug absorption. The microparticles show spherical shape, homogeneous particle size distribution (58 ± 1 µm), and pH-responsive dissolution behavior at pH > 6, and they prevent the premature release of curcumin in simulated pH conditions of the stomach and immediately release the curcumin in simulated pH conditions of the small intestine. The surface modification of HNT with mucoadhesive poly(methyl vinyl ether-co-maleic acid) significantly enhances its interactions with the intestinal Caco-2/HT29-MTX cells and the mouse small intestines, and increases the permeability of curcumin across the co-cultured Caco-2/HT29-MTX cell monolayers by about 13 times compared to the free curcumin. Therefore, the developed multifunctional nanotube–mucoadhesive poly(methyl vinyl ether-co-maleic acid)@hydroxypropyl methylcellulose acetate succinate composite is a promising oral drug delivery system for drugs with poor oral bioavailability.Multifunctional nano-in-micro particles composed of mucoadhesive polymer modified halloysite nanotubes and pH-responsive polymer are developed by microfluidics for oral drug delivery applications. The microparticles can release the drug site specifically in response to the pH condition of small intestine, strongly interact with small intestine, and significantly increase the permeability of a poorly water-soluble drug.
  • Surface-Modified Mesh Filter for Direct Nucleic Acid Extraction and its
           Application to Gene Expression Analysis
    • Abstract: Rapid and convenient isolation of nucleic acids (NAs) from cell lysate plays a key role for onsite gene expression analysis. Here, this study achieves one-step and efficient capture of NA directly from cell lysate by developing a cationic surface-modified mesh filter (SMF). By depositing cationic polymer via vapor-phase deposition process, strong charge interaction is introduced on the surface of the SMF to capture the negatively charged NAs. The NA capturing capability of SMF is confirmed by X-ray photoelectron spectroscopy, fluorescent microscopy, and zeta potential measurement. In addition, the genomic DNAs of Escherichia Coli O157:H7 can be extracted by the SMF from artificially infected food, and fluorescent signal is observed on the surface of SMF after amplification of target gene. The proposed SMF is able to provide a more simplified, convenient, and fast extraction method and can be applied to the fields of food safety testing, clinical diagnosis, or environmental pollutant monitoring.A surface-modified mesh filter (SMF) is devised via initiated chemical vapor deposition (iCVD) for convenient extraction, amplification, and detection of nucleic acids (NAs). The iCVD polymer coated on the filter interacts with NAs by charge interaction and facilitates NA extraction from cell lysate without the use of extra instrumentation. Foodborne pathogen can also be detected from real food samples using the SMF.
  • Stretchable Dry Electrodes with Concentric Ring Geometry for Enhancing
           Spatial Resolution in Electrophysiology
    • Abstract: The multichannel concentric-ring electrodes are stencil printed on stretchable elastomers modified to improve adhesion to skin and minimize motion artifacts for electrophysiological recordings of electroencephalography, electromyography, and electrocardiography. These dry electrodes with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate interface layer are optimized to show lower noise level than that of commercial gel disc electrodes. The concentric ring geometry enables Laplacian filtering to pinpoint the bioelectric potential source with spatial resolution determined by the ring distance. This work shows a new fabrication approach to integrate and create designs that enhance spatial resolution for high-quality electrophysiology monitoring devices.Multichannel concentric-ring electrodes are stencil printed on stretchable elastomers modified to improve adhesion to skin and minimize motion artifacts for electrophysiological recordings of electroencephalography, electromyography, and electrocardiography. These dry electrodes show lower noise than that of commercial gel electrodes. This work shows a new fabrication approach to integrate and create designs that enhance spatial resolution for high-quality electrophysiology monitoring devices.
  • Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control
           Endothelial Cell and Platelet Response for Cardiovascular Applications
    • Abstract: The main drawbacks of cardiovascular bare-metal stents (BMS) are in-stent restenosis and stent thrombosis as a result of an incomplete endothelialization after stent implantation. Nano- and microscale modification of implant surfaces is a strategy to recover the functionality of the artery by stimulating and guiding molecular and biological processes at the implant/tissue interface. In this study, cobalt-chromium (CoCr) alloy surfaces are modified via direct laser interference patterning (DLIP) in order to create linear patterning onto CoCr surfaces with different periodicities (≈3, 10, 20, and 32 µm) and depths (≈20 and 800 nm). Changes in surface topography, chemistry, and wettability are thoroughly characterized before and after modification. Human umbilical vein endothelial cells' adhesion and spreading are similar for all patterned and plain CoCr surfaces. Moreover, high-depth series induce cell elongation, alignment, and migration along the patterned lines. Platelet adhesion and aggregation decrease in all patterned surfaces compared to CoCr control, which is associated with changes in wettability and oxide layer characteristics. Cellular studies provide evidence of the potential of DLIP topographies to foster endothelialization without enhancement of platelet adhesion, which will be of high importance when designing new BMS in the future.This work offers a new use of direct laser interference patterning (DLIP) technique, on cobalt-chromium (CoCr) alloys, to obtain linear patterned and chemically modified surfaces. The obtained topography induces endothelial cell alignment and migration, and, chemical changes reduce platelet adhesion. Consequently, DLIP can be a one-step technique to obtain surfaces with the capacity to enhance endothelialization and reduce thrombogenicity.
  • pH-Responsive Nanoscale Coordination Polymer for Efficient Drug Delivery
           and Real-Time Release Monitoring
    • Abstract: Both excess dosages of drug and unwanted drug carrier can lead to severe side effects as well as the failure of tumor therapy. Here, an Fe3+–gallic acid based drug delivery system is designed for efficient monitoring of drug release in tumor. Fe3+ and polyphenol gallic acid can form polygonal nanoscale coordination polymer in aqueous solution, which exhibits certain antitumor effect. Importantly, this coordination polymer possesses extremely high doxorubicin (DOX) loading efficacy (up to 48.3%). In vitro studies demonstrate that the fluorescence of DOX can be quenched efficiently when DOX is loaded on the coordination polymer. The acidity in lysosome also triggers the release of DOX and fluorescence recovery simultaneously, which realizes real-time monitoring of drug release in tumor cells. In vivo studies further indicate that this polyphenol-rich drug delivery system can significantly inhibit tumor growth with negligible heart toxicity of DOX. This system with minimal side effects should be a promising nanoplatform for tumor treatment.A nanoscale coordination polymer is developed to deliver drug to tumor tissue and realize real-time monitoring of drug release. Extremely high drug loading efficiency is achieved, and pH-responsive drug release in lysosome is monitored by the recovered fluorescence of drug itself. Importantly, this polyphenol-rich coordination polymer significantly inhibits tumor growth with negligible heart toxicity.
  • Egg Albumen as a Fast and Strong Medical Adhesive Glue
    • Abstract: Sutures penetrate tissues to close wounds. This process leads to inflammatory responses, prolongs healing time, and increases operation complexity. It becomes even worse when sutures are applied to stress-sensitive and fragile tissues. By bonding tissues via forming covalent bonds, some medical adhesives are not convenient to be used by surgeons and have side effects to the tissues. Here egg albumen adhesive (EAA) is reported with ultrahigh adhesive strength to bond various types of materials and can be easily used without any chemical and physical modifications. Compared with several commercial medical glues, EAA exhibits stronger adhesive property on porcine skin, glass, polydimethylsiloxane. The EAA also shows exceptional underwater adhesive strength. Finally, wound closure using EAA on poly(caprolactone) nanofibrous sheet and general sutures is investigated and compared in a rat wound model. EAA also does not show strong long-term inflammatory response, suggesting that EAA has potential as a medical glue, considering its abundant source, simple fabrication process, inherent nontoxicity, and low cost.Egg albumen adhesive (EAA) is formed by simply adding raw egg albumen powder to water. EAA exhibits outstanding adhesion strength on pigskin tissues, polydimethylsiloxane, and glass substrates especially. EAA on nanofibrous mesh shows reliable biocompatibility and biodegradability, and great wound closure performance. EAA also has exceptional underwater adhesive strength when combined with Vaseline.
  • Impermeable Robust Hydrogels via Hybrid Lamination
    • Abstract: Hydrogels have been proposed for sensing, drug delivery, and soft robotics applications, yet most of these materials suffer from low mechanical robustness and high permeability to small molecules, limiting their widespread use. This study reports a general strategy and versatile method to fabricate robust, highly stretchable, and impermeable hydrogel laminates via hybrid lamination of an elastomer layer bonded between hydrogel layers. By controlling the layers' composition and thickness, it is possible to tune the stiffness of the impermeable hydrogels without sacrificing the stretchability. These hydrogel laminates exhibit ultralow surface coefficients of friction and, unlike common single-material hydrogels, do not allow diffusion of various molecules across the structure due to the presence of the elastomer layer. This feature is then used to release different model drugs and, in a subsequent experiment, to sense different pH conditions on the two sides of the hydrogel laminate. A potential healthcare application is shown using the presented method to coat medical devices (catheter, tubing, and condom) with hydrogel, to allow for drug release and sensing of environmental conditions for gastrointestinal or urinary tract.A general and versatile strategy to develop robust, stretchable and impermeable hydrogel laminates is presented to overcome common limitations of hydrogel materials such as weak mechanical properties and permeability. The laminates have tunable mechanical properties and enable spatial control of the sensing and release properties, as demonstrated by drug release and pH sensing to different sides of the laminate.
  • Centrifugal Lithography: Self-Shaping of Polymer Microstructures
           Encapsulating Biopharmaceutics by Centrifuging Polymer Drops
    • Abstract: Polymeric microstructures encapsulating biopharmaceutics must be fabricated in a controlled environment to preserve the biological activity. There is increasing demand for simple methods designed to preserve the biological activity by utilizing the natural properties of polymers. Here, the paper shows that centrifugal lithography (CL) can be used for the fabrication of such microstructures in a single centrifugation, by engineering the self-shaping properties of hyaluronic acid (HA). In this method, HA drops are self-shaped into hourglass-microstructures to produce two dissolving microneedles (DMN), which facilitate transdermal delivery via implantation on the skin. In addition, tuberculin purified protein derivatives are encapsulated into HA DMNs under refrigerated conditions (4 °C) during CL. Therefore, the tuberculin skin test (TST) with the DMNs indicates minimal damage, as opposed to the case of TST with traditional hypodermic needles. These findings on the fabrication of polymeric microstructures with biopharmaceutics may trigger the development of various biomedical devices and therapies.Centrifugal lithography (CL)enables fabrication of polymer microstructures via self-shaping during a centrifugation under controlled environment for biopharmaceutics. Dissolving microneedle (DMN) array composed of hyaluronic acid and tuberculin purified protein derivatives (PPD) is fabricated by CL under refrigerated conditions (4 °C) to preserve PPD. Diagnosis of tuberculosis with the DMNs indicates minimal damage, as opposed to the traditional hypodermic needles.
  • Self-Normalized Detection of ANXA3 from Untreated Urine of Prostate Cancer
           Patients without Digital Rectal Examination
    • Abstract: A noninvasive quantitative assay that is capable of identifying prostate cancer biomarkers in untreated urine is an attractive diagnosis tool, but this method is subject to various obstacles. Difficulties presented by untreated urine include varying salt concentrations, and pH levels that may be different even though they are from the same patient. Untreated urine also presents interference from other biomolecules and possesses a fewer number of cancer biomarkers than can be found in serum. As a result, urine preconditioning processes and digital rectal examination (DRE) to increase biomarker secretion are mandatory in current urine assays. To address these challenges, an ion-responsive urine sensor (IRUS) that measures differential electrical signals is proposed as a self-normalized detection method. The proposed IRUS is based on a FET biosensor with a disposable sensing gate and has the capability to detect the prostate cancer antigen ANXA3 in untreated patient urine. The IRUS can detect ANXA3 at
  • Timed Delivery of Therapy Enhances Functional Muscle Regeneration
    • Abstract: Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Previous investigations have typically focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here, this study reports how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell engraftment and the functional repair of severely injured muscle. Delivery of a biomaterial-based therapy timed with the peak of injury-induced inflammation leads to potent early and long-term regenerative benefits. Diminished inflammation and fibrosis, enhanced angiogenesis, and increased cell engraftment are seen during the acute stage following optimally timed treatment. Over the long term, treatment during peak inflammation leads to enhanced functional regeneration, as indicated by reduced chronic inflammation and fibrosis along with increased tissue perfusion and muscle contractile force. Treatments initiated immediately after injury or after inflammation had largely resolved provided more limited benefits. These results demonstrate the importance of appropriately timing the delivery of biologic therapy in the context of muscle regeneration. Biomaterial-based timed delivery can likely be applied to other tissues and is of potential wide utility in regenerative medicine.Externally actuated ferrogels are used to demonstrate the importance of timing of biologic therapies with respect to injury-induced inflammation. Delaying treatment until the peak of inflammation leads to both early and long-term regenerative benefits surpassing those seen with treatment initiated at the time of injury. This strategy can likely be applied broadly to both new and existing cell transplantation therapies.
  • Response to “Correspondence Concerning Hemocompatibility of
           Superhemophobic Titania Surfaces”
  • Phospholipid Capped Mesoporous Nanoparticles for Targeted High Intensity
           Focused Ultrasound Ablation
    • Abstract: The mechanical effects of cavitation can be effective for therapy but difficult to control, thus potentially leading to off-target side effects in patients. While administration of ultrasound active agents such as fluorocarbon microbubbles and nanodroplets can locally enhance the effects of high intensity focused ultrasound (HIFU), it has been challenging to prepare ultrasound active agents that are small and stable enough to accumulate in tumors and internalize into cancer cells. Here, this paper reports the synthesis of 100 nm nanoparticle ultrasound agents based on phospholipid-coated, mesoporous, hydrophobically functionalized silica nanoparticles that can internalize into cancer cells and remain acoustically active. The ultrasound agents produce bubbles when subjected to short HIFU pulses (≈6 µs) with peak negative pressure as low as ≈7 MPa and at particle concentrations down to 12.5 µg mL−1 (7 × 109 particles mL−1). Importantly, ultrasound agents are effectively uptaken by cancer cells without cytotoxic effects, but HIFU insonation causes destruction of the cells by the acoustically generated bubbles, as demonstrated by (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and lactate dehydrogenase assays and flow cytometry. Finally, it is showed that the HIFU dose required to effectively eliminate cancer cells in the presence of ultrasound agents causes only a small temperature increase of ≈3.5 °C.High intensity focused ultrasound (HIFU) is promising for tissue ablation but suffers from off-target side effects. This work reports 100 nm mesoporous, hydrophobically modified silica nanoparticles coated with phospholipid monolayers, polyethylene glycol, and folate. These particles are uptaken into breast cancer cells without change in viability, but administration of HIFU with uptaken particles results in cell death.
  • Promoting Cell Migration in Tissue Engineering Scaffolds with Graded
    • Abstract: Ideal bone scaffolds having good biocompatibility, good biodegradability, and beneficial mechanical properties are the basis for bone tissue engineering. Specifically, cell migration within 3D scaffolds is crucial for bone regeneration of critical size defects. In this research, hydroxyapatite scaffolds with three different types of architectures (tortuous, parallel, and graded channels) are fabricated using the freeze-casting (ice-templating) method. While most studies promote cell migration by chemical factors, it can be greatly enhanced by introducing only graded channels as compared with tortuous or parallel channels. The results provide insights and guidance in designing novel scaffolds to enhance cell migration behavior for bone tissue regeneration.Cell migration within 3D scaffolds is crucial for bone regeneration at critical size defects. Here, hydroxyapatite scaffolds with different microstructures are fabricated. Cell migration is greatly promoted within the scaffolds with graded channels comparing with those having tortuous or parallel channels. The results provide new insights and guidance for designing novel scaffolds to regulate cell migration behavior for bone regeneration.
  • Enzyme Prodrug Therapy Engineered into Electrospun Fibers with Embedded
           Liposomes for Controlled, Localized Synthesis of Therapeutics
    • Abstract: Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β-glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β-glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks. It is further shown that liposomes provide the highly beneficial stabilization of the enzyme when incubated in cell culture media. The assembled biocatalytic materials successfully produce antiproliferative drugs (SN-38) using externally administered prodrugs (SN-38-glucuronide) and effectively suppress cell proliferation, with envisioned utility in the design of cardiovascular grafts.β-glucuronidase is an enzyme with historically validated performance in enzyme prodrug therapy, however β-glucuronidase retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Here, encapsulation of β-glucuronidase in liposomal subcompartments within electrospun fibers affords a highly stable preparation of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks.
  • Melt Electrospinning Writing of
           Poly-Hydroxymethylglycolide-co-ε-Caprolactone-Based Scaffolds for Cardiac
           Tissue Engineering
    • Abstract: Current limitations in cardiac tissue engineering revolve around the inability to fully recapitulate the structural organization and mechanical environment of native cardiac tissue. This study aims at developing organized ultrafine fiber scaffolds with improved biocompatibility and architecture in comparison to the traditional fiber scaffolds obtained by solution electrospinning. This is achieved by combining the additive manufacturing of a hydroxyl-functionalized polyester, (poly(hydroxymethylglycolide-co-ε-caprolactone) (pHMGCL), with melt electrospinning writing (MEW). The use of pHMGCL with MEW vastly improves the cellular response to the mechanical anisotropy. Cardiac progenitor cells (CPCs) are able to align more efficiently along the preferential direction of the melt electrospun pHMGCL fiber scaffolds in comparison to electrospun poly(ε-caprolactone)-based scaffolds. Overall, this study describes for the first time that highly ordered microfiber (4.0–7.0 µm) scaffolds based on pHMGCL can be reproducibly generated with MEW and that these scaffolds can support and guide the growth of CPCs and thereby potentially enhance their therapeutic potential.Fabrication of highly ordered microfiber scaffolds for cardiac tissue engineering is achieved by melt electrospinning writing of a hydroxyl-functionalized polyester. These scaffolds can support and guide the growth of cardiac progenitor cells while recapitulating the mechanical environment of the native cardiac tissue. This approach provides a framework for the development of therapeutically viable in vitro engineered cardiac tissues.
  • tBHQ Suppresses Osteoclastic Resorption in Xenogeneic-Treated Dentin
           Matrix-Based Scaffolds
    • Abstract: Extracellularmatrix (ECM)-based scaffolds are important for their potential therapeutic application. Treated dentin matrix (TDM), a kind of ECM, seeded with allogeneic dental follicle stem cells (TDM/aDFC) provides a suitable inductive microenvironment for tooth root regeneration. Considering the limited sources, xenogeneic TDM (xTDM) is a possible alternative to allogeneic TDM; however, xTDM-based scaffold presents severe osteolysis and resorption lacunae causing regenerated tooth root failure. Immune response–induced excessive osteoclastogenesis plays a critical role in xenogeneic scaffold osteolysis and resorption. The impact of antioxidant, tert-butylhydroquinone (tBHQ), on xTDM/aDFCs-induced osteoclastogenesis and osteoclastic resorption in vivo and in vitro are investigated. tBHQ upregulates heme oxygenase-1 release and downregulates high mobility group box 1 mRNA expression. mRNA expression of other osteoclast-related genes including nuclear factor-kappa Bp65, receptor activator of nuclear factor kappa-B, nuclear factor of activated T-cells cytoplasmic 1, cathepsin K, and integrin β3, also decreases significantly. Furthermore, tBHQ-treated xTDM/aDFCs scaffolds implanted into rhesus macaques show reduced osteolysis and osteoclastic resorption by microcomputed tomography and tartrate-resistant acid phosphatase staining. tBHQ-induced suppression of xTDM/aDFC-induced osteoclastogenesis and osteoclastic resorption presents a new strategy for the regeneration of biological tooth root and could be applied to the regeneration of other complex tissues and organs.Xenogeneic-treated dentin matrix (xTDM)-based scaffolds present severe osteolysis and resorption lacunae causing regenerated tooth root failure. Antioxidant, tert-butylhydroquinone (tBHQ), inhibits xTDM seeded with allogeneic dental follicle cells (xTDM/aDFCs)-induced osteoclastogenesis and reduces osteolysis and osteoclastic resorption of xTDM/aDFCs scaffolds. The regenerated tooth root constructed of xTDM and aDFCs keep intact and regular in jaws of rhesus macaques under tBHQ treatment.
  • Evaluation of Electrical Impedance Spectroscopy-on-a-Needle as a Novel
           Tool to Determine Optimal Surgical Margin in Partial Nephrectomy
    • Abstract: A hypodermic needle has been introduced incorporating an electrical impedance spectroscopy (EIS) sensor, called micro-EIS-on-a-needle for depth profiling (μEoN-DP). The μEoN-DP can locate endophytic renal tumors as well as determine tumor margins by detecting the impedance difference between normal and cancer tissues. To evaluate the μEoN-DP as a novel tool to determine the optimal surgical margin during partial nephrectomy (PN), the electrical impedance differences between renal parenchymal tissues and renal cell carcinoma (RCC) tumors are investigated with regard to the distance from the tumors. Optimal frequencies at which the discrimination extent is maximized are suggested based on the discrimination index. The resistance and capacitance of normal and cancer tissues are extracted using electrical equivalent circuit by excluding the influences of other electrical components on the sensor output. The extracted resistance and capacitance of cancer tissues are 37.8% larger and 25.7% smaller than that of normal tissues, respectively. Additionally, high sensitivity and specificity are obtained by using extracted resistance and capacitance, thus implying that the μEoN-DP shows promise as a supplementary tool for PN margin evaluation and decreasing the prevalence of positive surgical margins while maximizing parenchymal preservation.Electrical impedance spectroscopy (EIS) on a hypodermic needle to determine optimal surgical margin during partial nephrectomy (PN). The electrical impedance differences between renal parenchymal tissues and renal cell carcinoma tumors are investigated with regard to the distance from the tumors.
  • Comment on: “Hemocompatibility of Superhemophobic Titania
  • Electrostimulated Release of Neutral Drugs from Polythiophene
           Nanoparticles: Smart Regulation of Drug–Polymer Interactions
    • Abstract: Poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles are loaded with curcumin and piperine by in situ emulsion polymerization using dodecyl benzene sulfonic acid both as a stabilizer and a doping agent. The loaded drugs affect the morphology, size, and colloidal stability of the nanoparticles. Furthermore, kinetics studies of nonstimulated drug release have evidenced that polymer···drug interactions are stronger for curcumin than for piperine. This observation suggests that drug delivery systems based on combination of the former drug with PEDOT are much appropriated to show an externally tailored release profile. This is demonstrated by comparing the release profiles obtained in presence and absence of electrical stimulus. Results indicate that controlled and time-programmed release of curcumin is achieved in a physiological medium by applying a negative voltage of −1.25 V to loaded PEDOT nanoparticles.An electric-field-responsive polymeric nanoparticles system for programmed drug delivery is presented. More specifically, curcumine loaded into stabilized poly(3,4-ethylenedioxythiophene) electroactive nanoparticles is released by applying a controlled external voltage. Curcumine···polymer interactions are crucial to regulate the release. This nontoxic biocompatible system is of potential use for advanced biomedical applications.
  • Ultrasound-Triggered Destruction of Folate-Functionalized Mesoporous
           Silica Nanoparticle-Loaded Microbubble for Targeted Tumor Therapy
    • Abstract: A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound-guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN-FA) to enhance cell membrane translocation. MSN-FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN-FA-TAN-MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN-FA-TAN-MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN-FA-TAN-MB are conducted on A549 and HeLa tumor cells. FA-facilitated MSN-FA-TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA-receptor-mediated endocytosis mechanism. The ultrasound response property of MSN-FA-TAN-MB is also verified. MSN-FA-TAN-MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy.A novel drug delivery vehicle based on folate-modified mesoporous silica nanoparticles and microbubbles is designed and fabricated. The resulting multifunctional vehicle, which combines the merits of high drug loading capacity, multitargeting, and ultrasound-guided drug release, can enhance the efficacy of anticancer drugs, reduce undesirable side effects, and provide a new strategy for tumor targeting.
  • Superoxide Dismutase-Loaded Porous Polymersomes as Highly Efficient
           Antioxidants for Treating Neuropathic Pain
    • Abstract: A highly efficient antioxidant is developed by encapsulating superoxide dismutase (SOD) within the aqueous interior of porous polymersomes. The porous polymersomes provide a permeable membrane that allows free superoxide radicals to pass into the aqueous interior and interact with the encapsulated antioxidant enzyme SOD. In vivo studies in the rat demonstrate that administration of SOD-encapsulated porous polymersomes can prevent neuropathic pain after nerve root compression more effectively than treatment with free antioxidant enzyme alone.Highly efficient antioxidants based on superoxide dismutase (SOD)-loaded porous polymersomes are developed for treating neuropathic pain. The SOD-loaded porous polymersomes are highly permeable to superoxide radical, while retaining the antioxidant enzyme within their aqueous interiors. Administration of the antioxidant porous polymersomes following a painful nerve root compression is substantially more effective in preventing the onset of pain in rats than comparable or higher doses of free SOD alone.
  • The Spontaneous Adhesion of BMMC onto Self-Assembled Peptide Nanoscaffold
           without Activation Inhibits Its IgE-Mediated Degranulation
    • Abstract: Mast cells play a distinct role in the innate immune response. Engineered microenvironments for the express purpose of influencing mast cell activity will provide a novel means of designing biomaterials, as well as a means to systematically investigate mast cell biology in a 3D setting. Here, the effect of nanoscaffolds composed of self-assembling peptides, namely (RADA)4, on bone-marrow-derived murine mast cell (BMMC) activity is reported. Unlike most studies that stimulate mast cells to induce adhesion, this results show that BMMCs spontaneously adhere to the artificial nanoscaffold without initiating their activation. It is observed that the classical immunoglobulin (IgE) antigen-mediated degranulation of adhered BMMC is inhibited by the nanoscaffold, while non-IgE (A23187)-induced degranulation is unaffected. The inhibition of IgE–antigen-mediated degranulation is likely a result of inhibited molecular diffusion within the matrix; antigen diffusion, IgE–FcεRI complex shuttling, and/or formation of multiple IgE–FcεRI clusters may be physically hindered in the presence of the polyvalent nanofiber network. Moreover, the IgE/antigen-induced inflammatory cytokine tumor necrosis factor α release from adherent BMMCs is significantly reduced likely due to interaction with the nanofiber matrix. This work is considered the first step in quantifying mast cell activity in artificial matrices composed of self-assembling peptides.Herein, for the first time, the effect of self-assembling (RADA)4 nanoscaffold on bone-marrow-derived murine mast cell (BMMC) activities is reported. BMMCs can spontaneously adhere to the synthetic matrix without stimulation. The nanofiber network selectively inhibits IgE-mediated degranulation of adhered BMMC, but not A23187-mediated degranulation. Moreover, tumor necrosis factor α released from adherent BMMCs can be significantly absorbed by the matrix.
  • Multifunctional Polymeric Micelles for Combining Chelation and Detection
           of Iron in Living Cells
    • Abstract: Multifunctional self-assembled micelles composed of Pluronics F127 polymer chains are developed and investigated for chelation and selective detection of iron(III) in vitro and in iron-overloaded cells. Tetraphenylethene (TPE) is encapsulated into the micelle core and the iron chelate drug deferoxamine (DFO) is conjugated to micelles to generate a fluorescence quenching detection system termed DFO-TFM for short, where T stands for TPE, F for F127, and M for micelle. The key to the successful formation of this fluorescence quenching system is due to the near-ideal overlap between the absorption spectrum of the DFO:iron(III) complex and fluorescence spectrum of TPE. DFO-TFM can retain the iron-chelation properties of DFO and exhibits negligible cytotoxicity compared to free DFO. Furthermore, this fluorescence “turn-off” system can be utilized to detect the presence of iron and to monitor the chelation process in an iron overload cell model. This study serves as an effective proof-of-concept model for designing future in vivo systems capable of combining the features of iron chelation with iron detection and efforts toward the development of such detection systems are currently underway.Multifunctional Pluronics F127 micelles are constructed for iron chelation and fluorescence detection by introducing tetraphenylethene and the chelating drug deferoxamine into self-assembling polymeric micelles. Deferoxamine can simultaneously be used to chelate iron(III) and quench the fluorescence emission of tetraphenylethene. This fluorescence “turn-off” process can be used to monitor the iron chelation process in an iron overload cell model.
  • Efficient Skin Temperature Sensor and Stable Gel-Less Sticky ECG Sensor
           for a Wearable Flexible Healthcare Patch
    • Abstract: Wearable, flexible healthcare devices, which can monitor health data to predict and diagnose disease in advance, benefit society. Toward this future, various flexible and stretchable sensors as well as other components are demonstrated by arranging materials, structures, and processes. Although there are many sensor demonstrations, the fundamental characteristics such as the dependence of a temperature sensor on film thickness and the impact of adhesive for an electrocardiogram (ECG) sensor are yet to be explored in detail. In this study, the effect of film thickness for skin temperature measurements, adhesive force, and reliability of gel-less ECG sensors as well as an integrated real-time demonstration is reported. Depending on the ambient conditions, film thickness strongly affects the precision of skin temperature measurements, resulting in a thin flexible film suitable for a temperature sensor in wearable device applications. Furthermore, by arranging the material composition, stable gel-less sticky ECG electrodes are realized. Finally, real-time simultaneous skin temperature and ECG signal recordings are demonstrated by attaching an optimized device onto a volunteer's chest.The effect of film thickness on the precision of monitoring skin temperature as well as a gel-less sticky electrode for electrocardiogram monitoring is studied in this report. Based on the optimized sensor sheet structure, real-time healthcare recording is successfully demonstrated.
  • 3D Near-Field Electrospinning of Biomaterial Microfibers with Potential
           for Blended Microfiber-Cell-Loaded Gel Composite Structures
    • Abstract: This paper describes the development of a novel low-cost and efficient method, 3D near-field electrospinning, to fabricate high-resolution, and repeatable 3D polymeric fiber patterns on nonconductive materials with potential use in tissue engineering. This technology is based on readily available hobbyist grade 3D printers. The result is exquisite control of the deposition of single fibers in an automated manner. Additionally, the fabrication of various fiber patterns, which are subsequently translated to unique cellular patterns, is demonstrated. Finally, poly(methyl methacrylate) fibers are printed within 3D collagen gels loaded with cells to introduce anisotropic properties of polymeric fibers within the cell-loaded gels.3D Near-Field Electrospinning (3DNFES) is a new method for printing polymeric fibers in highly organized, controlled, and reproducible manner. 3DNFES offers several significant advantages including: (1) producing precise patterns of fibers on relatively large-scale area, (2) printing in all three directions, (3) offering an inexpensive method, and (4) readily combines with other prepatterned nanostructures or microstructures such as gels.
  • Liposomes with Silk Fibroin Hydrogel Core to Stabilize bFGF and Promote
           the Wound Healing of Mice with Deep Second-Degree Scald
    • Abstract: How to maintain the stability of basic fibroblast growth factor (bFGF) in wounds with massive wound fluids is important to accelerate wound healing. Here, a novel liposome with hydrogel core of silk fibroin (SF-LIP) is successfully developed by the common liposomal template, followed by gelation of liquid SF inside vesicle under sonication. SF-LIP is capable of encapsulating bFGF (SF-bFGF-LIP) with high efficiency, having a diameter of 99.8 ± 0.5 nm and zeta potential of −9.41 ± 0.10 mV. SF-LIP effectively improves the stability of bFGF in wound fluids. After 8 h of incubation with wound fluids at 37 °C, more than 50% of free bFGF are degraded, while only 18.6% of the encapsulated bFGF in SF-LIP are destroyed. Even after 3 d of preincubation with wound fluids, the cell proliferation activity and wound healing ability of SF-bFGF-LIP are still preserved but these are severely compromised for the conventional bFGF-liposome (bFGF-LIP). In vivo experiments reveal that SF-bFGF-LIP accelerates the wound closure of mice with deep second-degree scald. Moreover, due to the protective effect and enhanced penetration ability, SF-bFGF-LIP is very helpful to induce regeneration of vascular vessel in comparison with free bFGF or bFGF-LIP. The liposome with SF hydrogel core may be a potential carrier as growth factors for wound healing.Maintaining the stability of basic fibroblast growth factor (bFGF) in wound fluids is important to accelerate wound healing. In this study, a novel liposome (LIP) with silk fibroin (SF) hydrogel core has been proposed as an innovative carrier of bFGF for deep second-degree scald. Due to the protective effect and enhanced penetration ability, SF-bFGF-LIP exhibits a better wound healing effect than free bFGF or the common bFGF-liposome.
  • Cotransporting Ion is a Trigger for Cellular Endocytosis of
           Transporter-Targeting Nanoparticles: A Case Study of High-Efficiency
           SLC22A5 (OCTN2)-Mediated Carnitine-Conjugated Nanoparticles for Oral
           Delivery of Therapeutic Drugs
    • Abstract: OCTN2 (SLC22A5) is a Na+-coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+. Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+-LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.Cotransporting ion, Na+, is found as a trigger for the proceeding of l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) targeting to Na+-coupled organic cation/carnitine transporter 2 (OCTN2). In this case, LC-PLGA NPs and Na+ bind to specific binding sites of OCTN2, and then initiate the conformation change from outward-facing to occluded state to form an energetically stable intermediate complex (OCTN2-Na+-LC-PLGA NPs). The complex induces membrane invagination and the following endocytosis.
  • A Core–Shell-Satellite Structured Fe3O4@g-C3N4–UCNPs–PEG for
           T1/T2-Weighted Dual-Modal MRI-Guided Photodynamic Therapy
    • Abstract: Reactive oxygen species (ROS) produced in the specific tumor site plays the key role in photodynamic therapy (PDT). Herein, a multifunctional nanoplatform is designed by absorbing ultrasmall upconversion nanoparticles (UCNPs) on mesoporous graphitic-phase carbon nitride (g-C3N4) coated superparamagnetic iron oxide nanospheres, then further modified with polyethylene glycol (PEG)molecules (abbreviated as Fe3O4@g-C3N4–UCNPs–PEG). The inert g-C3N4 layer between Fe3O4 core and outer UCNPs can substantially depress the quenching effect of Fe3O4 on the upconversion emission. Upon near-infrared (NIR) laser irradiation, the UCNPs convert the energy to the photosensitizer (g-C3N4 layer) through fluorescence resonance energy transfer process, thus producing a vast amount of ROS. In vitro experiment exhibits an obvious NIR-triggered cell inhibition due to the cellular uptake of nanoparticles and the effective PDT efficacy. Notably, this platform is responsive to magnetic field, which enables targeted delivery under the guidance of an external magnetic field and supervises the therapeutic effect by T1/T2-weighted dual-modal magnetic resonance imaging. Moreover, in vivo therapeutic effect reveals that the magnetism guided accumulation of Fe3O4@g-C3N4–UCNPs–PEG can almost trigger a complete tumor inhibition without any perceived side effects. The experiments emphasize that the excellent prospect of Fe3O4@g-C3N4–UCNPs–PEG as a magnetic targeted platform for PDT application.A multifunctional nanoplatform demonstrates NIR-irradiated, magnetic targeted, and T1/T2-weighted dual-modal magnetic resonance imaging guided photodynamic anticancer therapy. The platform is constructed by coating mesoporous g-C3N4 on Fe3O4 nanoparticles, following by attaching ultrasmall upconversion nanoparticles (UCNPs) and PEG molecules (denoted as Fe3O4@g-C3N4–UCNPs–PEG).
  • Cell-Engineered Nanovesicle as a Surrogate Inducer of Contact-Dependent
    • Abstract: Heterotypic interactions between cells are crucial in various biological phenomena. Particularly, stimuli that regulate embryonic stem cell (ESC) fate are often provided from neighboring cells. However, except for feeder cultures, no practical methods are identified that can provide ESCs with contact-dependent cell stimuli. To induce contact-dependent cell stimuli in the absence of living cells, a novel method that utilizes cell-engineered nanovesicles (CNVs) that are made by extruding living cells through microporous membranes is described. Protein compositions of CNVs are similar to their originating cells, as well as freely diffusible and precisely scalable. Treatment of CNVs produced from three different stromal cells successfully induces the same effect as feeder cultures. The results suggest that the effects of CNVs are mainly mediated by membrane-associated components. The use of CNVs might constitute a novel and efficient tool for ESC research.Cell-engineered nanovesicles (CNVs) fabricated from feeder cells successfully regulate the fates of embryonic stem cells through contact-dependent stimulus. Unlike feeder layer methods, scalable, diffusible, and storable characteristics of CNVs can constitute a novel tool for embryonic stem cell research. The CNV method might be used in various other applications that require heterotipic cell–cell interactions.
  • Interactions of Neurons with Physical Environments
    • Abstract: Nerve growth strongly relies on multiple chemical and physical signals throughout development and regeneration. Currently, a cure for injured neuronal tissue is an unmet need. Recent advances in fabrication technologies and materials led to the development of synthetic interfaces for neurons. Such engineered platforms that come in 2D and 3D forms can mimic the native extracellular environment and create a deeper understanding of neuronal growth mechanisms, and ultimately advance the development of potential therapies for neuronal regeneration. This progress report aims to present a comprehensive discussion of this field, focusing on physical feature design and fabrication with additional information about considerations of chemical modifications. We review studies of platforms generated with a range of topographies, from micro-scale features down to topographical elements at the nanoscale that demonstrate effective interactions with neuronal cells. Fabrication methods are discussed as well as their biological outcomes. This report highlights the interplay between neuronal systems and the important roles played by topography on neuronal differentiation, outgrowth, and development. The influence of substrate structures on different neuronal cells and parameters including cell fate, outgrowth, intracellular remodeling, gene expression and activity is discussed. Matching these effects to specific needs may lead to the emergence of clinical solutions for patients suffering from neuronal injuries or brain-machine interface (BMI) applications.Neurons rely on physical signals throughout development and regeneration. Recent advances in fabrication and materials led to the development of 2D and 3D engineered platforms that can mimic the native extracellular environment. This Progress Report exploits studies of platforms generated with a range of physical topographies, from micro- down to nano- scale, that interact effectively with neurons, affecting differentiation, outgrowth and activity. Matching these specific needs may advance therapies and brain-machine interface applications.
  • Multicompartment Drug Release System for Dynamic Modulation of Tissue
    • Abstract: Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core–shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes.A multicompartment drug release system is developed for dynamic modulation of tissue responses. The system is composed of electrosprayed spheres embedded within an electrospun mat of core–shell fibers. Different compartments are formed that are capable of releasing drugs over distinct timescales. When anti-inflammatory and antifibrotic drugs are incorporated, these systems are able to reduce the foreign body response to implants.
  • Directional Matrix Nanotopography with Varied Sizes for Engineering Wound
    • Abstract: Topographic features play a crucial role in the regulation of physiologically relevant cell and tissue functions. Here, an analysis of feature-size-dependent cell–nanoarchitecture interactions is reported using an array of scaffolds in the form of uniformly spaced ridge/groove structures for engineering wound healing. The ridge and groove widths of nanopatterns are varied from 300 to 800 nm and the nanotopography features are classified into three size ranges: dense (300–400 nm), intermediate (500–600 nm), and sparse (700–800 nm). On these matrices, fibroblasts demonstrate a biphasic trend of cell body and nucleus elongation showing the maximum at intermediate feature density, whereas maximum migration speed is observed at the dense case with monotonic decrease upon increasing feature size. The directional organization of cell-synthesized fibronectin fibers can be regulated differently via the nanotopographical features. In an in vitro wound healing model, the covering rate of cell-free regions is maximized on the dense nanotopography and decreased with increasing feature size, showing direct correlation with the trend of migration speed. It is demonstrated that the properties of repaired tissue matrices in the process of wound healing may be controlled via the feature-size-dependent cell–nanoarchitecture interactions, which can be an important consideration for designing tissue engineering scaffolds.Nanotopographic features play a crucial role in the regulation of physiologically relevant cell and tissue functions. Here, the feature-size-dependent cell–nanoarchitecture interactions are systemically analyzed using an array of directional matrix nanotopography. It is shown that the properties of repaired tissue matrices in the process of dermis wound healing may be controlled via nanotopographical density-mediated cellular behaviors.
  • Nonmediated, Label-Free Based Detection of Cardiovascular Biomarker in a
           Biological Sample
    • Abstract: Direct electrochemical (EC) monitoring in a cell culture medium without electron transporter as called mediator is attractive topic in vitro organoid based on chip with frequently and long-time monitoring since it can avoid to its disadvantage as stability, toxicity. Here, direct monitoring with nonmediator is demonstrated based on impedance spectroscopy under the culture medium in order to overcome the limitation of mediator. The applicability of EC monitoring is shown by detecting alpha-1-anti trypsin (A1AT) which is known as biomarkers for cardiac damage and is widely chosen in organoid cardiac cell-based chip. The validity of presented EC monitoring is proved by observing signal processing and transduction in medium, mediator, medium–mediator complex. After the observation of electron behavior, A1AT as target analyte is immobilized on the electrode and detected using antibody–antigen interaction. As a result, the result indicates limit of detection is 10 ng mL−1 and linearity for the 10–1000 ng mL−1 range, with a sensitivity of 3980 nF (log [g mL])−1 retaining specificity. This EC monitoring is based on label-free and reagentless detection, will pave the way to use for continuous and simple monitoring of in vitro organoid platform.“Direct monitoring with nonmediator” is demonstrated based on impedance spectroscopy under the culture medium in order to overcome the limitation of mediator. The applicability of electrochemical monitoring is shown by detecting alpha-1-anti trypsin, which is known as biomarkers for cardiac damage and is widely chosen in organoid cardiac cell-based chip.
  • 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.
  • 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.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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