Michael L Shuler

Cornell University, Итак, New York, United States

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Publications (192)617.88 Total impact

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    ABSTRACT: We have developed a low-cost liver cell culture device that creates fluidic flow over a 3D primary liver cell culture that consists of multiple liver cell types, including hepatocytes and non-parenchymal cells (fibroblasts, stellate cells, and Kupffer cells). We tested the performance of the cell culture under fluidic flow for 14 days, finding that hepatocytes produced albumin and urea at elevated levels compared to static cultures. Hepatocytes also responded with induction of P450 (CYP1A1 and CYP3A4) enzyme activity when challenged with P450 inducers, although we did not find significant differences between static and fluidic cultures. Non-parenchymal cells were similarly responsive, producing interleukin 8 (IL-8) when challenged with 10 μM bacterial lipoprotein (LPS). To create the fluidic flow in an inexpensive manner, we used a rocking platform that tilts the cell culture devices at angles between ±12°, resulting in a periodically changing hydrostatic pressure drop between reservoirs and the accompanying periodically changing fluidic flow (average flow rate of 650 μL min(-1), and a maximum shear stress of 0.64 dyne cm(-2)). The increase in metabolic activity is consistent with the hypothesis that, similar to unidirectional fluidic flow, primary liver cell cultures increase their metabolic activity in response to fluidic flow periodically changes direction. Since fluidic flow that changes direction periodically drastically changes the behavior of other cells types that are shear sensitive, our findings support the theory that the increase in hepatic metabolic activity associated with fluidic flow is either activated by mechanisms other than shear sensing (for example increased opportunities for gas and metabolite exchange), or that it follows a shear sensing mechanism that does not depend on the direction of shear. Our mode of device operation allows us to evaluate drugs under fluidic cell culture conditions and at low device manufacturing and operation costs.
    Lab on a Chip 04/2015; DOI:10.1039/c5lc00237k · 5.75 Impact Factor
  • Hasan Erbil Abaci, Michael L Shuler
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    ABSTRACT: Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in developing microphysiological systems for drug development studies. Determining the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic model (PD) -aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in different stages of PBPK modeling and drug development; these are a µOrgans-on-a-chip and a µHuman-on-a-chip. Then we establish design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations on estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on designing microphysiological platforms for PBPK/PD based drug discovery.
    Integrative Biology 02/2015; DOI:10.1039/C4IB00292J · 4.00 Impact Factor
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    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 is to review the different TEER measurement techniques and analyze their strengths and weaknesses, determine the significance of TEER in drug toxicity studies, examine the various in vitro models and microfluidic organs-on-chips implementations using TEER measurements in some widely studied barrier models (BBB, GI tract, and pulmonary), and discuss the various factors that can affect TEER measurements. © 2015 Society for Laboratory Automation and Screening.
    Journal of the Association for Laboratory Automation 01/2015; DOI:10.1177/2211068214561025 · 1.50 Impact Factor
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    ABSTRACT: Animal surrogate or cell culture analog (CCA) systems mimic the biochemical response of an animal or human when challenged with a chemical or drug. A true animal surrogate is a device that replicates the circulation, metabolism, and adsorption of a chemical and its metabolites using interconnected multiple compartments to represent key organs. These compartments make use of engineered tissues or cell cultures. Physiologically based pharmacokinetic models (PBPK) guide the design of the device. The animal surrogate, particularly a human surrogate, can provide important insights into toxicity and efficacy of a drug or chemical when it is impractical or imprudent to use living animals (or humans) for testing. The combination of a CCA and PBPK provides a rational basis to relate molecular mechanisms to whole-animal response.
    The Biomedical Engineering Handbook: Molecular, Cellular, and Tissue Engineering, 4th edited by Joseph D. Bronzino, Donald R. Peterson, 01/2015: chapter 11: pages 11-1 - 11-10; CRC Press., ISBN: 978-1-4398-2531-0
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    ABSTRACT: 7.1 Introduction Government approval of a novel therapeutic agent is the desired outcome of a complex research and development process oen lasting 10–15 years and costing roughly £750 million (US$ 1.2 billion). 1,2 A signicant percentage of this cost can be attributed to the high rate of attrition of compounds subjected to pharmaceutical testing and evaluation. For every 10 000 compounds identied with possible therapeutic potential, typically only one will be determined to be both safe for use in humans and to have medicinal value, and be approved to become a licensed medicine. 3 A major contribution to this high rate of attrition is the relative inadequacy of current test beds for preclinical evaluation protocols. Due to the inherent complexity of living systems, drug trials on animal models oen produce data that is difficult to interpret. More importantly, animal models have, on numerous occasions, been shown to be poor predictors of drug effects in humans. 4 Data collected between 1991 and 2000 highlights that only 11% of compounds found to be benecial during preclinical evaluation in animals RSC Drug Discovery Series No. 41 Human-based Systems for Translational Research Edited by Robert Coleman
    Human-based Systems for Translational Research, 12/2014: chapter 7; , ISBN: 978-1-84973-825-5
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    ABSTRACT: Advances in bio-mimetic in vitro human skin models increase the efficiency of drug screening studies. In this study, we designed and developed a microfluidic platform that allows for long-term maintenance of full thickness human skin equivalents (HSE) which are comprised of both the epidermal and dermal compartments. The design is based on the physiologically relevant blood residence times in human skin tissue and allows for the establishment of an air-epidermal interface which is crucial for maturation and terminal differentiation of HSEs. The small scale of the design reduces the amount of culture medium and the number of cells required by 36 fold compared to conventional transwell cultures. Our HSE-on-a-chip platform has the capability to recirculate the medium at desired flow rates without the need for pump or external tube connections. We demonstrate that the platform can be used to maintain HSEs for three weeks with proliferating keratinocytes similar to conventional HSE cultures. Immunohistochemistry analyses show that the differentiation and localization of keratinocytes was successfully achieved, establishing all sub-layers of the epidermis after one week. Basal keratinocytes located at the epidermal-dermal interface remain in a proliferative state for three weeks. We use a transdermal transport model to show that the skin barrier function is maintained for three weeks. We also validate the capability of the HSE-on-a-chip platform to be used for drug testing purposes by examining the toxic effects of doxorubucin on skin cells and structure. Overall, the HSE-on-a-chip is a user-friendly and cost-effective in vitro platform for drug testing of candidate molecules for skin disorders.
    Lab on a Chip 12/2014; DOI:10.1039/C4LC00999A · 5.75 Impact Factor
  • Michael L Shuler, James J Hickman
    Proceedings of the National Academy of Sciences 09/2014; 111(38). DOI:10.1073/pnas.1414484111 · 9.81 Impact Factor
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    ABSTRACT: The use of nanoparticles in medical applications is highly anticipated, and at the same time little is known about how these nanoparticles affect human tissues. Here we have simulated the oral uptake of 50 nm carboxylated polystyrene nanoparticles with a microscale body-on-a-chip system (also referred to as multi-tissue microphysiological system or micro Cell Culture Analog). Using the 'GI tract-liver-other tissues' system allowed us to observe compounding effects and detect liver tissue injury at lower nanoparticle concentrations than was expected from experiments with single tissues. To construct this system, we combined in vitro models of the human intestinal epithelium, represented by a co-culture of enterocytes (Caco-2) and mucin-producing cells (TH29-MTX), and the liver, represented by HepG2/C3A cells, within one microfluidic device. The device also contained chambers that together represented the liquid portions of all other organs of the human body. Measuring the transport of 50 nm carboxylated polystyrene nanoparticles across the Caco-2/HT29-MTX co-culture, we found that this multi-cell layer presents an effective barrier to 90.5 ± 2.9% of the nanoparticles. Further, our simulation suggests that a larger fraction of the 9.5 ± 2.9% nanoparticles that travelled across the Caco-2/HT29-MTX cell layer were not large nanoparticle aggregates, but primarily single nanoparticles and small aggregates. After crossing the GI tract epithelium, nanoparticles that were administered in high doses estimated in terms of possible daily human consumption (240 and 480 × 10(11) nanoparticles mL(-1)) induced the release of aspartate aminotransferase (AST), an intracellular enzyme of the liver that indicates liver cell injury. Our results indicate that body-on-a-chip devices are highly relevant in vitro models for evaluating nanoparticle interactions with human tissues.
    Lab on a Chip 06/2014; 14(16):3081-3092. DOI:10.1039/c4lc00371c · 5.75 Impact Factor
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    ABSTRACT: The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology, and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a "body-on-a-chip", and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses.
    Experimental Biology and Medicine 06/2014; 239(9):1225-1239. DOI:10.1177/1535370214529397 · 2.23 Impact Factor
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    ABSTRACT: Multi-organ microdevices can mimic tissue-tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue-tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices presents an opportunity to improve the drug development process. The goals are to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices' capabilities can present unique opportunities for the study of drug action. We also discuss the challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion.
    Advanced Drug Delivery Reviews 01/2014; 69-70:158-169. DOI:10.1016/j.addr.2013.12.003 · 12.71 Impact Factor
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    ABSTRACT: A multiorgan, functional, human in vitro assay system or 'Body-on-a-Chip' would be of tremendous benefit to the drug discovery and toxicology industries, as well as providing a more biologically accurate model for the study of disease as well as applied and basic biological research. Here, we describe the advances our team has made towards this goal, as well as the most pertinent issues facing further development of these systems. Description is given of individual organ models with appropriate cellular functionality, and our efforts to produce human iterations of each using primary and stem cell sources for eventual incorporation into this system. Advancement of the 'Body-on-a-Chip' field is predicated on the availability of abundant sources of human cells, capable of full differentiation and maturation to adult phenotypes, for which researchers are largely dependent on stem cells. Although this level of maturation is not yet achievable in all cell types, the work of our group highlights the high level of functionality that can be achieved using current technology, for a wide variety of cell types. As availability of functional human cell types for in vitro culture increases, the potential to produce a multiorgan in vitro system capable of accurately reproducing acute and chronic human responses to chemical and pathological challenge in real time will also increase.
    Stem Cell Research & Therapy 12/2013; 4 Suppl 1(Suppl 1):S9. DOI:10.1186/scrt370 · 4.63 Impact Factor
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    Dataset: 1579 ftp
    Beum Jun Kim, Jinpian Diao, Michael L Shuler
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    ABSTRACT: While in vitro cell based systems have been an invaluable tool in biology, they often suffer from a lack of physiological relevance. The discrepancy between the in vitro and in vivo systems has been a bottleneck in drug development process and biological sciences. The recent progress in microtechnology has enabled manipulation of cellular environment at a physiologically relevant length scale, which has led to the development of novel in vitro organ systems, often termed 'organ-on-a-chip' systems. By mimicking the cellular environment of in vivo tissues, various organ-on-a-chip systems have been reported to reproduce target organ functions better than conventional in vitro model systems. Ultimately, these organ-on-a-chip systems will converge into multi-organ 'body-on-a-chip' systems composed of functional tissues that reproduce the dynamics of the whole-body response. Such microscale in vitro systems will open up new possibilities in medical science and in the pharmaceutical industry.
    Lab on a Chip 02/2013; 13(7):1201-1212. DOI:10.1039/c3lc41017j · 5.75 Impact Factor
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    ABSTRACT: Animal surrogate or cell culture analog (CCA) systems mimic the biochemical response of an animal or human when challenged with a chemical or drug. A true animal surrogate is a device that replicates the circulation, metabolism, and adsorption of a chemical and its metabolites using interconnected multiple compartments to represent key organs. These compartments make use of engineered tissues or cell cultures. Physiologically based pharmacokinetic models (PBPK) guide the design of the device. The animal surrogate, particularly a human surrogate, can provide important insights into toxicity and efficacy of a drug or chemical when it is impractical or imprudent to use living animals (or humans) for testing. The combination of a CCA and PBPK provides a rational basis to relate molecular mechanisms to whole-animal response.
    Transport Phenomena in Biomedical Engineering, Edited by Robert A. Peattie, Robert J. Fisher, Joseph D. Bronzino, Donal R. Peterson, 01/2013: pages 5-1 - 5-10; CRC Press., ISBN: 978-1-4398-7462-2
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    ABSTRACT: We describe a novel fabrication method that creates microporous, polymeric membranes that are either flat or contain controllable 3-dimensional shapes that, when populated with Caco-2 cells, mimic key aspects of the intestinal epithelium such as intestinal villi and tight junctions. The developed membranes can be integrated with microfluidic, multi-organ cell culture systems, providing access to both sides, apical and basolateral, of the 3D epithelial cell culture. Partial exposure of photoresist (SU-8) spun on silicon substrates creates flat membranes with micrometer-sized pores (0.5-4.0 μm) that-supported by posts-span across 50 μm deep microfluidic chambers that are 8 mm wide and 10 long. To create three-dimensional shapes the membranes were air dried over silicon pillars with aspect ratios of up to 4:1. Space that provides access to the underside of the shaped membranes can be created by isotropically etching the sacrificial silicon pillars with xenon difluoride. Depending on the size of the supporting posts and the pore sizes the overall porosity of the membranes ranged from 4.4 % to 25.3 %. The microfabricated membranes can be used for integrating barrier tissues such as the gastrointestinal tract epithelium, the lung epithelium, or other barrier tissues with multi-organ "body-on-a-chip" devices.
    Biomedical Microdevices 07/2012; 14(5):895-906. DOI:10.1007/s10544-012-9669-0 · 2.77 Impact Factor
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    Michael L Shuler, Jong Hwan Sung
    Annals of Biomedical Engineering 05/2012; 40(6):1209-10. DOI:10.1007/s10439-012-0589-1 · 3.23 Impact Factor
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    Beum Jun Kim, Jinpian Diao, Michael L Shuler
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    ABSTRACT: Animal cells have been used extensively in therapeutic protein production. The growth of animal cells and the expression of therapeutic proteins are highly dependent on the culturing environments. A large number of experimental permutations need to be explored to identify the optimal culturing conditions. Miniaturized bioreactors are well suited for such tasks as they offer high-throughput parallel operation and reduce cost of reagents. They can also be automated and be coupled to downstream analytical units for online measurements of culture products. This review summarizes the current status of miniaturized bioreactors for animal cell cultivation based on the design categories: microtiter plates, flasks, stirred tank reactors, novel designs with active mixing, and microfluidic cell culture devices. We compare cell density and product titer, for batch or fed-batch modes for each system. Monitoring/controlling devices for engineering parameters such as pH, dissolved oxygen, and dissolved carbon dioxide, which could be applied to such systems, are summarized. Finally, mini-scale tools for process performance evaluation for animal cell cultures are discussed: total cell density, cell viability, product titer and quality, substrates, and metabolites profiles.
    Biotechnology Progress 05/2012; 28(3):595-607. DOI:10.1002/btpr.1554 · 1.88 Impact Factor
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    Michael L Shuler
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    ABSTRACT: We seek to construct physical and mathematical models of life. Such models allow us to test our understanding of how living systems function and how they respond to human imposed stimuli. One system is a genomically and chemically complete model of a minimal cell. This cell is a hypothetical bacterium with the fewest number of genes possible. Such a minimal cell provides a platform to ask about the essential features of a living cell and forms a platform to investigate "synthetic biology." A second system is "Body-on-a-Chip" which is a microfabricated microfluidic system with cells or tissue constructs representing various organs in the body. It can be constructed from human or animal cells and used in drug discovery development. That model is a physical representation of a physiologically based pharmacokinetic model. Both the computer and the physical models provide insight into the underlying biology and provide new tools to make use of that understanding to provide benefits to society.
    Annals of Biomedical Engineering 04/2012; 40(7):1399-407. DOI:10.1007/s10439-012-0567-7 · 3.23 Impact Factor
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    ABSTRACT: Commercially available permeable supports with microporous membranes have led to significant improvements in the culture of polarized cells because they permit them to feed basolaterally and thus carry out metabolism in a more in vivo-like setting. The porous nature of these membranes enables permeability measurements of drugs or biomolecules across the cellular barrier. However, current porous membranes have a high flow resistance due to great thickness (20-40 μm), low porosity, and a wide pore size distribution with tortuous diffusion paths, which make them low-throughput for permeability studies. Here we describe an alternate platform that is more flexible, allows for more control over physical parameters of the membranes, and is high-throughput. This study reports on the synthesis, nanofabrication, and surface characterization of a 3-μm-thick transparent membrane based on poly(4-hydroxy styrene) (PHOST). The membranes are nanofabricated using electron beam lithography and deep ion plasma etching to achieve an organized array of straight pores from 50 to 800 nm in diameter, with at least 23 times less flow resistance. It also shows for the first time the potential utility of PHOST as a cell culture substrate without cytotoxicity, and suitability for nanofabrication processes due to temperature stability.
    Tissue Engineering Part C Methods 03/2012; 18(9):667-76. DOI:10.1089/ten.TEC.2011.0598 · 4.64 Impact Factor
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    ABSTRACT: Metarhizium acridum, an entomopathogenic fungus, has been commercialized and used successfully for biocontrol of grasshopper pests in Africa and Australia. Its conidia produce two novel 17-membered macrocycles, metacridamides A and B, which consist of a Phe unit condensed with a nonaketide. Planar structures were elucidated by a combination of mass spectrometric and NMR techniques. Following hydrolysis of 1, chiral amino acid analysis assigned the L-configuration to the Phe unit. A crystal structure established the absolute configuration of the eight remaining stereogenic centers in 1. Metacridamide A showed cytotoxicity to three cancer lines with IC₅₀'s of 6.2, 11.0, and 10.8 μM against Caco-2 (epithelial colorectal adenocarcinoma), MCF-7 (breast cancer), and HepG2/C3A (hepatoma) cell lines, respectively. In addition, metacridamide B had an IC₅₀ of 18.2 μM against HepG2/C3A, although it was inactive at 100 μM against Caco-2 and MCF-7. Neither analogue showed antimicrobial, phytotoxic, or insecticidal activity.
    Journal of Natural Products 02/2012; 75(2):175-80. DOI:10.1021/np2007044 · 3.95 Impact Factor

Publication Stats

5k Citations
617.88 Total Impact Points

Institutions

  • 1985–2015
    • Cornell University
      • • Department of Biomedical Engineering
      • • Department of Chemical and Biomolecular Engineering
      • • Department of Civil and Environmental Engineering
      • • Department of Plant Biology
      Итак, New York, United States
  • 2012
    • Binghamton University
      • Department of Bioengineering
      Binghamton, NY, United States
  • 2006–2007
    • Yonsei University
      • Department of Electrical and Electronic Engineering
      Sŏul, Seoul, South Korea
  • 1989
    • Ithaca College
      Ithaca, New York, United States