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Publisher: John Wiley and Sons   (Total: 1579 journals)

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Showing 1 - 200 of 1579 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: 65, 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: 51, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 153, 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: 4)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 13, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, 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: 258, 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: 34, 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: 15, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, 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: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 139, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 33, 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: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 271, 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: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 132, 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: 172)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 216, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 38, 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: 7, 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: 47, 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: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, 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: 90, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 47, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 7, 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: 145, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 49, 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: 36, 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: 15, 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: 238, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, 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: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, 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: 4, 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: 5, 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: 14, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, 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: 46, 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: 29, 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: 14, 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: 407, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 71, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 32, 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: 24, 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 180, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 37, 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: 231, 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  [1579 journals]
  • Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms
           with Therapeutic Potential
    • Abstract: Injectable delivery systems that respond to biologically relevant stimuli present an attractive strategy for tailorable drug release. Here, the design and synthesis of unique polymers are reported for the creation of hydrogels that are formed in situ and degrade in response to clinically relevant endogenous and exogenous stimuli, specifically reducing microenvironments and externally applied light. Hydrogels are formed with polyethylene glycol and heparin‐based polymers using a Michael‐type addition reaction. The resulting hydrogels are investigated for the local controlled release of low molecular weight proteins (e.g., growth factors and cytokines), which are of interest for regulating various cellular functions and fates in vivo yet remain difficult to deliver. Incorporation of reduction‐sensitive linkages and light‐degradable linkages affords significant changes in the release profiles of fibroblast growth factor‐2 (FGF‐2) in the presence of the reducing agent glutathione or light, respectively. The bioactivity of the released FGF‐2 is comparable to pristine FGF‐2, indicating the ability of these hydrogels to retain the bioactivity of cargo molecules during encapsulation and release. Further, in vivo studies demonstrate degradation‐mediated release of FGF‐2. Overall, our studies demonstrate the potential of these unique stimuli‐responsive chemistries for controlling the local release of low molecular weight proteins in response to clinically relevant stimuli.Injectable depots that sequester small bioactive proteins and respond to clinically relevant internal and external stimuli enable local controlled release of therapeutics in the body. Degradation of these depots in response to reducing microenvironments, such as found in tumors, and externally applied light allows tailored release of therapeutic proteins, including basic fibroblast growth factor, with relevance for a variety of biomedical applications.
  • Synthesis of Metal Nanoparticles in Metal‐Phenolic Networks: Catalytic
           and Antimicrobial Applications of Coated Textiles
    • Abstract: The synthesis of metal nanoparticle (NP)‐coated textiles (nanotextiles) is achieved by a dipping process in water without toxic chemicals or complicated synthetic procedures. By taking advantage of the unique nature of tannic acid, metal‐phenolic network‐coated textiles serve as reducing and stabilizing sites for the generation of metal nanoparticles of controllable size. The textiles can be decorated with various metal nanoparticles, including palladium, silver, or gold, and exhibit properties derived from the presence of the metal nanoparticles, for example, catalytic activity in water (>96% over five cycles using palladium nanoparticles) and antibacterial activity against Gram‐negative bacteria (inhibition of Escherichia coli using silver nanoparticles) that outperforms a commercial bandage. The reported strategy offers opportunities for the development of hybrid nanomaterials that may have application in fields outside of catalysis and antimicrobials, such as sensing and smart clothing.Just dipping produces metal nanoparticle‐coated textiles (nanotextiles) without involving toxic chemicals or complicated synthetic steps. This versatile method enables the incorporation of various metal nanoparticles of controllable size, including palladium, silver, or gold, on the textiles. These nanotextiles show >96% catalytic activity in water over five cycles and superior antibacterial activity when compared against a commercial antibacterial bandage.
  • Scaffold Composition Determines the Angiogenic Outcome of Cell‐Based
           Vascular Endothelial Growth Factor Expression by Modulating Its
           Microenvironmental Distribution
    • Abstract: Delivery of genetically modified cells overexpressing Vascular Endothelial Growth Factor (VEGF) is a promising approach to induce therapeutic angiogenesis in ischemic tissues. The effect of the protein is strictly modulated by its interaction with the components of the extracellular matrix. Its therapeutic potential depends on a sustained but controlled release at the microenvironmental level in order to avoid the formation of abnormal blood vessels. In this study, it is hypothesized that the composition of the scaffold plays a key role in modulating the binding, hence the therapeutic effect, of the VEGF released by 3D‐cell constructs. It is found that collagen sponges, which poorly bind VEGF, prevent the formation of localized hot spots of excessive concentration, therefore, precluding the development of aberrant angiogenesis despite uncontrolled expression by a genetically engineered population of adipose tissue‐derived stromal cells. On the contrary, after seeding on VEGF‐binding egg‐white scaffolds, the same cell population caused aberrantly enlarged vascular structures after 14 d. Collagen‐based engineered tissues also induced a safe and efficient angiogenesis in both the patch itself and the underlying myocardium in rat models. These findings open new perspectives on the control and the delivery of proangiogenic stimuli, and are fundamental for the vascularization of engineered tissues/organs.Promising angiogenic approaches rely on cell‐based delivery of exogenous VEGF. However, the 3D microenvironmental distribution of VEGF levels needs to be precisely controlled in vivo around each producing cell to avoid the formation of aberrant vascular structures. Our findings show that the matrix composition, used to deliver the genetically modified cells, is the unique discriminating factor between normal and aberrant angiogenesis.
  • Synthesis, Functionalization, and Design of Magnetic Nanoparticles for
           Theranostic Applications
    • Abstract: In order to translate nanotechnology into medical practice, magnetic nanoparticles (MNPs) have been presented as a class of non‐invasive nanomaterials for numerous biomedical applications. In particular, MNPs have opened a door for simultaneous diagnosis and brisk treatment of diseases in the form of theranostic agents. This review highlights the recent advances in preparation and utilization of MNPs from the synthesis and functionalization steps to the final design consideration in evading the body immune system for therapeutic and diagnostic applications with addressing the most recent examples of the literature in each section. This study provides a conceptual framework of a wide range of synthetic routes classified mainly as wet chemistry, state‐of‐the‐art microfluidic reactors, and biogenic routes, along with the most popular coating materials to stabilize resultant MNPs. Additionally, key aspects of prolonging the half‐life of MNPs via overcoming the sequential biological barriers are covered through unraveling the biophysical interactions at the bio–nano interface and giving a set of criteria to efficiently modulate MNPs' physicochemical properties. Furthermore, concepts of passive and active targeting for successful cell internalization, by respectively exploiting the unique properties of cancers and novel targeting ligands are described in detail. Finally, this study extensively covers the recent developments in magnetic drug targeting and hyperthermia as therapeutic applications of MNPs. In addition, multi‐modal imaging via fusion of magnetic resonance imaging, and also innovative magnetic particle imaging with other imaging techniques for early diagnosis of diseases are extensively provided.In this review, a wide range of synthetic routes for the preparation of magnetic nanoparticles (MNPs), classified as wet chemistry, microfluidic reactors, and biogenic routes is provided. Design considerations of MNPs for prolonging their half‐life via overcoming biological barriers as well as their therapeutic and diagnostic applications are also detailed.
  • Organ‐on‐a‐Chip Systems for Women's Health Applications
    • Abstract: Biomedical research, for a long time, has paid little attention to the influence of sex in many areas of study, ranging from molecular and cellular biology to animal models and clinical studies on human subjects. Many studies solely rely on male cells/tissues/animals/humans, although there are profound differences in male and female physiology, which can significantly impact disease mechanisms, toxicity of compounds, and efficacy of pharmaceuticals. In vitro systems have been traditionally very limited in their capacity to recapitulate female‐specific physiology and anatomy such as dynamic sex‐hormone levels and the complex interdependencies of female reproductive tract organs. However, the advent of microphysiological organ‐on‐a‐chip systems, which attempt to recreate the 3D structure and function of human organs, now gives researchers the opportunity to integrate cells and tissues from a variety of individuals. Moreover, adding a dynamic flow environment allows mimicking endocrine signaling during the menstrual cycle and pregnancy, as well as providing a controlled microfluidic environment for pharmacokinetic modeling. This review gives an introduction into preclinical and clinical research on women's health and discusses where organ‐on‐a‐chip systems are already utilized or have the potential to deliver new insights and enable entirely new types of studies.Microphysiological organ‐on‐a‐chip systems constitute a powerful new opportunity for translational as well as fundamental research in the field of women's health. The systems have the potential to help implement sex‐balanced preclinical studies as well as to provide novel mechanistic insides into both female‐specific diseases and sex‐differences of diseases affecting both sexes.
  • Centrifugal Lithography: Centrifugal Lithography: Self‐Shaping of
           Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging
           Polymer Drops (Adv. Healthcare Mater. 19/2017)
    • Abstract: Centrifugal lithography (CL) enables fabrication of microstructures via self‐shaping of viscous polymer drops during a centrifugation. Hyungil Jung and co‐workers fabricate dissolving microneedles (DMNs) composed of polymer matrix and biopharmaceutics by CL under controlled environments to preserve their activity in article number 1700326. DMNs are penetrated and implanted into skin and delivered their ingredients through the skin to induce biopharmaceutical effects with minimal damage.
  • Biosensing: Graphene Field‐Effect Transistors for the Sensitive and
           Selective Detection of Escherichia coli Using Pyrene‐Tagged DNA Aptamer
           (Adv. Healthcare Mater. 19/2017)
    • Abstract: An aptamer modified graphene field‐effect transistor (G‐FET) based biosensor for electrical detection of E. coli is developed by King Wai Chiu Lai and co‐workers in article number 1700736. The change of the carrier density in graphene due to the attachment of E. coli is correlated with the electrical response of the graphene biosensors. The electrical response is analyzed and optimized by tuning the gate voltage which affects the carrier mobility of graphene. The excellent sensing performance (high sensitivity, selectivity and stability) opens up the possibility to utilize aptamer modified graphene device for pathogens detection in food and water quality monitoring and early diagnosis of pathogen infections.
  • Wound Dressings: An Advanced Multifunctional Hydrogel‐Based Dressing for
           Wound Monitoring and Drug Delivery (Adv. Healthcare Mater. 19/2017)
    • Abstract: Wound management is a major global challenge and poses a significant financial burden to the healthcare system. In article 1700718, Mohsen Akbari and co‐workers develop an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site. GelDerm makes wound care easier and less painful to the patient, and more cost‐effective for the healthcare system.
  • Masthead: (Adv. Healthcare Mater. 19/2017)
  • Contents: (Adv. Healthcare Mater. 19/2017)
  • Electrospinning: 3D Near‐Field Electrospinning of Biomaterial
           Microfibers with Potential for Blended Microfiber‐Cell‐Loaded Gel
           Composite Structures (Adv. Healthcare Mater. 19/2017)
    • Abstract: 3D near‐field electrospinning is capable of depositing single nano‐ and microfibers with extraordinary precision. This image demonstrates a stem cell attached to perpendicular microfibers. As described by Justin L. Brown and co‐workers in article number 1700456, this process can be multiplexed with other 3D printing techniques to build a wide array of complex structures for applications, such as, regenerative medicine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • A Physicochemically Optimized and Neuroconductive Biphasic Nerve Guidance
           Conduit for Peripheral Nerve Repair
    • Abstract: Clinically available hollow nerve guidance conduits (NGCs) have had limited success in treating large peripheral nerve injuries. This study aims to develop a biphasic NGC combining a physicochemically optimized collagen outer conduit to bridge the transected nerve, and a neuroconductive hyaluronic acid‐based luminal filler to support regeneration. The outer conduit is mechanically optimized by manipulating crosslinking and collagen density, allowing the engineering of a high wall permeability to mitigate the risk of neuroma formation, while also maintaining physiologically relevant stiffness and enzymatic degradation tuned to coincide with regeneration rates. Freeze‐drying is used to seamlessly integrate the luminal filler into the conduit, creating a longitudinally aligned pore microarchitecture. The luminal stiffness is modulated to support Schwann cells, with laminin incorporation further enhancing bioactivity by improving cell attachment and metabolic activity. Additionally, this biphasic NGC is shown to support neurogenesis and gliogenesis of neural progenitor cells and axonal outgrowth from dorsal root ganglia. These findings highlight the paradigm that a successful NGC requires the concerted optimization of both a mechanical support phase capable of bridging a nerve defect and a neuroconductive phase with an architecture capable of supporting both Schwann cells and neurons in order to achieve functional regenerative outcome.A biphasic nerve guidance conduit is fabricated by combining a physicochemically optimized collagen‐based outer conduit with a neuroconductive hyaluronic acid‐laminin luminal filler that has a longitudinally aligned porous microarchitecture capable of supporting dorsal root ganglia axonal outgrowth, neurogenesis & gliogenesis, and Schwann cell growth.
  • Programmable Hydrogels for Cell Encapsulation and Neo‐Tissue Growth to
           Enable Personalized Tissue Engineering
    • Abstract: Biomimetic and biodegradable synthetic hydrogels are emerging as a promising platform for cell encapsulation and tissue engineering. Notably, synthetic‐based hydrogels offer highly programmable macroscopic properties (e.g., mechanical, swelling and transport properties) and degradation profiles through control over several tunable parameters (e.g., the initial network structure, degradation kinetics and behavior, and polymer properties). One component to success is the ability to maintain structural integrity as the hydrogel transitions to neo‐tissue. This seamless transition is complicated by the fact that cellular activity is highly variable among donors. Thus, computational models provide an important tool in tissue engineering due to their unique ability to explore the coupled processes of hydrogel degradation and neo‐tissue growth across multiple length scales. In addition, such models provide new opportunities to develop predictive computational tools to overcome the challenges with designing hydrogels for different donors. In this report, programmable properties of synthetic‐based hydrogels and their relation to the hydrogel's structural properties and their evolution with degradation are reviewed. This is followed by recent progress on the development of computational models that describe hydrogel degradation with neo‐tissue growth when cells are encapsulated in a hydrogel. Finally, the potential for predictive models to enable patient‐specific hydrogel designs for personalized tissue engineering is discussed.Synthetic‐based degradable hydrogels are promising for cell encapsulation. However, success requires the closely coupled processes of hydrogel degradation and neo‐tissue growth. Computational models can greatly assist hydrogel designs. A review of programmable hydrogel properties and their tunable parameters and recent progress in computational model development are presented. With the advent of computational models, creating personalized hydrogel designs is possible.
  • Recent Advances in the Generation of Antibody–Nanomaterial
    • Abstract: Targeted nanomedicines have significantly changed the way new therapeutics are designed to treat disease. Central to successful therapeutics is the ability to control the dynamics of protein–nanomaterial interactions to enhance the therapeutic effect of the nanomedicine. The aim of this review is to illustrate the diversity and versatility of the conjugation approaches involved in the synthesis of antibody–nanoparticle conjugates, and highlight significant new advances in the field of bioconjugation. Such nanomedicines have found utility as both advanced therapeutic agents, as well as more complex imaging contrast agents that can provide both anatomical and functional information of diseased tissue. While such conjugates show significant promise as next generation targeted nanomedicines, it is recognized that there are in fact no clinically approved targeted therapeutics on the market. This fact is reflected upon within this review, and attempts are made to draw some reasoning from the complexities associated with the bioconjugation chemistry approaches that are typically utilized. Present trends, as well as future directions of next generation targeted nanomedicines are also discussed.Antibody–nanoparticle conjugates are employed as advanced therapeutic agents. In this review, the different strategies used in the production of antibody‐conjugated nanoparticles are highlighted with the intention of providing the reader with a synopsis of current and emerging trends in the field. In particular, attempts are made to draw some reasoning from the complexities associated with the existing bioconjugation approaches.
  • Droplet‐Templated Antisolvent Spherical Crystallization of Hydrophilic
           and Hydrophobic Drugs with an in situ Formed Binder
    • Abstract: This study presents a novel droplet‐templated antisolvent spherical crystallization method applicable to both hydrophilic and hydrophobic drugs. In both cases, an alginate hydrogel binder forms in situ, concurrently with the crystallization process, effectively binding the drug crystals into monodisperse spheres. This study presents a detailed process description with mass transfer modeling, and with characterization of the obtained alginate/drug spheres in terms of morphology, composition, and drug loading. Although glycine and carbamazepine are used as model hydrophilic and hydrophobic drugs, this method is easily generalized to other drugs, and offers several benefits such as minimal thermal impact, fast crystallization rates, high drug–binder loading ratios, and high selectivity toward metastable polymorphs.This paper presents a novel antisolvent crystallization method for both hydrophilic and hydrophobic drugs using droplets as templates and alginate hydrogel as an in situ binder. The simultaneous crystallization and gelation processes effectively encapsulate the precipitated crystals of different sizes into highly monodisperse spherical particles to facilitate the downstream formulation processes in pharmaceutical manufacturing.
  • Droplet Microarray Based on Patterned Superhydrophobic Surfaces Prevents
           Stem Cell Differentiation and Enables High‐Throughput Stem Cell
    • Abstract: Over the past decades, stem cells have attracted growing interest in fundamental biological and biomedical research as well as in regenerative medicine, due to their unique ability to self‐renew and differentiate into various cell types. Long‐term maintenance of the self‐renewal ability and inhibition of spontaneous differentiation, however, still remain challenging and are not fully understood. Uncontrolled spontaneous differentiation of stem cells makes high‐throughput screening of stem cells also difficult. This further hinders investigation of the underlying mechanisms of stem cell differentiation and the factors that might affect it. In this work, a dual functionality of nanoporous superhydrophobic–hydrophilic micropatterns is demonstrated in their ability to inhibit differentiation of mouse embryonic stem cells (mESCs) and at the same time enable formation of arrays of microdroplets (droplet microarray) via the effect of discontinuous dewetting. Such combination makes high‐throughput screening of undifferentiated mouse embryonic stem cells possible. The droplet microarray is used to investigate the development, differentiation, and maintenance of stemness of mESC, revealing the dependence of stem cell behavior on droplet volume in nano‐ and microliter scale. The inhibition of spontaneous differentiation of mESCs cultured on the droplet microarray for up to 72 h is observed. In addition, up to fourfold increased cell growth rate of mESCs cultured on our platform has been observed. The difference in the behavior of mESCs is attributed to the porosity and roughness of the polymer surface. This work demonstrates that the droplet microarray possesses the potential for the screening of mESCs under conditions of prolonged inhibition of stem cells' spontaneous differentiation. Such a platform can be useful for applications in the field of stem cell research, pharmacological testing of drug efficacy and toxicity, biomedical research as well as in the field of regenerative medicine and tissue engineering.The demonstrated nanoporous poly(2‐hydroxyethyl methacrylate‐co‐ethylene dimethacrylate) polymer with defined surface roughness possesses dual functionality enabling the generation of a miniaturized array of multiple droplets on a superhydrophobic–hydrophilic micropattern (droplet microarray) and simultaneously promoting a prolonged inhibition of spontaneous differentiation of mouse embryonic stem cells (mESCs). This renders a miniaturized platform allowing screening of mESC while maintaining their undifferentiated state.
  • Development of Antifouling and Bactericidal Coatings for Platelet Storage
           Bags Using Dopamine Chemistry
    • Abstract: Platelets have a limited shelf life, due to the risk of bacterial contamination and platelet quality loss. Most platelet storage bags are made of a mixture of polyvinyl chloride with a plasticizer, denoted as pPVC. To improve biocompatibility of pPVC with platelets and to inhibit bacterial biofilm formation, an antifouling polymer coating is developed using mussel‐inspired chemistry. A copolymer of N,N‐dimethylacrylamide and N‐(3‐aminopropyl)methacrylamide hydrochloride is synthesized and coupled with catechol groups, named DA51‐cat. Under mild aqueous conditions, pPVC is first equilibrated with an anchoring polydopamine layer, followed by a DA51‐cat layer. Measurements show this coating decreases fibrinogen adsorption to 5% of the control surfaces. One‐step coating with DA51‐cat does not coat pPVC efficiently although it is sufficient for coating silicon wafers and gold substrates. The dual layer coating on platelet bags resists bacterial biofilm formation and considerably decreases platelet adhesion. A cationic antimicrobial peptide, E6, is conjugated to DA51‐cat then coated on silicon wafers and introduces bactericidal activity to these surfaces. Time‐of‐flight second ion‐mass spectroscopy is successfully applied to characterize these surfaces. pPVC is widely used in medical devices; this method provides an approach to controlling biofouling and bacterial growth on it without elaborate surface modification procedures.A facile two‐step coating of platelet storage bag material with polydopamine and DA51‐cat under mild aqueous conditions protects it against fibrinogen adsorption and platelet and bacterial adhesion. Addition of an antimicrobial peptide to DA51‐cat introduces bactericidal activity, demonstrating the potential of such an approach for improving platelet storage, one of the challenges in blood product transfusion.
  • Strategies for Optimizing the Soft Tissue Seal around Osseointegrated
    • Abstract: Percutaneous and permucosal devices such as catheters, infusion pumps, orthopedic, and dental implants are commonly used in medical treatments. However, these useful devices breach the soft tissue barrier that protects the body from the outer environment, and thus increase bacterial infections resulting in morbidity and mortality. Such associated infections can be prevented if these devices are effectively integrated with the surrounding soft tissue, and thus creating a strong seal from the surrounding environment. However, so far, there are no percutaneous/permucosal medical devices able to prevent infection by achieving strong integration at the soft tissue–device interface. This review gives an insight into the current status of research into soft tissue–implant interface and the challenges associated with these interfaces. Biological soft/hard tissue interfaces may provide insights toward engineering better soft tissue interfaces around percutaneous devices. In this review, focus is put on the history and current findings as well as recent progress of the strategies aiming to develop a strong soft tissue seal around osseointegrated implants, such as orthopedic and dental implants.Insight into the current status of research related to the integration of soft tissues around implants inserted through the human skin and gingiva is provided in this review. Moreover, this review discusses the current findings and recent progress of the strategies aiming to establish a strong soft tissue seal around osseointegrated implants, such as orthopedic and dental implants.
  • Preservation of Cell Structure, Metabolism, and Biotransformation Activity
           of Liver‐On‐Chip Organ Models by Hypothermic Storage
    • Abstract: The liver is a central organ in the metabolization of nutrition, endogenous and exogenous substances, and xenobiotic drugs. The emerging organ‐on‐chip technology has paved the way to model essential liver functions as well as certain aspects of liver disease in vitro in liver‐on‐chip models. However, a broader use of this technology in biomedical research is limited by a lack of protocols that enable the short‐term preservation of preassembled liver‐on‐chip models for stocking or delivery to researchers outside the bioengineering community. For the first time, this study tested the ability of hypothermic storage of liver‐on‐chip models to preserve cell viability, tissue morphology, metabolism and biotransformation activity. In a systematic study with different preservation solutions, liver‐on‐chip function can be preserved for up to 2 d using a derivative of the tissue preservation solution TiProtec, containing high chloride ion concentrations and the iron chelators LK614 and deferoxamine, supplemented with polyethylene glycol (PEG). Hypothermic storage in this solution represents a promising method to preserve liver‐on‐chip function for at least 2 d and allows an easier access to liver‐on‐chip technology and its versatile and flexible use in biomedical research.Liver‐on‐chip has paved the way to model individual organ functions and disease aspects in vitro. However, due to the lack of reliable protocols for short‐term preservation (i.e., for stocking or shipment) its broader use is still limited. This study describes the use of specifically designed storage solutions that fully preserve liver‐on‐chip function for at least 2 d during hypothermic storage.
  • Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other
           Pathogenic Viruses
    • Abstract: Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad‐spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure–activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad‐spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer‐based antivirals and represent promising candidates for further development as preventive microbicides.Broad spectrum antiviral agents are designed through systematic variation of the polymer composition, specifically the nature of the anionic charge of the polymer and hydrophobicity of the backbone. Structure–function relationship reveals unexpected lead candidates with inhibitory antiviral activity against all tested enveloped viruses.
  • Organ‐on‐a‐Chip Technology for Reproducing Multiorgan
    • Abstract: In the drug development process, the accurate prediction of drug efficacy and toxicity is important in order to reduce the cost, labor, and effort involved. For this purpose, conventional 2D cell culture models are used in the early phase of drug development. However, the differences between the in vitro and the in vivo systems have caused the failure of drugs in the later phase of the drug‐development process. Therefore, there is a need for a novel in vitro model system that can provide accurate information for evaluating the drug efficacy and toxicity through a closer recapitulation of the in vivo system. Recently, the idea of using microtechnology for mimicking the microscale tissue environment has become widespread, leading to the development of “organ‐on‐a‐chip.” Furthermore, the system is further developed for realizing a multiorgan model for mimicking interactions between multiple organs. These advancements are still ongoing and are aimed at ultimately developing “body‐on‐a‐chip” or “human‐on‐a‐chip” devices for predicting the response of the whole body. This review summarizes recently developed organ‐on‐a‐chip technologies, and their applications for reproducing multiorgan functions.Recent progresses in organ‐on‐a‐chip and multiorgan‐on‐a‐chip models are summarized in this review. The achievements in creating gut, liver, vascularized models, and multiorgan models are presented. The concepts of pharmacokinetics and pharmacodynamic modeling are introduced for designing and analyzing multiorgan systems. The future direction of the organ‐on‐a‐chip field and the existing challenges in improving the current models are discussed.
  • Enhanced EGFR Targeting Activity of Plasmonic Nanostructures with
           Engineered GE11 Peptide
    • Abstract: Plasmonic nanostructures show important properties for biotechnological applications, but they have to be guided on the target for exploiting their potentialities. Antibodies are the natural molecules for targeting. However, their possible adverse immunogenic activity and their cost have suggested finding other valid substitutes. Small molecules like peptides can be an alternative source of targeting agents, even if, as single molecules, their binding affinity is usually not very good. GE11 is a small dodecapeptide with specific binding to the epidermal growth factor receptor (EGFR) and low immunogenicity. The present work shows that thousands of polyethylene glycol (PEG) chains modified with lysines and functionalized with GE11 on clusters of naked gold nanoparticles, obtained by laser ablation in water, achieves a better targeting activity than that recorded with nanoparticles decorated with the specific anti‐EGFR antibody Cetuximab (C225). The insertion of the cationic spacer between the polymeric part of the ligand and the targeting peptide allows for a proper presentation of GE11 on the surface of the nanosystems. Surface enhanced resonance Raman scattering signals of the plasmonic gold nanoparticles are used for quantifying the targeting activity. Molecular dynamic calculations suggest that subtle differences in the exposition of the peptide on the PEG sea are important for the targeting activity.Cell targeting activity of nanostructures is of great importance for biotechnology applications. Functionalization with antibodies is a natural choice but they can show adverse immunogenic activities and their cost is usually very high. Here it is shown that, for epidermal growth factor receptor targeting, thousands of small peptides with engineered functionalization and organized on naked gold nanoparticles offer an alternative with higher sensitivity and specificity.
  • Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous
           Wound Healing
    • Abstract: The transformation of fibrotic healing process to regenerative one has great potential to fully restore wounded skin. The M2 macrophage phenotype promotes constructive tissue remodeling and instructs tissue repair in a regenerative manner. It is hypothesized that hydrogels that can establish robustness of endogenous cells to regulate M2 phenotype will promote constructive dermal remodeling. Toward this end, a series of dextran‐based bioabsorbable hydrogels are developed and self‐crosslinkable dextran‐isocyanatoethyl methacrylate‐ethylamine (DexIEME) is identified as the potential scaffold. The initial screening study revealed that DexIEME has superior biocompatibility in varying concentrations. Although DexIEME brings about low proinflammatory responses, it promotes M2 macrophage phenotype. Then the optimized hydrogel formulation is tested for acute skin injuries using both murine and porcine models. Preliminary data demonstrated that the innovative DexIEME hydrogel promotes complete skin regeneration with hair regrowth on pre‐existing scars, while untreated scars remain intact. Preclinical studies further demonstrated that the DexIEME hydrogel regenerated perfect skin during deep porcine wound healing. Overall, the approach to investigate immune‐modulated hydrogels yields pro‐regenerative DexIEME hydrogel, which may lead to greater clinical success in treating deep dermal injury and attenuating scar formation.Pro‐regenerative hydrogel scaffolds that can unlock the body's innate powers of regeneration restore complete skin structures on both pre‐existing scarred skin and deep full skin injuries by producing mature epithelial structures with hair follicles and glands.
  • Biomechanical Regulation of Mesenchymal Stem Cells for Cardiovascular
           Tissue Engineering
    • Abstract: Mesenchymal stem cells (MSCs) are an appealing potential therapy for vascular diseases; however, many challenges remain in their clinical translation. While the use of biochemical, pharmacological, and substrate‐mediated treatments to condition MSCs has been subjected to intense investigation, there has been far less exploration of using these treatments in combination with applied mechanical force for conditioning MSCs toward vascular phenotypes. This review summarizes the current understanding of the use of applied mechanical forces to differentiate MSCs into vascular cells and enhance their therapeutic potential for cardiovascular disease. First recent work on the use of material‐based mechanical cues for differentiation of MSCs into vascular and cardiovascular phenotypes is examined. Then a summary of the studies using mechanical stretch or shear stress in combination with biochemical treatments to enhance vascular phenotypes in MSCs is presented.Published work relating to the use of mechanical forces to condition mesenchymal stem cells into vascular phenotypes for therapeutic applications is examined in this review. The synergistic interactions of substrate compliance, nanopatterning, and biochemical treatments with applied mechanical stretch or fluidic shear stress on the vascular and cardiac differentiation of mesenchymal stem cells are examined.
  • Nonmineralized and Mineralized Collagen Scaffolds Induce Differential
           Osteogenic Signaling Pathways in Human Mesenchymal Stem Cells
    • Abstract: The instructive capabilities of extracellular matrix components in progenitor cell differentiation have recently generated significant interest in the development of bioinspired materials for regenerative applications. Previously, a correlation was described between the osteogenic capabilities of nanoparticulate mineralized collagen glycosaminoglycan scaffolds (MC‐GAG) and an autogenous activation of small mothers against decapentaplegic ( Smad1/5) in the canonical bone morphogenetic protein receptor (BMPR) pathway with a diminished extracellular signal regulated kinase 1/2 (ERK1/2) activation when compared to nonmineralized collagen glycosaminoglycan scaffolds (Col‐GAG). This work utilizes a canonical BMPR inhibitor (dorsomorphin homologue 1, DMH1) and an inhibitor of the mitogen activated protein kinase/ERK kinase (MEK)/(ERK) cascade (PD98059) to characterize the necessity of each pathway for osteogenesis. While DMH1 inhibits runt‐related transcription factor 2 (Runx2) and bone sialoprotein II (BSPII) gene expression of primary human mesenchymal stem cells (hMSCs) on MC‐GAG, PD98059 inhibits BSPII expression on Col‐GAG independent of Runx2 expression. DMH1 inhibits mineralization on both Col‐GAG and MC‐GAG, however, PD98059 only inhibits mineralization on Col‐GAG. DMH1 inhibits both Smad1/5 phosphorylation and Runx2 protein expression, whereas PD98059 inhibits ERK1/2 and c‐Jun amino‐terminal kinase 1/2 (JNK1/2) phosphorylation without affecting Runx2. Thus, activation of the canonical BMPR signaling is necessary for osteogenic differentiation and mineralization of hMSCs on Col‐GAG or MC‐GAG. The MEK/ERK cascade, intimately tied to JNK activation, is necessary for Runx2‐independent osteogenesis on Col‐GAG, while completely dispensable in osteogenesis on MC‐GAG.Extracellular matrix‐inspired materials have demonstrated promise in bone regeneration; however, the mechanistic interplay between materials and progenitor cells is incompletely understood. Using small molecule inhibitors, differential requirements are demonstrated between nanoparticulate mineralized (MC‐GAG) and nonmineralized (Col‐GAG) collagen glycosaminoglycan materials for the canonical and noncanonical bone morphogenetic protein receptor signaling pathway in osteogenesis of primary human mesenchymal stem cells.
  • Membrane Fusion Mediated Intracellular Delivery of Lipid Bilayer Coated
           Mesoporous Silica Nanoparticles
    • Abstract: Protein delivery into the cytosol of cells is a challenging topic in the field of nanomedicine, because cellular uptake and endosomal escape are typically inefficient, hampering clinical applications. In this contribution cuboidal mesoporous silica nanoparticles (MSNs) containing disk‐shaped cavities with a large pore diameter (10 nm) are studied as a protein delivery vehicle using cytochrome‐c (cytC) as a model membrane‐impermeable protein. To ensure colloidal stability, the MSNs are coated with a fusogenic lipid bilayer (LB) and cellular uptake is induced by a complementary pair of coiled‐coil (CC) lipopeptides. Coiled‐coil induced membrane fusion leads to the efficient cytosolic delivery of cytC and triggers apoptosis of cells. Delivery of these LB coated MSNs in the presence of various endocytosis inhibitors strongly suggests that membrane fusion is the dominant mechanism of cellular uptake. This method is potentially a universal way for the efficient delivery of any type of inorganic nanoparticle or protein into cells mediated by CC induced membrane fusion.Mesoporous silica nanoparticles (MSNs) are delivered into cells via membrane fusion thereby omitting endocytosis pathways. Fusion is induced by a pair of complementary coiled‐coil lipopeptides inserted into the membrane of cells and in the bilayer of lipid‐coated MSNs. In this manner proteins can be efficiently delivered into the cytoplasm of cells.
  • A Reloadable Self‐Healing Hydrogel Enabling Diffusive Transport of
           C‐Dots Across Gel–Gel Interface for Scavenging Reactive Oxygen Species
    • Abstract: While reloadable drug delivery platforms are highly prized for the treatment of a broad spectrum of diseases, the gel–gel interface between hydrogels hinders the intergel diffusive transport of drugs and thus limits the application of hydrogels as reloadable depots. Here, this study reports the circumvention of this barrier by employing a self‐healing hydrogel prepared from N‐carboxyethyl chitosan and sodium alginate dialdehyde, which are cross‐linked via a reversible Schiff base linkage. The injectable and bioadhesive hydrogel shows a rapid gelation time of 47 s. The dynamic self‐healing process enables the efficient diffusive transport of carbon quantum dots (C‐dots) into an adjacent hydrogel, and thus, the C‐dots can be used to scavenge reactive oxygen species from a remote inflammation site. Specifically, the diffusive transport of the C‐dots in the self‐healing hydrogel after three sequential reloading steps is sevenfold greater than that in the non‐self‐healing counterpart. In vivo, hematoxylin and eosin staining of the murine skin at the injection site shows no apparent symptoms of inflammation in the group treated with the reloadable self‐healing hydrogel. The current strategy represents a promising and straightforward route for the design of a reloadable drug delivery system for future use in clinical application.An injectable , bioadhesive, and self‐healing hydrogel is developed encapsulating fluorescent and antioxidant carbon quantum dots to scavenge the excess reactive oxygen species (ROS) and relieve the oxidative stress at local inflammation site. The self‐healing process enables intergel diffusive transport of carbon quantum dots and efficient dynamic removal of remote ROS both in vitro and in vivo.
  • An Advanced Multifunctional Hydrogel‐Based Dressing for Wound
           Monitoring and Drug Delivery
    • Abstract: Wound management is a major global challenge and poses a significant financial burden to the healthcare system due to the rapid growth of chronic diseases such as diabetes, obesity, and aging population. The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient patient care. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site. This study demonstrates the ability of GelDerm to detect bacterial infections using in vitro and ex vivo tests with accuracies comparable to the commercially available systems. Wireless interfaces to digital image capture hardware such as smartphones serve as a means for quantitation and enable the patient to record the wound condition at home and relay the information to the healthcare personnel for following treatment strategies. Additionally, the dressing is integrated within commercially available patches and can be placed on the wound without chemical or physical irritation. This study demonstrates the ability of GelDerm to eradicate bacteria by the sustained release of antibiotics. The proposed technology holds great promise in managing chronic and acute injuries caused by trauma, surgery, or diabetes.The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient wound management. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site.
  • Fabrication of Calcium Phosphate‐Based Nanocomposites Incorporating DNA
           Origami, Gold Nanorods, and Anticancer Drugs for Biomedical Applications
    • Abstract: DNA origami is designed by folding DNA strands at the nanoscale with arbitrary control. Due to its inherent biological nature, DNA origami is used in drug delivery for enhancement of synergism and multidrug resistance inhibition, cancer diagnosis, and many other biomedical applications, where it shows great potential. However, the inherent instability and low payload capacity of DNA origami restrict its biomedical applications. Here, this paper reports the fabrication of an advanced biocompatible nano‐in‐nanocomposite, which protects DNA origami from degradation and facilities drug loading. The DNA origami, gold nanorods, and molecular targeted drugs are co‐incorporated into pH responsive calcium phosphate [Ca3(PO4)2] nanoparticles. Subsequently, a thin layer of phospholipid is coated onto the Ca3(PO4)2 nanoparticle to offer better biocompatibility. The fabricated nanocomposite shows high drug loading capacity, good biocompatibility, and a photothermal and pH‐responsive payload release profile and it fully protects DNA origami from degradation. The codelivery of DNA origami with cancer drugs synergistically induces cancer cell apoptosis, reduces the multidrug resistance, and enhances the targeted killing efficiency toward human epidermal growth factor receptor 2 positive cells. This nanocomposite is foreseen to open new horizons for a variety of clinical and biomedical applications.A biocompatible photothermal and pH dual responsive nano‐in‐nanocomposite is developed to both protect DNA origami from degradation and facilitate loading of therapeutics. The DNA origami, gold nanorods, and anticancer drugs are co‐incorporated into calcium phosphate nanoparticles coated with a thin layer of phospholipid. The nanocomposites synergistically induce cancer cell apoptosis and reduce the multidrug resistance for potential clinical and biomedical applications.
  • The Influence of Hyaluronic Acid and Glioblastoma Cell Coculture on the
           Formation of Endothelial Cell Networks in Gelatin Hydrogels
    • Abstract: Glioblastoma (GBM) is the most common and deadly form of brain cancer. Interactions between GBM cells and vasculature in vivo contribute to poor clinical outcomes, with GBM‐induced vessel co‐option, regression, and subsequent angiogenesis strongly influencing GBM invasion. Here, elements of the GBM perivascular niche are incorporated into a methacrylamide‐functionalized gelatin hydrogel as a means to examine GBM–vessel interactions. The complexity of 3D endothelial cell networks formed from human umbilical vein endothelial cells and normal human lung fibroblasts as a function of hydrogel properties and vascular endothelial growth factor (VEGF) presentation is presented. While overall length and branching of the endothelial cell networks decrease with increasing hydrogel stiffness and incorporation of brain‐mimetic hyaluronic acid, it can be separately altered by changing the vascular cell seeding density. It is shown that covalent incorporation of VEGF supports network formation as robustly as continuously available soluble VEGF. The impact of U87‐MG GBM cells on the endothelial cell networks is subsequently investigated. GBM cells localize in proximity to the endothelial cell networks and hasten network regression in vitro. Together, this in vitro platform recapitulates the close association between GBM cells and vessel structures as well as elements of vessel co‐option and regression preceding angiogenesis in vivo.The glioblastoma perivascular niche is incorporated into a gelatin hydrogel via coculture of endothelial, stromal, and glioblastoma cells. Endothelial network complexity can be manipulated through hydrogel stiffness and covalent immobilization of brain‐mimetic hyaluronic acid and vascular endothelial growth factor into the hydrogel network. Glioblastoma cells associate closely with endothelial cell networks and promote processes similar to vessel co‐option and regression seen in vivo.
  • Co‐Delivery of Drugs and Genes Using Polymeric Nanoparticles for
           Synergistic Cancer Therapeutic Effects
    • Abstract: Drug and gene delivery systems based on nanoparticles, microparticles and hydrogels have been widely studied for cancer treatment in the past decade. To achieve an efficient and safe delivery, selection of drug and gene delivery carrier is critical. Biocompatible polymeric nanoparticles are considerably promising carrier candidates in delivery of drugs and genes because of their unique chemical and physical properties. However, delivery of a drug or gene sometimes cannot achieve a satisfactory treatment effect. Therefore, co‐delivery of dual drugs or co‐delivery of a drug and a gene in a polymeric nanoparticle has attracted attention. Such co‐delivery systems can overcome multi‐drug resistance of chemical drugs and achieve a synergistic therapeutic effect. In this progress report, we summarize recent progress in the preparation and application of polymeric drug and gene co‐delivery nanosystems. The remaining challenges and future trends in this field are also included.Polymeric nanoparticles‐mediated combination therapy is an effective strategy in cancer treatment. Co‐delivery of dual drugs or drug/gene can enhance anti‐cancer efficacy due to a synergistic effect. Moreover, polymeric nanocarriers can improve biodistribution of the therapeutics as well as release them at target sites. In this Progress Report, recent progresses in preparation and application of polymeric drug and gene co‐delivery nanosystems are summarized.
  • Nanomaterials in the Prevention, Diagnosis, and Treatment of Mycobacterium
           Tuberculosis Infections
    • Abstract: Despite the tremendous advancements that have been made in biomedical research, Mycobacterium tuberculosis (TB) still remains one of the top 10 causes of death worldwide, outpacing the Human Immunodeficiency Virus as a leading cause of death from an infectious disease. In the light of such significant disease burden, tremendous efforts have been made worldwide to stem this burgeoning spread of disease. The use of nanomaterials in TB management has increased in the past decade, particularly in the areas of early TB detection, prevention, and treatment. Nanomaterials have been proven to be efficacious in the rapid and accurate detection of TB pathogens. Novel nanocarriers have also shown tremendous promise in improving drug delivery, potentially enhancing drug concentrations in target organs while at the same time, reducing treatment frequency. In addition, the engineering of antigen nanocarriers represents an exciting front in TB research, potentially paving the way for the successful development of a new class of effective TB vaccines. This article discusses epidemiology and pathogenesis of TB infections, current TB therapeutics, advanced nanomaterials for anti‐TB drug delivery, and TB vaccines. In addition, challenges and future perspectives in developing safe and effective nanomaterials in TB diagnosis and therapy are also presented.The use of nanomaterials in mycobacterium tuberculosis (TB) detection, treatment, and prevention has made significant progress in the past decade. This review discusses nanomaterials for rapid and accurate detection of TB pathogens, nanocarriers for enhancing anti‐TB drug concentrations in target organs, and antigen nanocarriers as effective TB vaccine adjuvants.
  • Coordination‐Accelerated “Iron Extraction” Enables Fast
           Biodegradation of Mesoporous Silica‐Based Hollow Nanoparticles
    • Abstract: Biodegradation behavior of inorganic silica‐based nanoplatforms is of critical importance in their clinical translations, but still remains a great challenge in achieving this goal by composition regulation of biocompatible silica framework. In the present work, a chemical coordination‐accelerated biodegradation strategy to endow hollow mesoporous silica nanoparticles (HMSNs) with unique coordination‐responsive biodegradability, on‐demand coordination‐responsive drug releasing behavior, and significantly enhanced chemotherapeutic efficacy by directly doping iron (Fe) ions into the framework of mesoporous silica is reported. A simple but versatile dissolution‐regrowth strategy has been developed to enable the framework Fe doping via chemical bonding. The deferiprone‐mediated biodegradation of Fe‐doped HMSNs (Fe‐HMSNs) has been comprehensively evaluated both in simulated body fluid and intracellular level, which have exhibited a specific coordination‐accelerated biodegradation behavior. In addition to high biocompatibility of Fe‐HMSNs, the anticancer drug doxorubicin (DOX)‐loaded Fe‐HMSNs show enhanced tumor‐suppressing effect on 4T1 mammary cancer xenograft. This work paves a new way for tuning the biodegradation performance of mesoporous silica‐based nanoplatforms simply by biocompatible Fe‐ion doping into silica framework based on the specific coordination property between introduced metal Fe ions with Fe‐coordination proteins.Coordination‐accelerated biodegradation strategy: A chemical coordination‐accelerated biodegradation strategy is illustrated to endow hollow mesoporous silica nanoparticles with proteinous coordination‐responsive biodegradability (via “iron extraction”), on‐demand coordination‐responsive drug releasing behavior, and significantly enhanced chemotherapeutic efficacy by directly doping iron (Fe) ions into the framework of mesoporous silica.
  • Biodegradable Shape Memory Polymers in Medicine
    • Abstract: Shape memory materials have emerged as an important class of materials in medicine due to their ability to change shape in response to a specific stimulus, enabling the simplification of medical procedures, use of minimally invasive techniques, and access to new treatment modalities. Shape memory polymers, in particular, are well suited for such applications given their excellent shape memory performance, tunable materials properties, minimal toxicity, and potential for biodegradation and resorption. This review provides an overview of biodegradable shape memory polymers that have been used in medical applications. The majority of biodegradable shape memory polymers are based on thermally responsive polyesters or polymers that contain hydrolyzable ester linkages. These materials have been targeted for use in applications pertaining to embolization, drug delivery, stents, tissue engineering, and wound closure. The development of biodegradable shape memory polymers with unique properties or responsiveness to novel stimuli has the potential to facilitate the optimization and development of new medical applications.Biodegradable shape memory polymers represent an important class of materials in medicine. The ability of materials to change shape in response to specific stimuli enables the simplification of medical procedures, use of minimally invasive techniques, and access to new treatment modalities. This Review provides an overview of available biodegradable shape memory polymers and their use in medical applications.
  • Accelerated Wound Healing on Skin by Electrical Stimulation with a
           Bioelectric Plaster
    • Abstract: Wound healing on skin involves cell migration and proliferation in response to endogenous electric current. External electrical stimulation by electrical equipment is used to promote these biological processes for the treatment of chronic wounds and ulcers. Miniaturization of the electrical stimulation device for wound healing on skin will make this technology more widely available. Using flexible enzymatic electrodes and stretchable hydrogel, a stretchable bioelectric plaster is fabricated with a built‐in enzymatic biofuel cell (EBFC) that fits to skin and generates ionic current along the surface of the skin by enzymatic electrochemical reactions for more than 12 h. To investigate the efficacy of the fabricated bioelectric plaster, an artificial wound is made on the back skin of a live mouse and the wound healing is observed for 7 d in the presence and absence of the ionic current of the bioelectric plaster. The time course of the wound size as well as the hematoxylin and eosin staining of the skin section reveals that the ionic current of the plaster leads to faster and smoother wound healing. The present work demonstrates a proof of concept for the electrical manipulation of biological functions by EBFCs.Wound healing on skin is accelerated by a plaster device with a built‐in enzymatic biofuel cell that drives ionic current on the wound. Cells in the skin respond to electric current during wound healing processes. A stretchable bioelectric plaster fits to skin and generates ionic current on the wound by enzymatic electrochemical reactions to promote these processes.
  • Controlling Differentiation of Stem Cells for Developing Personalized
           Organ‐on‐Chip Platforms
    • Abstract: Organ‐on‐chip (OOC) platforms have attracted attentions of pharmaceutical companies as powerful tools for screening of existing drugs and development of new drug candidates. OOCs have primarily used human cell lines or primary cells to develop biomimetic tissue models. However, the ability of human stem cells in unlimited self‐renewal and differentiation into multiple lineages has made them attractive for OOCs. The microfluidic technology has enabled precise control of stem cell differentiation using soluble factors, biophysical cues, and electromagnetic signals. This study discusses different tissue‐ and organ‐on‐chip platforms (i.e., skin, brain, blood–brain barrier, bone marrow, heart, liver, lung, tumor, and vascular), with an emphasis on the critical role of stem cells in the synthesis of complex tissues. This study further recaps the design, fabrication, high‐throughput performance, and improved functionality of stem‐cell‐based OOCs, technical challenges, obstacles against implementing their potential applications, and future perspectives related to different experimental platforms.Stem‐cell‐based organ‐on‐chips (OOCs) are powerful platforms for drug screening and development. This study discusses different OOCs (e.g., brain, liver, heart, tumor, and lung) with the emphasis on the critical role of stem cells. This further recaps the design, improved functionality, high‐throughput performance, technical challenges, and future perspectives of stem‐cell‐based OOCs.
  • Tailored Approaches in Drug Development and Diagnostics: From Molecular
           Design to Biological Model Systems
    • Abstract: Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer‐aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century.Recent advances and concepts in novel materials and technologies for drug delivery and diagnostics, illustrating how the convergence of biological, pharmaceutical, and medical disciplines is needed to meet the medical challenges of the 21st century, are covered in this review.
  • Glycan Stimulation Enables Purification of Prostate Cancer Circulating
           Tumor Cells on PEDOT NanoVelcro Chips for RNA Biomarker Detection
    • Abstract: A glycan‐stimulated and poly(3,4‐ethylene‐dioxythiophene)s (PEDOT)‐based nanomaterial platform is fabricated to purify circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This new platform, phenylboronic acid (PBA)‐grafted PEDOT NanoVelcro, combines the 3D PEDOT nanosubstrate, which greatly enhances CTC capturing efficiency, with a poly(EDOT‐PBA‐co‐EDOT‐EG3) interfacial layer, which not only provides high specificity for CTC capture upon antibody conjugation but also enables competitive binding of sorbitol to gently release the captured cells. CTCs purified by this PEDOT NanoVelcro chip provide well‐preserved RNA transcripts for the analysis of the expression level of several PCa‐specific RNA biomarkers, which may provide clinical insights into the disease.A glycan‐stimulated and poly(3,4‐ethylene‐dioxythiophene) (PEDOT)‐based nanomaterial platform is fabricated to purify circulating tumor cells. This PEDOT NanoVelcro chip not only provides highly efficient and specific capture of cancer cells but also enables competitive binding of glycan with higher affinity (i.e., sorbitol) to release them. Cancer cells purified are further utilized to correlate disease‐related RNA biomarkers in prostate cancer patients.
  • Fabrication of Trabecular Bone‐Templated Tissue‐Engineered Constructs
           by 3D Inkjet Printing
    • Abstract: 3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient‐specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the
  • Biomimetic Artificial Basilar Membranes for Next‐Generation Cochlear
    • Abstract: Patients with sensorineural hearing loss can recover their hearing using a cochlear implant (CI). However, there is a need to develop next‐generation CIs to overcome the limitations of conventional CIs caused by extracorporeal devices. Recently, artificial basilar membranes (ABMs) are actively studied for next‐generation CIs. The ABM is an acoustic transducer that mimics the mechanical frequency selectivity of the BM and acoustic‐to‐electrical energy conversion of hair cells. This paper presents recent progress in biomimetic ABMs. First, the characteristics of frequency selectivity of the ABMs by the trapezoidal membrane and beam array are addressed. Second, to reflect the latest research of energy conversion technologies, ABMs using various piezoelectric materials and triboelectric‐based ABMs are discussed. Third, in vivo evaluations of the ABMs in animal models are discussed according to the target position for implantation. Finally, future perspectives of ABM studies for the development of practical hearing devices are discussed.Artificial basilar membrane (ABM) is an acoustic transducer that mimics cochlear tonotopy. This Progress Report provides a brief review of the ABMs for next‐generation cochlear implants. The scope includes tonotopic characteristics of the ABM, in vivo experiments using animal models, and future perspectives of the ABM for next‐generation cochlear implants.
  • 3D Miniaturization of Human Organs for Drug Discovery
    • Abstract: “Engineered human organs” hold promises for predicting the effectiveness and accuracy of drug responses while reducing cost, time, and failure rates in clinical trials. Multiorgan human models utilize many aspects of currently available technologies including self‐organized spherical 3D human organoids, microfabricated 3D human organ chips, and 3D bioprinted human organ constructs to mimic key structural and functional properties of human organs. They enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues. Thus, engineered human organs can provide the microstructures and biological functions of target organs and advantageously substitute multiscaled drug‐testing platforms including the current in vitro molecular assays, cell platforms, and in vivo models. This review provides an overview of advanced innovative designs based on the three main technologies used for organ construction leading to single and multiorgan systems useable for drug development. Current technological challenges and future perspectives are also discussed.“Engineered human organs” hold promises for predicting the effectiveness and accuracy of human drug responses with reduced cost and improved success in clinical trials. This review provides an overview of the three major technologies for organ construction, and recent successful examples of single and multiorgan systems usable for drug development. Furthermore, current technological challenges and future perspectives are discussed.
  • Field‐Effect Biosensors for On‐Site Detection: Recent Advances
           and Promising Targets
    • Abstract: There is an explosive interest in the immediate and cost‐effective analysis of field‐collected biological samples, as many advanced biodetection tools are highly sensitive, yet immobile. On‐site biosensors are portable and convenient sensors that provide detection results at the point of care. They are designed to secure precision in highly ionic and heterogeneous solutions with minimal hardware. Among various methods that are capable of such analysis, field‐effect biosensors are promising candidates due to their unique sensitivity, manufacturing scalability, and integrability with computational circuitry. Recent developments in nanotechnological surface modification show promising results in sensing from blood, serum, and urine. This report gives a particular emphasis on the on‐site efficacy of recently published field‐effect biosensors, specifically, detection limits in physiological solutions, response times, and scalability. The survey of the properties and existing detection methods of four promising biotargets, exosomes, bacteria, viruses, and metabolites, aims at providing a roadmap for future field‐effect and other on‐site biosensors.On‐site biosensors offer great promise in immediate and cost‐effective analysis of field samples compared to immobile biosensors. Field‐effect biosensors are promising candidates due to their unique sensitivity, manufacturing scalability, and integrability with computational circuitry. This report summarizes the challenges for on‐site detection, current literature on field‐effect biosensors, and attractive targets for future on‐site biosensors.
  • Thermosensitive Hydrogel Containing Doxycycline Exerts Inhibitory Effects
           on Abdominal Aortic Aneurysm Induced By Pancreatic Elastase in Mice
    • Abstract: Doxycycline (DOX) is reported to exert therapeutic effects against abdominal aortic aneurysm (AAA), a severe degenerative disease. In this study, a DOX hydrogel formulation of DOX/PECTgel is studied, and its phase transition behavior and in vitro release profiles are explored. In addition, the anti‐AAA effects and bioavailability of DOX/PECTgel are evaluated in an elastase induced AAA mouse model. The results show that the phase transition temperature of 30% poly(e‐caprolactone‐co‐1,4,8‐trioxa[4.6]spiro‐9‐undecanone) (PECT) solution is above 34 °C. In vitro release profiles of DOX/PECTgel indicate a fast release of DOX at the first two days, followed by a slow and sustained release for 14 d. In vivo single‐dose single subcutaneous injection of DOX/PECTgel containing 8.4 or 4.2 mg mL−1 DOX presents comparatively preventive effects on AAA, compared to intraperitoneal injections of DOX alone at a dose of 15 mg kg−1 for seven injections, while DOX bioavailability of the DOX/PECTgel treated groups is 1.39 times or 1.19 times of the DOX alone treated group, respectively.A sustained release formulation of doxycycline (DOX) is prepared based on poly(e‐caprolactone‐co‐1,4,8‐trioxa[4.6]spiro‐9‐undecanone) (PECT) hydrogel (DOX/PECTgel). DOX release from the DOX/PECTgel is dose‐dependent and can last for 14 d. One single s.c. injection of the DOX/PECTgel exhibits significant anti‐abdominal aortic aneurysm effects, which is as efficient as seven i.p. injections of DOX alone at an equal dose.
  • An Inexpensive, Point‐of‐Care Urine Test for Bladder Cancer in
           Patients Undergoing Hematuria Evaluation
    • Abstract: Although hematuria (blood in urine) is the most common symptom of bladder cancer, 70–98% of hematuria cases are benign. These hematuria patients unnecessarily undergo costly, invasive, and expensive evaluation for bladder cancer. Therefore, there remains a need for noninvasive office‐based tests that can rapidly and reliably rule out bladder cancer in patients undergoing hematuria evaluation. Herein, a clinical assay for matrix metalloproteinases (“Ammps”) is presented, which generates a visual signal based on the collagenase activity (in urine of patients) on the Ammps substrates. Ammps substrates are generated by crosslinking gelatin with Fe(II) chelated alginate nanoparticles, which precipitate in urine samples. The cleavage of gelatin‐conjugated alginate (Fe(II)) nanoparticles by collagenases generates free‐floating alginate (Fe(II)) nanoparticles that participate in Fenton's reaction to generate a visual signal. In a pilot study of 88 patients, Ammps had 100% sensitivity, 85% specificity, and a negative predictive value (NPV) of 100% for diagnosing bladder cancer. This high NPV can be useful in ruling out bladder cancer in patients referred for hematuria evaluation.In this work, a novel point‐of‐care urine test for detection of bladder cancer that is low cost (5.5 cents/test), ultrasensitive, provides high negative predictive value (100%, in a pilot study of 88 patients), and aims to improve detection/monitoring for bladder cancer by decreasing costs and possibly reducing the number of necessary invasive procedures (i.e. cystoscopies) is presented for the first time.
  • Biomimicry, Biofabrication, and Biohybrid Systems: The Emergence and
           Evolution of Biological Design
    • Abstract: The discipline of biological design has a relatively short history, but has undergone very rapid expansion and development over that time. This Progress Report outlines the evolution of this field from biomimicry to biofabrication to biohybrid systems’ design, showcasing how each subfield incorporates bioinspired dynamic adaptation into engineered systems. Ethical implications of biological design are discussed, with an emphasis on establishing responsible practices for engineering non‐natural or hypernatural functional behaviors in biohybrid systems. This report concludes with recommendations for implementing biological design into educational curricula, ensuring effective and responsible practices for the next generation of engineers and scientists.Dynamic problems require adaptive solutions. This Progress Report outlines the development of adaptive biomimetic and biohybrid systems for targeting engineering grand challenges, as well as the microfabrication and biofabrication technologies that have enabled these advances. In this report, the authors discuss the ethics of biological forward design, and propose educational practices that could enable future progress in this field.
  • In Vitro Microfluidic Models for Neurodegenerative Disorders
    • Abstract: Microfluidic devices enable novel means of emulating neurodegenerative disease pathophysiology in vitro. These organ‐on‐a‐chip systems can potentially reduce animal testing and substitute (or augment) simple 2D culture systems. Reconstituting critical features of neurodegenerative diseases in a biomimetic system using microfluidics can thereby accelerate drug discovery and improve our understanding of the mechanisms of several currently incurable diseases. This review describes latest advances in modeling neurodegenerative diseases in the central nervous system and the peripheral nervous system. First, this study summarizes fundamental advantages of microfluidic devices in the creation of compartmentalized cell culture microenvironments for the co‐culture of neurons, glial cells, endothelial cells, and skeletal muscle cells and in their recapitulation of spatiotemporal chemical gradients and mechanical microenvironments. Then, this reviews neurodegenerative‐disease‐on‐a‐chip models focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Finally, this study discusses about current drawbacks of these models and strategies that may overcome them. These organ‐on‐chip technologies can be useful to be the first line of testing line in drug development and toxicology studies, which can contribute significantly to minimize the phase of animal testing steps.Neurodegenerative disease‐on‐a‐chip models and their limitations are described. Strategies and advanced methods to overcome current limitations are reviewed along with applications to drug development and toxicology. Studies that combine microfluidic systems with patient‐derived induced pluripotent stem cells are also discussed along with their potential to uncover novel biological mechanisms of currently incurable neurodegenerative diseases.
  • Densification of Type I Collagen Matrices as a Model for Cardiac Fibrosis
    • Abstract: Cardiac fibrosis is a disease state characterized by excessive collagenous matrix accumulation within the myocardium that can lead to ventricular dilation and systolic failure. Current treatment options are severely lacking due in part to the poor understanding of the complexity of molecular pathways involved in cardiac fibrosis. To close this gap, in vitro model systems that recapitulate the defining features of the fibrotic cellular environment are in need. Type I collagen, a major cardiac extracellular matrix protein and the defining component of fibrotic depositions, is an attractive choice for a fibrosis model, but demonstrates poor mechanical strength due to solubility limits. However, plastic compression of collagen matrices is shown to significantly increase its mechanical properties. Here, confined compression of oligomeric, type I collagen matrices is utilized to resemble defining hallmarks seen in fibrotic tissue such as increased collagen content, fibril thickness, and bulk compressive modulus. Cardiomyocytes seeded on compressed matrices show a strong beating abrogation as observed in cardiac fibrosis. Gene expression analysis of selected fibrosis markers indicates fibrotic activation and cardiomyocyte maturation with regard to the existing literature. With these results, a promising first step toward a facile heart‐on‐chip model is presented to study cardiac fibrosis.New collagen matrices are fabricated that are densified to mimic excess matrix accumulation observed in cardiac fibrosis. The densification process also allows for the easy seeding of cells, leading to strong beating abrogation of cardiomyocytes, and fibrotic activation. It is anticipated that this densification process presents a promising first step toward a facile heart‐on‐chip model to study cardiac fibrosis.
  • Injectable Mussel‐Inspired Immobilization of Platelet‐Rich Plasma on
           Microspheres Bridging Adipose Micro‐Tissues to Improve Autologous Fat
           Transplantation by Controlling Release of PDGF and VEGF, Angiogenesis,
           Stem Cell Migration
    • Abstract: Platelets‐rich plasma (PRP) can produce growth factors (GFs) to improve angiogenesis. However, direct injection of PRP does not lead to highly localized GFs. The current study employs a mussel‐inspired polydopamine to immobilize PRP on gelatin microspheres (GMs) with the purpose of bridging adipose micro‐tissues to help implanted fat survive (GM‐pDA‐PRP). Enhanced PRP adhesion leads to a prolonged and localized production of GFs, which is verified by platelet counting and by ELISA of vascular endothelial growth factors (VEGFs) and of platelet derived growth factors (PDGFs). The GM‐pDA‐PRP “hatches” a microenvironment for the proliferation of adipose‐derived stem cells. After the adipose micro‐tissue has bridged with GM‐pDA‐PRP after 16 weeks, triple‐fluorescence staining reveals that the mature adipocytes, blood vessels, and capillaries are arranged like in normal adipose tissue. The survival fat increases significantly compared to that in control, PRP, and GM‐PRP groups (84.8 ± 11.4% versus 47.8 ± 8.9%, 56.9 ± 9.7%, and 60.2 ± 10.5%, respectively). Both histological assessments and CD31 immunofluorescence indicate that the improvement of angiogenesis in GM‐pDA‐PRP is higher than in the fat graft group (6.4‐fold in quantitative CD31 positive cells). The CD34 positive cells in the GM‐pDA‐PRP group are around 3.5‐fold the amount in the fat graft group, which suggests that more stem cells migrate to the implant area. Cell proliferation staining shows that the number of Ki67 positive cells is around five times as high as that in the fat graft group.A facile strategy to immobilize platelets‐rich plasma (PRP) on gelatin microspheres is achieved with mussel‐inspired polydopamine adhesion. This reinforced platelets adhesion and release system leads to a prolonged and localized production of growth factors, and hatches a microenvironment for chemotaxis and proliferation of adipose‐derived stem cells. The PRP improves angiogenesis and enhances the final autologous fat transplantation survival.
  • Three-Dimensional Models of the Human Brain Development and Diseases
    • Abstract: Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21st century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer's disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases.Neurological disorders represent a significant proportion of human diseases; however, understanding brain pathology is challenging, in part because of the complexity of the brain structure and function. Sophisticated models are required to reconstitute the tangled architecture and complex functions of brain cells. Here we review the most recent advances, chalenges, and future directions of 3D cell culture systems for modeling the human brain.
  • Introduction of Nature's Complexity in Engineered Blood-compatible
    • Abstract: Biomaterials with excellent blood-compatibility are needed for applications in vascular replacement therapies, such as vascular grafts, heart valves and stents, and in extracorporeal devices such as hemodialysis machines and blood-storage bags. The modification of materials that are being used for blood-contacting devices has advanced from passive surface modifications to the design of more complex, smart biomaterials that respond to relevant stimuli from blood to counteract coagulation. Logically, the main source of inspiration for the design of new biomaterials has been the endogenous endothelium. Endothelial regulation of hemostasis is complex and involves a delicate interplay of structural components and feedback mechanisms. Thus, challenges to develop new strategies for blood-compatible biomaterials now lie in incorporating true feedback controlled mechanisms that can regulate blood compatibility in a dynamic way. Here, supramolecular material systems are highlighted as they provide a promising platform to introduce dynamic reciprocity, due to their inherent dynamic nature.Blood-compatible biomaterial development moves towards complex and smart biomaterials that are able to respond to and influence stimuli in a similar fashion as nature's blood-contacting surfaces. Here, the progress from passive surface modifications to functionalization with feedback controlled systems that can regulate blood compatibility in a dynamic way is highlighted, with a special interest for strategies based on supramolecular chemistry.
  • Synthetic Biomaterials to Rival Nature's Complexity—a Path Forward with
           Combinatorics, High-Throughput Discovery, and High-Content Analysis
    • Abstract: Cells in tissue receive a host of soluble and insoluble signals in a context-dependent fashion, where integration of these cues through a complex network of signal transduction cascades will define a particular outcome. Biomaterials scientists and engineers are tasked with designing materials that can at least partially recreate this complex signaling milieu towards new materials for biomedical applications. In this progress report, recent advances in high throughput techniques and high content imaging approaches that are facilitating the discovery of efficacious biomaterials are described. From microarrays of synthetic polymers, peptides and full-length proteins, to designer cell culture systems that present multiple biophysical and biochemical cues in tandem, it is discussed how the integration of combinatorics with high content imaging and analysis is essential to extracting biologically meaningful information from large scale cellular screens to inform the design of next generation biomaterials.Recent advances in biomaterials discovery aided by combinatorics, high-throughput arraying, and high content analysis are discussed. Synthetic polymer libraries, extracellular matrix protein and peptide microarrays are explored, and new tools for multivariate systems that are guiding the development of 3D model tissues towards next-generation assays for biomedicine and biotechnology are discussed.
  • Cholera Toxin Subunit B Enabled Multifunctional Glioma-Targeted Drug
    • Abstract: Glioma is among the most formidable brain cancers due to location in the brain. Cholera toxin subunit B (CTB) is investigated to facilitate multifunctional glioma-targeted drug delivery by targeting the glycosphingolipid GM1 expressed in the blood–brain barrier (BBB), neovasulature, and glioma cells. When modified on the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CTB-NPs), CTB fully retains its bioactivity after 24 h incubation in the fresh mouse plasma. The formed protein corona (PC) of CTB-NP and plain PLGA nanoparticles (NP) after incubation in plasma is analyzed using liquid chromatography tandem massspectrometry (nano-LC-MS/MS). CTB modification does not alter the protein components of the formed PC, macrophage phagocytosis, or pharmacokinetic profiles. CTB-NP can efficiently penetrate the in vitro BBB model and target glioma cells and human umbilical vascular endothelial cells. Paclitaxel is loaded in NP (NP/PTX) and CTB-NP (CTB-NP/PTX), and their antiglioma effects are assessed in nude mice bearing intracranial glioma. CTB-NP/PTX can efficiently induce apoptosis of intracranial glioma cells and ablate neovasulature in vivo, resulting in significant prolongation of survival of nude mice bearing intracranial glioma (34 d) in comparison to those treated with NP/PTX (29 d), Taxol (24 d), and saline (21 d). The present study suggests a potential multifunctional glioma-targeted drug delivery system enabled by cholera toxin subunit B.Cholera toxin subunit B (CTB), the nontoxic moiety of cholera toxin, is able to circumvent the blood–brain barrier, and to target neovasculature and glioma cells. CTB modification on the surface of polymeric nanoparticles does not significantly alter components of the formed protein corona. CTB retains bioactivity during blood circulation, presenting a promising ligand for multifunctional targeting of glioma.
  • Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic
    • Abstract: A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing.This paper combines pharmacokinetic models of glucose–insulin metabolism with mathematical models of glucose-responsive insulins to explore the effective parameter space of these new types of therapeutics. The model reveals that there is a range of parameter values that can maintain glycemic control over a 24 h period, from a single bolus over a wide range of conditions.
  • Particle Targeting in Complex Biological Media
    • Abstract: Over the past few decades, nanoengineered particles have gained increasing interest for applications in the biomedical realm, including diagnosis, imaging, and therapy. When functionalized with targeting ligands, these particles have the potential to interact with specific cells and tissues, and accumulate at desired target sites, reducing side effects and improve overall efficacy in applications such as vaccination and drug delivery. However, when targeted particles enter a complex biological environment, the adsorption of biomolecules and the formation of a surface coating (e.g., a protein corona) changes the properties of the carriers and can render their behavior unpredictable. For this reason, it is of importance to consider the potential challenges imposed by the biological environment at the early stages of particle design. This review describes parameters that affect the targeting ability of particulate drug carriers, with an emphasis on the effect of the protein corona. We highlight strategies for exploiting the protein corona to improve the targeting ability of particles. Finally, we provide suggestions for complementing current in vitro assays used for the evaluation of targeting and carrier efficacy with new and emerging techniques (e.g., 3D models and flow-based technologies) to advance fundamental understanding in bio-nano science and to accelerate the development of targeted particles for biomedical applications.Nanoengineered particles are gaining increasing interest for applications in the biomedical realm. However, the behavior of targeted particles in complex biological environments is still poorly understood. In this Review, Dai et al. discuss parameters that affect the biological performance of particles and highlight strategies for how the targeting ability of particles can be improved.
  • 3D Bioprinting for Cartilage and Osteochondral Tissue Engineering
    • Abstract: Significant progress has been made in the field of cartilage and bone tissue engineering over the last two decades. As a result, there is real promise that strategies to regenerate rather than replace damaged or diseased bones and joints will one day reach the clinic however, a number of major challenges must still be addressed before this becomes a reality. These include vascularization in the context of large bone defect repair, engineering complex gradients for bone-soft tissue interface regeneration and recapitulating the stratified zonal architecture present in many adult tissues such as articular cartilage. Tissue engineered constructs typically lack such spatial complexity in cell types and tissue organization, which may explain their relatively limited success to date. This has led to increased interest in bioprinting technologies in the field of musculoskeletal tissue engineering. The additive, layer by layer nature of such biofabrication strategies makes it possible to generate zonal distributions of cells, matrix and bioactive cues in 3D. The adoption of biofabrication technology in musculoskeletal tissue engineering may therefore make it possible to produce the next generation of biological implants capable of treating a range of conditions. Here, advances in bioprinting for cartilage and osteochondral tissue engineering are reviewed.In this paper, advances in 3D bioprinting for articular cartilage and osteochondral tissue engineering are reviewed. An overview of the field and a description of the current state of the art are provided for the first time. Then, future research directions are discussed and a description of how emerging bioprinting strategies could be used to engineer functional implants for joint regeneration is given.
  • Electroenhanced Antimicrobial Coating Based on Conjugated Polymers with
           Covalently Coupled Silver Nanoparticles Prevents Staphylococcus aureus
           Biofilm Formation
    • Abstract: The incidence of hospital-acquired infections is to a large extent due to device-associated infections. Bacterial attachment and biofilm formation on surfaces of medical devices often act as seeding points of infection. To prevent such infections, coatings based on silver nanoparticles (AgNPs) are often applied, however with varying clinical success. Here, the traditional AgNP-based antibacterial technology is reimagined, now forming the base for an electroenhanced antimicrobial coating. To integrate AgNPs in an electrically conducting polymer layer, a simple, yet effective chemical strategy based on poly(hydroxymethyl 3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT-MeOH:PSS) and (3-aminopropyl)triethoxysilane is designed. The resultant PEDOT-MeOH:PSS–AgNP composite presents a consistent coating of covalently linked AgNPs, as shown by scanning electron microscopy and surface plasmon resonance analysis. The efficacy of the coatings, with and without electrical addressing, is then tested against Staphylococcus aureus, a major colonizer of medical implants. Using custom-designed culturing devices, a nearly complete prevention of biofilm growth is obtained in AgNP composite devices addressed with a square wave voltage input. It is concluded that this electroenhancement of the bactericidal effect of the coupled AgNPs offers a novel, efficient solution against biofilm colonization of medical implants.A novel antimicrobial coating against Staphylococcus aureus is fabricated by covalent coupling of silver nanoparticles to the electrically conducting polymer poly(3,4-ethylenedioxythiophene). When applying an electrical input to the silver nanoparticle-coated elctrode, the antibacterial capability of the silver nanoparticles is greatly enhanced. This demonstrates the potential of combined, electroenhanced strategies in the fight against bacterial contaminations of indwelling devices.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
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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