Search results for: cell-culture-models-of-biological-barriers

Cell Culture Models of Biological Barriers

Author : Claus-Michael Lehr
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Over the past ten years several sophisticated in vitro test systems based on epithelial cell cultures have been introduced in the field of drug delivery. These models have been found to be very useful in characterizing the permeability of drugs across epithelial tissues, and in studying formulations or carrier systems for improved drug delivery and

Drug Delivery

Author : Binghe Wang
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An indispensable tool for those working at the front lines of new drug development Written for busy professionals at the forefront of new drug development, Drug Delivery gets readers quickly up to speed on both the principles and latest applications in the increasingly important field of drug delivery. Recent developments in such areas as combinatorial chemistry, proteomics, and genomics have revolutionized researchers' ability to rapidly identify and synthesize new pharmacological compounds. However, delivery-related properties remain a significant reason for clinical trial failures. Bringing together contributions by leading international experts, Drug Delivery covers the entire field in a systematic but concise way. It begins with an in-depth review of key fundamentals, such as physiochemical and biological barriers; drug delivery pathways; metabolism; drug formulation; pharmacokinetic and pharmacodynamic issues; and more. The remainder of the book is devoted to the systematic examination-including overviews, timely examples, and extensive references-of a host of specific subjects, including: * Receptor-mediated drug delivery * Prodrug delivery approaches * Oral protein and peptide drug delivery * Gene therapy and gene delivery * Ultrasound-mediated drug delivery * Polycationic peptides and proteins in drug delivery * Pulmonary drug delivery * Antibody-directed drug delivery * Efflux transporters in drug excretion * Intellectual property issues in drug delivery

Epithelial Cell Culture Protocols

Author : Clare Wise
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There have been significant advances in research involving the isolation and culture of epithelial cells in the past decade, and many new techniques have been developed. Monolayer cultures can be used to evaluate the nature and behavior of cells, while the use of epithelial cells in model systems has allowed a deeper understanding of cellular and molecular mechanisms and interactions. The aim of this book is to provide a comprehensive, step-by-step guide to many techniques for epithelial cell culture, combining in one volume the more commonly used protocols along with many that are more speci- ized. Epithelial Cell Culture Protocols should help those who are new to this field and want to learn the basic culture techniques, as well as those needing to use more wide ranging and specific protocols. It should be a useful resource on its own, and also complement the other volumes that have been written about cell culture in the Methods in Molecular Biology series. Epithelial Cell Culture Protocols covers a wide variety of protocols, mostly aimed at the researcher, but also a few aimed at clinicians. The est- lishment and maintenance of primary cultures derived from many different tissues and different species is covered. Particular emphasis has been placed on protocols needed to further analyze and assess epithelial cells, for example, by looking at apoptosis and integrins and by measuring membrane capa- tance and confluence. Using different co-culture techniques, it is possible also to develop models to investigate many different systems in vitro.

Characterization and Application of a Human Corneal in Vitro Model for Controlled Release of Ophthalmic Drugs

Author : Shahabedin Eslami
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The cornea acts as a transparent shield protecting the eye from germs, dust and pathogens as well as regulating the ocular environment by controlling the diffusion of external substances like oxygen or drugs via the tear film into the intraocular tissues. The design and development of an intraocular-drug delivery device highly depend upon the understanding of the interactions between the biological system of the eye and the drug-ophthalmic material complex. In vivo models have been used in clinical studies as the necessary and most valid testing platforms for regulatory authorities, but animal experiments have always been widely criticized for ethical and economical reasons. Furthermore, when studying interactions in the eye environment, using animal models has other disadvantages such as difference in blinking patterns, tear composition, and organ size when compared to the human eye. Therefore, in vitro cell culture models using human cells have been considered as a powerful pre-screening tool for drug testing to study interactions with the ocular tissue. In vitro models also provide an experimental environment, in which each parameter can be controlled. With a lower complexity level and less variability, in vitro models allow gaining a better understanding of the parameters involved in the drug delivery system. Using eye drops for ocular drug delivery to the anterior section of the eye is a significant challenge due the rapid washout in tears and the corneal barrier to drug diffusion. Therefore mimicking this environment in vitro can help in designing more robust drug delivery system for the front of the eye. This research focuses on the application and characterization of an in vitro human corneal model which mimics in part the in vivo environment to assess corneal interaction with the drug/biomaterial complexes. In this project, an in vitro model using human corneal epithelial cells is used to characterize the drug release profile and transport from commercially available contact lenses. Three model drugs for treatment of glaucoma, eye inflammation and infection respectively were tested in combination with two commercial contact lenses with different surface chemistry and their release profiles were measured. The effects of biological transporters on the controlled release systems were investigated. The role of organic anion transporter protein OATP 2A1 (prostaglandin transporter) in transcellular transport of Latanoprost was characterized and the presence of its gene in the HPV16 E6/E7 immortalized corneal epithelial cell line was verified by real-time polymerase chain reaction. To assess the role of OATP 2A1, transporters were inhibited by Diclofenac sodium and the release kinetics of Latanoprost from Pure Vision® (balafilcon A) and Acuvue Oasys® (senofilcon A) contact lenses in three in vitro conditions with live corneal cells monolayer, fixed epithelial cells and transporter inhibited epithelial cells were studied. The presence of corneal epithelial cells in vitro had a significant effect on release kinetics of Latanoprost resulting in a zero-order release profile. Complete inhibition of the OATP 2A1 transporter reduced the release rate of Latanoprost by 30% and 52% from balafilcon A and senofilcon A respectively. Comparison between live, fixed and transport inhibited models indicated that Latanoprost transport occurred mainly through the active transcellular pathway but was not mediated only by OATP 2A1. Other transporters might be involved in the transport and further research is required to identify these. The effect of initial loading concentration of Latanoprost on release rate and amount of drug eluted from contact lenses was also investigated. Reduction in initial loading concentration of the drug increased the released percentage of the drug from 6.9% to 14.1% for balafilcon A and from 11.4% to 57.3% for senofilcon A. Both silicone hydrogel contact lenses, regardless of initial loading concentrations, released Latanoprost at above therapeutic daily dose up to 96 hours with zero-order constant rate. The release kinetics of two hydrophilic ophthalmic drugs, Ciprofloxacin HCl and Timolol Maleate also from the soft contact lenses were evaluated in the corneal in vitro model over 48 hours. The effect of corneal epithelial barrier on the release kinetics of these hydrophilic drugs was evaluated. The release kinetics of hydrophilic Ciprofloxacin HCl and Timolol maleate followed a first-order rate. The presence of corneal epithelial cells in vitro had no significant effect on the release rate of hydrophilic drugs. However, presence of cells (live or fixed) acted as a diffusion barrier by decreasing the amount of Ciprofloxacin released from silicone hydrogel contact lenses compared to no-cell in vitro model. No significant difference in released amount of Timolol was observed between live, fixed and no cell in vitro models Our results further confirmed the effect of chemical interaction between drug molecules and contact lens polymer on a controlled release system and the importance of selecting the appropriate in vitro model. Testing conditions and presence of biological barriers provided by cells can have a significant impact on release profile and provided a more realistic test platform for studying the release kinetics for the ocular environment. All in all, this thesis confirms the importance of proper selection of in vitro test models for the assessment of ocular drug delivery system and suggests that commercially available silicone hydrogel ocular materials may be used effectively for the release of hydrophobic therapeutics.

Models for Assessing Drug Absorption and Metabolism

Author : Ronald T. Borchardt
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Pharmaceutical scientists in industry and academia will appreciate this single reference for its detailed experimental procedures for conducting biopharmaceutical studies. This well-illustrated guide allows them to establish, validate, and implement commonly used in situ and in vitro model systems. Chapters provide ready access to these methodologies for studies of the intestinal, buccal, nasal and respiratory, vaginal, ocular, and dermal epithelium as well as the endothelial and elimination barriers.

Mechanistic Understanding of Oral Drug Absorption Enhancement of Cromolyn Sodium by an Amino Acid Derivitive

Author : Adam Wathah Ghassan Alani
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Epithelial Cell Culture Protocols Methods in Molecular Biology

Author : Clare Wise
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Well-versed experimenters and clinical researchers share their best methods for establishing and maintaining epithelial cell cultures, for analyzing and studying their characteristics, and for using them to set up models of critical biological systems. The emphasis is on the analysis and assessment of epithelial cells, for example by looking at apoptosis and integrins, or by measuring membrane capacitance and confluence. Also described in step-by-step detail are co-culture techniques valuable in developing models for investigating many different in vitro systems, including the blood-brain barrier, drug uptake, and the interaction of epithelial cells with bacteria. Epithelial Cell Culture Protocols offers a step-by-step guide toward a deeper understanding of cellular and molecular mechanisms, as well as a set of robust techniques for specifically evaluating the nature and behavior of epithelial cells.

Concepts and Models for Drug Permeability Studies

Author : Bruno Filipe Carmelino Cardoso Sarmento
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This book intends to be an updated compilation of the most important buccal, gastric, intestinal, pulmonary, nasal, vaginal, ocular, skin and blood-brain barrier in vitro models for predicting the permeability of drugs. Concepts and Models for Drug Permeability Studies focuses on different approaches and comprises of various models. Each model describes the protocol of seeding and conservation, the application for specific drugs, and takes into account the maintenance of physiologic characteristics and functionality of epithelium, from the simplest immortalized cell-based monoculture to the most complex engineered-tissue models. Chapters also discuss the equivalence between in vitro cell and tissue models and in vivo conditions, highlighting how each model may provisionally resemble a different drug absorption route. Updated information regarding the most recent in vitro models to study the permeability of drugs Short and concise chapters covering all the biological barriers with interest in drug permeability A combination of bibliographic information related with individual models and footnote instructions of technical procedures for construction of cell and tissue-based models Simple and clear scientific content, adaptable for young scientists and experimented researchers

Epithelial Cell Culture Protocols

Author : Clare Wise
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There have been significant advances in research involving the isolation and culture of epithelial cells in the past decade, and many new techniques have been developed. Monolayer cultures can be used to evaluate the nature and behavior of cells, while the use of epithelial cells in model systems has allowed a deeper understanding of cellular and molecular mechanisms and interactions. The aim of this book is to provide a comprehensive, step-by-step guide to many techniques for epithelial cell culture, combining in one volume the more commonly used protocols along with many that are more speci- ized. Epithelial Cell Culture Protocols should help those who are new to this field and want to learn the basic culture techniques, as well as those needing to use more wide ranging and specific protocols. It should be a useful resource on its own, and also complement the other volumes that have been written about cell culture in the Methods in Molecular Biology series. Epithelial Cell Culture Protocols covers a wide variety of protocols, mostly aimed at the researcher, but also a few aimed at clinicians. The est- lishment and maintenance of primary cultures derived from many different tissues and different species is covered. Particular emphasis has been placed on protocols needed to further analyze and assess epithelial cells, for example, by looking at apoptosis and integrins and by measuring membrane capa- tance and confluence. Using different co-culture techniques, it is possible also to develop models to investigate many different systems in vitro.

Particle Toxicology

Author : Ken Donaldson
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Exposure to particles in industry and mining and from accidental anthropogenic sources constitutes an ongoing threat. Most recently nanoparticles arising from advances in technology are exposing a wider population to pathogenic stimuli. The effects of inhaled particles are no longer confined to the lung as nanoparticles have the potential to translocate to the bloodstream, the brain, and other target sites. The new questions posed by nanoparticles underscore the importance of interdisciplinary research and exchange and highlight the need for new collaborations among disciplines in medicine, toxicology, chemistry, and material sciences. Particle Toxicology brings together the state of the science in particle physico-chemistry, cell biology, and toxicology in a single volume. While organized around the classical toxicology paradigm of exposure - dose - response, the book is unique in its emphasis on mechanistic toxicology. Preparing the reader with a brief historical overview and a conceptual framework for particle research, the book provides reviews on the mechanisms and properties of pathogenic particles and their effects on target cells at various sites in the body. The text describes how adverse effects are a consequence of deposition, translocation, and the complex issue of “dose” dominates. Contributions from leading researchers address particle-associated pro-inflammatory effects and inflammatory signaling, cellular and extracellular oxidative and nitrosative stress, particulate interactions in the pulmonary, cardiovascular, and central nervous systems, as well as genotoxic effects. Exemplar particles include quartz, asbestos, particulate material and nanoparticles. The book also covers mathematical modeling and human studies as avenues for future research. Responding to the evolving trend of consumer applications for particulate matter, Particle Toxicology provides the comprehensive resource for current knowledge from which to develop new concepts to understanding particle actions, measurement, testing, and pathogenic exposure to fine and ultrafine particles.

Nanostructured Biomaterials for Overcoming Biological Barriers

Author : Maria Jose Alonso
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Overcoming biological barriers is of importance for solving the problems of many current drugs and vaccines, and is especially relevant in the commerical exploitation of new therapeutic strategies. This book focuses on the mechanistic issues related to the interaction between drug delivery systems and biological barriers.

Characterisation of ATP binding Cassette ABC Transporters in Bronchial Epithelial Cell Culture Models

Author : Victoria Hutter
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In vitro epithelial cell cultures are increasingly used to model drug permeability, as predictive tools for absorption in humans. Medical regulatory agencies recommend in vitro permeability screening for biopharmaceutical classification of novel therapeutic compounds, and recently published guidelines on investigating interactions of novel therapeutic compounds with clinically relevant transporters. The expression and functionality of drug transporters in the lung is poorly characterised, and insufficient to allow detailed understanding of drug-transporter interactions in the airways. Additionally, as human in vitro permeability is used to predict absorption from rat in vivo, a rat bronchial epithelium in vitro cell line would aid the understanding of interspecies differences in transporter-mediated drug trafficking. This thesis investigates the morphological and physiological barrier properties of Calu-3, normal human bronchial epithelial (NHBE) cell layers and rat airway epithelial cell (RL-65) cultures. The morphology and barrier integrity of RL-65 layers were shown to be in agreement with existing human bronchial epithelial cell models after culture for 8 days at air-liquid interface. The expression of >30 ABC, SLC and SLCO transporters in human models was in general agreement with published expression levels in human lungs. MDR1 functionality was investigated, and whilst no asymmetric transport of 3H-digoxin was observed in RL-65 cell layers, net secretory transport was observed for Calu-3 cell layers at both low (25-30) and high (45-45) passage number and for some batches of NHBE cell layers. Chemical, metabolic and biological inhibitors were employed to evaluate MDR1 contribution to 3H-digoxin trafficking, however the exact transporter(s) involved could not be determined. Whilst MDR1 functionality could not be ruled out, results suggest that it is unlikely to be the main transporter involved in 3H-digoxin trafficking in the bronchial epithelium. These studies have highlighted the need for more specific approaches to investigating transporter functionality in in vitro systems.

Transmucosal Absorption Enhancers in the Drug Delivery Field

Author : Luca Casettari
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Development of strategies to assist the movement of poorly permeable molecules across biological barriers has long been the goal of drug delivery science. In the last three decades, there has been an exponential increase in advanced drug delivery systems that aim to address this issue. However, most proprietary delivery technologies that have progressed to clinical development are based on permeation enhancers (PEs) that have a history of safe use in man. This Special Issue entitled “Transmucosal Absorption Enhancers in the Drug Delivery Field” aims to present the current state-of-the-art in the application of PEs to improve drug absorption. Emphasis is placed on identification of novel permeation enhancers, mechanisms of barrier alteration, physicochemical properties of PEs that contribute to optimal enhancement action, new delivery models to assess PEs, studies assessing safety of PEs, approaches to assist translation of PEs into effective oral, nasal, ocular and vaginal dosage forms and combining PEs with other delivery strategies.

Proceedings of the IEEE Annual Northeast Bioengineering Conference

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Comprehensive Medicinal Chemistry III

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Comprehensive Medicinal Chemistry III provides a contemporary and forward-looking critical analysis and summary of recent developments, emerging trends, and recently identified new areas where medicinal chemistry is having an impact. The discipline of medicinal chemistry continues to evolve as it adapts to new opportunities and strives to solve new challenges. These include drug targeting, biomolecular therapeutics, development of chemical biology tools, data collection and analysis, in silico models as predictors for biological properties, identification and validation of new targets, approaches to quantify target engagement, new methods for synthesis of drug candidates such as green chemistry, development of novel scaffolds for drug discovery, and the role of regulatory agencies in drug discovery. Reviews the strategies, technologies, principles, and applications of modern medicinal chemistry Provides a global and current perspective of today's drug discovery process and discusses the major therapeutic classes and targets Includes a unique collection of case studies and personal assays reviewing the discovery and development of key drugs

The Effect of Restricting Sulfur containing Amino Acids on the Barrier Function of an Epithelial Cell Culture Model

Author : Sonja Skrovanek
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Microfluidic Cell Culture Systems

Author : Jeffrey T Borenstein
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Techniques for microfabricating intricate microfluidic structures that mimic the microenvironment of tissues and organs, combined with the development of biomaterials with carefully engineered surface properties, have enabled new paradigms in and cell culture-based models for human diseases. The dimensions of surface features and fluidic channels made accessible by these techniques are well-suited to the size scale of biological cells. Microfluidic Cell Culture Systems applies design and experimental techniques used in in microfluidics, and cell culture technologies to organ-on-chip systems. This book is intended to serve as a professional reference, providing a practical guide to design and fabrication of microfluidic systems and biomaterials for use in cell culture systems and human organ models. The book covers topics ranging from academic first principles of microfluidic design, to clinical translation strategies for cell culture protocols. The goal is to help professionals coming from an engineering background to adapt their expertise for use in cell culture and organ models applications, and likewise to help biologists to design and employ microfluidic technologies in their cell culture systems. This 2nd edition contains new material that strengthens the focus on in vitro models useful for drug discovery and development. One new chapter reviews liver organ models from an industry perspective, while others cover new technologies for scaling these models and for multi-organ systems. Other new chapters highlight the development of organ models and systems for specific applications in disease modeling and drug safety. Previous chapters have been revised to reflect the latest advances. Provides design and operation methodology for microfluidic and microfabricated materials and devices for organ-on-chip disease and safety models. This is a rapidly expanding field that will continue to grow along with advances in cell biology and microfluidics technologies. Comprehensively covers strategies and techniques ranging from academic first principles to industrial scale-up approaches. Readers will gain insight into cell-material interactions, microfluidic flow, and design principles. Offers three fundamental types of information: 1) design principles, 2) operation techniques, and 3) background information/perspectives. The book is carefully designed to strike a balance between these three areas, so it will be of use to a broad range of readers with different technical interests and educational levels.

Blood Brain Barrier in Drug Discovery

Author : Li Di
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Focused on central nervous system (CNS) drug discovery efforts, this book educates drug researchers about the blood-brain barrier (BBB) so they can affect important improvements in one of the most significant – and most challenging – areas of drug discovery. • Written by world experts to provide practical solutions to increase brain penetration or minimize CNS side-effects • Reviews state-of-the-art in silico, in vitro, and in vivo tools to assess brain penetration and advanced CNS drug delivery strategies • Covers BBB physiology, medicinal chemistry design principles, free drug hypothesis for the BBB, and transport mechanisms including passive diffusion, uptake/efflux transporters, and receptor-mediated processes • Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK) • Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market

Biology and Physiology of the Blood Brain Barrier

Author : Pierre-Olivier Couraud
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The endothelial cells of the cerebral vasculature constitute, together with perivascular elements (astrocytes, pcricytes, basement membrane), the blood-brain barrier (BBB), which strictly limits and specifically controls the exchanges between the blood and the cerebral extracellular spacc.The existence of such a physical, enzymatic, and active barrier isolating the central nervous system has broad physiological, biological, pharmacological, and patho logical consequences, most of which are not yet fully elucidated. The Cerebral Vascular Biology conference (CVB '95) was organized and held at the "Carre des Sciences" in Paris on July I 0-12, 1995. Like the CVB '92 conference held in Duluth, Minnesota, three years ago, the objectives were to provide a forum for presentation of the most recent progresses and to stimulate discussions in the ticld of the biology, physiology. and pathology of the blood-brain barrier. The Paris conference gathered more than !50 participants. including investigators in basic neuroscience, physicians. and stu dents, who actively contributed to the scientific program by their oral or poster presentations. This volume contains a collection of short articles that summarize most of the new data that were presented at the conference. Six thematic parts focus on physiological transports. drug delivery, multidrug resistance P-glycoprotein, signal transduction at the BBB. interactions between the immune system and the cerebral endothelial cells, and the blood-brain barrier-related pathologies in the central nervous system. In addition, two introductory articles present new insights in the rapidly evolving topics of cerebral angiogenesis and gene transfer to the brain.

Three Dimensional Human Organotypic Models for Biomedical Research

Author : Fabio Bagnoli
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