Michael L. Shuler

Bio: Michael L. Shuler is an academic researcher from Cornell University. The author has contributed to research in topics: Cell culture & Surface plasmon resonance. The author has an hindex of 74, co-authored 344 publications receiving 20923 citations. Previous affiliations of Michael L. Shuler include Ithaca College.

Bioprocess Engineering: Basic Concepts

Abstract: Preface to the Second Edition. Preface to the First Edition. I. INTRODUCTION. 1. What is a Bioprocess Engineer? Introductory Remarks. Biotechnology and Bioprocess Engineering. Biologists and Engineers Differ in Their Approach to Research. The Story of Penicillin: How Biologists and Engineers Work Together. Bioprocesses: Regulatory Constraints. Suggestions for Further Reading. Problems. II. THE BASICS OF BIOLOGY: AN ENGINEER'S PERSPECTIVE. 2. An Overview of Biological Basics. Are All Cells the Same? Cell Construction. Cell Nutrients. Summary. Suggestions for Further Reading. Problems. 3. Enzymes. Introduction. How Enzymes Work. Enzyme Kinetics. Immobilized Enzyme Systems. Large-scale Production of Enzymes. Medical and Industrial Utilization of Enzymes. Summary. Suggestions for Further Reading. Problems. 4. How Cells Work. Introduction. The Central Dogma. DNA Replication: Preserving and Propagating the Cellular Message. Transcription: Sending the Message. Translation: Message to Product. Metabolic Regulation. How the Cell Senses Its Extracellular Environment. Summary. Appendix: Examples of Regulation of Complex Pathways. Suggestions for Further Reading. Problems. 5. Major Metabolic Pathways. Introduction. Bioenergetics. Glucose Metabolism: Glycolysis and the TCA Cycle. Respiration. Control Sites in Aerobic Glucose Metabolism. Metabolism of Nitrogenous Compounds. Nitrogen Fixation. Metabolism of Hydrocarbons. Overview of Biosynthesis. Overview of Anaerobic Metabolism. Overview of Autotrophic Metabolism. Summary. Suggestions for Further Reading. Problems. 6. How Cells Grow. Introduction. Batch Growth. Quantifying Growth Kinetics. How Cells Grow in Continuous Culture. Summary. Suggestions for Further Reading. Problems. 7. Stoichiometry of Microbial Growth and Product Formation. Introduction. Some Other Definitions. Stoichiometric Calculations. Theoretical Predictions of Yield Coefficients. Summary. Suggestions for Further Reading. Problems. 8. How Cellular Information is Altered. Introduction. Evolving Desirable Biochemical Activities through Mutation and Selection. Natural Mechanisms for Gene Transfer and Rearrangement. Genetically Engineering Cells. Genomics. Summary. Suggestions for Further Reading. Problems. III. ENGINEERING PRINCIPLES FOR BIOPROCESSES. 9. Operating Considerations for Bioreactors for Suspension and Immobilized Cultures. Introduction. Choosing the Cultivation Method. Modifying Batch and Continuous Reactors. Immobolized Cell Systems. Solid-state Fermentations. Summary. Suggestions for Further Reading. Problems. 10. Selection, Scale-Up, Operation, and Control of Bioreactors. Introduction. Scale-up and Its Difficulties. Bioreactor Instrumentation and Control. Sterilization of Process Fluids. Summary. Suggestions for Further Reading. Problems. 11. Recovery and Purification of Products. Strategies to Recover and Purify Products. Separation of Insoluble Products. Cell Disruption. Separation of Soluble Products. Finishing Steps for Purification. Integration of Reaction and Separation. Summary. Suggestions for Further Reading. Problems. IV. APPLICATIONS TO NONCONVENTIONAL BIOLOGICAL SYSTEMS. 12. Bioprocess Considerations in Using Animal Cell Cultures. Structure and Biochemistry of Animal Cells. Methods Used for the Cultivation of Animal Cells. Bioreactor Considerations for Animal Cell Culture. Products of Animal Cell Cultures. Summary. Suggestions for Further Reading. Problems. 13. Bioprocess Considerations in Using Plant Cell Cultures. Why Plant Cell Cultures? Plant Cells in Culture Compared to Microbes. Bioreactor Considerations. Economics of Plant Cell Tissue Cultures. Summary. Suggestions for Further Reading. Problems. 14. Utilizing Genetically Engineered Organisms. Introduction. How the Product Influences Process Decisions. Guidelines for Choosing Host-Vector Systems. Process Constraints: Genetic Instability. Considerations in Plasmid Design to Avoid Process Problems. Predicting HostDVector Interactions and Genetic Instability. Regulatory Constraints on Genetic Processes. Metabolic Engineering. Protein Engineering. Summary. Suggestions for Further Reading. Problems. 15. Medical Applications of Bioprocess Engineering. Introduction. Tissue Engineering. Gene Therapy Using Viral Vectors. Bioreactors. Summary. Suggestions for Further Reading. Problems. 16. Mixed Cultures. Introduction. Major Classes of Interactions in Mixed Cultures. Simple Models Describing Mixed-culture Interactions. Mixed Cultures in Nature. Industrial Utilization of Mixed Cultures. Biological Waste Treatment: An Example of the Industrial Utilization of Mixed Cultures. Summary. Suggestions for Further Reading. Problems. 17. Epilogue. Appendix: Traditional Industrial Bioprocesses. Anaerobic Bioprocesses. Aerobic Processes. Suggestions for Further Reading. Index.

TEER Measurement Techniques for In Vitro Barrier Model Systems

Abstract: Transepithelial/transendothelial electrical resistance (TEER) is a widely accepted quantitative technique to measure the integrity of tight junction dynamics in cell culture models of endothelial and epithelial monolayers. TEER values are strong indicators of the integrity of the cellular barriers before they are evaluated for transport of drugs or chemicals. TEER measurements can be performed in real time without cell damage and generally are based on measuring ohmic resistance or measuring impedance across a wide spectrum of frequencies. The measurements for various cell types have been reported with commercially available measurement systems and also with custom-built microfluidic implementations. Some of the barrier models that have been widely characterized using TEER include the blood–brain barrier (BBB), gastrointestinal (GI) tract, and pulmonary models. Variations in these values can arise due to factors such as temperature, medium formulation, and passage number of cells. The aim of this article ...

Integration of cell culture and microfabrication technology.

Abstract: Recent progress in cell culture and microfabrication technologies has contributed to the development of cell-based biosensors for the functional characterization and detection of drugs, pathogens, toxicants, and odorants. The cell-based biosensors are composed of two transducers, where the primary transducer is cellular and the secondary transducer is typically electrical. Advances in gene manipulation and cell culture techniques have contributed to the development of the cell as a transducer, while microfabrication techniques have been applied to the development of integrating the cell with the second transducer. Cellular patterning using microfabrication techniques is essential for cell-based biosensors, cell culture analogues, tissue engineering, and fundamental studies of cell biology. The photolithographic technique is highly developed and has been widely used for patterning cells. Recently, a set of alternative techniques, largely based on soft lithoghraphy, has been developed for biological applications. Those techniques include microcontact printing, microfluidic patterning using microchannels, and laminar flow patterning. A classical metallic stencil patterning method has been improved by employing a rubber-like stencil. These cellular micropatterning techniques have been usefully employed to understand questions in fundamental cell biology, especially cellular interactions with various materials and other cells. Using these micropatterning tecchniques and insights into the interaction of cellular biology with surfaces, a wide array of biosensors have been developed. In this manuscript examples of cell-based biosensors are described. Neurons have a great potential for use in a cell-based biosensor because they are electrically excitable cells, from which electrical signals are generated with the binding of detecting molecules. Consequently, the electrical signals generated in the cell can be determined in a noninvasive manner. A microphysiometer is a device to detect functional responses from cells by measuring the change of extracellular pH. The main application of the microphysiometer is the analysis of functional responses of cells upon receptor stimulation. Development of a microscale cell culture analogue system, an in vitro animal or human surrogate, is another promising area using cell culture and microfabrication technologies. Such devices are potentially very useful in the fields of toxicology and drug testing because they may increase the accuracy of in vitro predictions, simplify testing procedures, and reduce the cost of such tests, allowing many more tests to be done with a limited set of resources.

A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

Abstract: Drug discovery is often impeded by the poor predictability of in vitro assays for drug toxicity. One primary reason for this observation is the inability to reproduce the pharmacokinetics (PK) of drugs in vitro. Mathematical models to predict the pharmacokinetics-pharmacodynamics (PK-PD) of drugs are available, but have several limitations, preventing broader application. A microscale cell culture analog (microCCA) is a microfluidic device based on a PK-PD model, where multiple cell culture chambers are connected with fluidic channels to mimic multi-organ interactions and test drug toxicity in a pharmacokinetic-based manner. One critical issue with microfluidics, including the microCCA, is that specialized techniques are required for assembly and operation, limiting its usability to non-experts. Here, we describe a novel design, with enhanced usability while allowing hydrogel-cell cultures of multiple types. Gravity-induced flow enables pumpless operation and prevents bubble formation. Three cell lines representing the liver, tumor and marrow were cultured in the three-chamber microCCA to test the toxicity of an anticancer drug, 5-fluorouracil. The result was analyzed with a PK-PD model of the device, and compared with the result in static conditions. Each cell type exhibited differential responses to 5-FU, and the responses in the microfluidic environment were different from those in static environment. Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.

A micro cell culture analog (µCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs

Abstract: A microfluidic device with 3-D hydrogel cell cultures has been developed to test the cytotoxicity of anti-cancer drugs while reproducing multi-organ interactions. In this device, a micro cell culture analog (µCCA), cells embedded in 3-D hydrogels are cultured in separate chambers representing the liver, tumor, and marrow, which are connected by channels mimicking blood flow. While the microfluidic network provides a platform for mimicking the pharmacokinetic and pharmacodynamic profiles of a drug in humans, the 3-D hydrogel provides a more physiologically realistic environment to mimic the tissue than monolayer culture. Colon cancer cells (HCT-116) and hepatoma cells (HepG2/C3A) were encapsulated in Matrigel and cultured in the tumor and the liver chamber in a µCCA, respectively. Myeloblasts (Kasumi-1) were encapsulated in alginate in the marrow chamber; a stiffer hydrogel was necessary to prevent cell migration out of the matrix. The cytotoxic effect of Tegafur, an oral prodrug of 5-fluorouracil (5-FU), on each cell line was tested using the µCCA with cell-embedded hydrogel. The comparison of experimental results using a 96-well microtiter plate and a µCCA demonstrated that the µCCA was able to reproduce the metabolism of Tegafur to 5-FU in the liver and consequent death of cells by 5-FU, while the cultures in a 96-well microtiter plate were unable to do so. The µCCA utilizing 3-D hydrogel cell cultures has potential as a platform for pharmacokinetic-based drug screening in a more physiologically realistic environment.

Quantitative assessment of worldwide contamination of air, water and soils by trace metals

Abstract: Calculated loading rates of trace metals into the three environmental compartments demonstrate that human activities now have major impacts on the global and regional cycles of most of the trace elements. There is significant contamination of freshwater resources and an accelerating accumulation of toxic metals in the human food chain.

The geometry of biological time , by A. T. Winfree. Pp 544. DM68. Corrected Second Printing 1990. ISBN 3-540-52528-9 (Springer)

Abstract: 1980 Preface * 1999 Preface * 1999 Acknowledgements * Introduction * 1 Circular Logic * 2 Phase Singularities (Screwy Results of Circular Logic) * 3 The Rules of the Ring * 4 Ring Populations * 5 Getting Off the Ring * 6 Attracting Cycles and Isochrons * 7 Measuring the Trajectories of a Circadian Clock * 8 Populations of Attractor Cycle Oscillators * 9 Excitable Kinetics and Excitable Media * 10 The Varieties of Phaseless Experience: In Which the Geometrical Orderliness of Rhythmic Organization Breaks Down in Diverse Ways * 11 The Firefly Machine 12 Energy Metabolism in Cells * 13 The Malonic Acid Reagent ('Sodium Geometrate') * 14 Electrical Rhythmicity and Excitability in Cell Membranes * 15 The Aggregation of Slime Mold Amoebae * 16 Numerical Organizing Centers * 17 Electrical Singular Filaments in the Heart Wall * 18 Pattern Formation in the Fungi * 19 Circadian Rhythms in General * 20 The Circadian Clocks of Insect Eclosion * 21 The Flower of Kalanchoe * 22 The Cell Mitotic Cycle * 23 The Female Cycle * References * Index of Names * Index of Subjects

Reconstituting Organ-Level Lung Functions on a Chip

Abstract: Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active "organ-on-a-chip" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.

Neuroscience 細胞死：最近の知見

Abstract: 中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Microfluidic organs-on-chips

Abstract: Organ-level physiology is recapitulated in vitro by culturing cells in perfused, microfluidic devices.