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Microphysiological system

Peter G Alexander, Karen L Clark, Rocky S Tuan
Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact...
October 21, 2016: Birth Defects Research. Part C, Embryo Today: Reviews
Nikolaos Tsamandouras, Tomasz Kostrzewski, Cynthia L Stokes, Linda G Griffith, David J Hughes, Murat Cirit
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from 5 different donors cultured in a perfused 3D human liver microphysiological system and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of 6 compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability (LDH release, albumin and urea production)...
October 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Paula G Miller, Michael L Shuler
Cover Legend The design and operation of a bidirectional flow, pumpless 14 chamber system representing 13 tissues/organs with both barrier and nonbarrier tissue chambers is described. Viability across all compartments was initially demonstrated with one cell line. Then viability and functionality in the device was retained for 7 days using 5 representative cell lines and compared to static controls. The cover image, by Michael L. Shuler and Paula G. Miller, is based on the Article Design and demonstration of a pumpless 14 compartment microphysiological system, DOI: 10...
October 2016: Biotechnology and Bioengineering
Patrícia Moura Rosa, Nimi Gopalakrishnan, Hany Ibrahim, Markus Haug, Øyvind Halaas
T cells play a central role in immunity towards cancer and infectious diseases. T cell responses are initiated in the T cell zone of the lymph node (LN), where resident antigen-bearing dendritic cells (DCs) prime and activate antigen-specific T cells passing by. In the present study, we investigated the T cell : DC interaction in a microfluidic device to understand the intercellular dynamics and physiological conditions in the LN. We show random migration of antigen-specific T cells onto the antigen-presenting DC monolayer independent of the flow direction with a mean T cell : DC dwell time of 12...
October 7, 2016: Lab on a Chip
Agua Sobrino, Duc T T Phan, Rupsa Datta, Xiaolin Wang, Stephanie J Hachey, Mónica Romero-López, Enrico Gratton, Abraham P Lee, Steven C George, Christopher C W Hughes
There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This "organs-on-chips" approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs). This "tumor-on-a-chip" platform incorporates human tumor and stromal cells that grow in a 3D extracellular matrix and that depend for survival on nutrient delivery through living, perfused microvessels...
2016: Scientific Reports
Elijah J Weber, Alenka Chapron, Brian D Chapron, Jenna L Voellinger, Kevin A Lidberg, Catherine K Yeung, Zhican Wang, Yoshiyuki Yamaura, Dale W Hailey, Thomas Neumann, Danny D Shen, Kenneth E Thummel, Kimberly A Muczynski, Jonathan Himmelfarb, Edward J Kelly
The kidney proximal tubule is the primary site in the nephron for excretion of waste products through a combination of active uptake and secretory processes and is also a primary target of drug-induced nephrotoxicity. Here, we describe the development and functional characterization of a 3-dimensional flow-directed human kidney proximal tubule microphysiological system. The system replicates the polarity of the proximal tubule, expresses appropriate marker proteins, exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with proximal tubule function in vivo...
September 2016: Kidney International
S Y Chang, E J Weber, Kp Van Ness, D L Eaton, E J Kelly
Because of complex cellular microenvironments of both the liver and kidneys, accurate modeling of transport function has remained a challenge, leaving a dire need for models that can faithfully recapitulate both the architecture and cell-cell interactions observed in vivo. The study of hepatic and renal transport function is a fundamental component of understanding the metabolic fate of drugs and xenobiotics; however, there are few in vitro systems conducive for these types of studies. For both the hepatic and renal systems, we provide an overview of the location and function of the most significant phase I/II/III (transporter) of enzymes, and then review current in vitro systems for the suitability of a transporter function study and provide details on microphysiological systems that lead the field in these investigations...
November 2016: Clinical Pharmacology and Therapeutics
Amanda M Clark, Bo Ma, D Lansing Taylor, Linda Griffith, Alan Wells
The liver is a highly metastasis-permissive organ, tumor seeding of which usually portends mortality. Its unique and diverse architectural and cellular composition enable the liver to undertake numerous specialized functions, however, this distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells. The particular focus for this perspective is the bidirectional interactions between the disseminated tumor cells and the unique resident cell populations of the liver; notably, parenchymal hepatocytes and non-parenchymal liver sinusoidal endothelial, Kupffer, and hepatic stellate cells...
September 2016: Experimental Biology and Medicine
George A Truskey
Cardiovascular tissue engineering offers the promise of biologically based repair of injured and damaged blood vessels, valves, and cardiac tissue. Major advances in cardiovascular tissue engineering over the past few years involve improved methods to promote the establishment and differentiation of induced pluripotent stem cells (iPSCs), scaffolds from decellularized tissue that may produce more highly differentiated tissues and advance clinical translation, improved methods to promote vascularization, and novel in vitro microphysiological systems to model normal and diseased tissue function...
2016: F1000Research
Jaewon Lee, Jin-Ha Choi, Hyun Jung Kim
No abstract text is available yet for this article.
August 2016: Expert Review of Gastroenterology & Hepatology
Cassidy Blundell, Emily R Tess, Ariana S R Schanzer, Christos Coutifaris, Emily J Su, Samuel Parry, Dongeun Huh
During human pregnancy, the fetal circulation is separated from maternal blood in the placenta by two cell layers - the fetal capillary endothelium and placental trophoblast. This placental barrier plays an essential role in fetal development and health by tightly regulating the exchange of endogenous and exogenous materials between the mother and the fetus. Here we present a microengineered device that provides a novel platform to mimic the structural and functional complexity of this specialized tissue in vitro...
August 2, 2016: Lab on a Chip
Uwe Marx, Tommy B Andersson, Anthony Bahinski, Mario Beilmann, Sonja Beken, Flemming R Cassee, Murat Cirit, Mardas Daneshian, Susan Fitzpatrick, Olivier Frey, Claudia Gaertner, Christoph Giese, Linda Griffith, Thomas Hartung, Minne B Heringa, Julia Hoeng, Wim H de Jong, Hajime Kojima, Jochen Kuehnl, Marcel Leist, Andreas Luch, Ilka Maschmeyer, Dmitry Sakharov, Adrienne J A M Sips, Thomas Steger-Hartmann, Danilo A Tagle, Alexander Tonevitsky, Tewes Tralau, Sergej Tsyb, Anja van de Stolpe, Rob Vandebriel, Paul Vulto, Jufeng Wang, Joachim Wiest, Marleen Rodenburg, Adrian Roth
The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing...
2016: ALTEX
Paula G Miller, Michael L Shuler
We describe a human "Body-on-a-chip" device (or microphysiological system) that could be used to emulate drug distribution, metabolism, and action in the body. It is based upon a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model, where multiple chambers representing different organs are connected with fluidic channels to mimic multi-organ interactions within the body. Here we describe a pumpless 14 chamber (13 organs) microfluidic cell culture device that provides a separation between barrier and nonbarrier types of cell cultures...
October 2016: Biotechnology and Bioengineering
C E Fernandez, R W Yen, S M Perez, H W Bedell, T J Povsic, W M Reichert, G A Truskey
In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture...
2016: Scientific Reports
Xiaolin Wang, Duc T T Phan, Da Zhao, Steven C George, Christopher C W Hughes, Abraham P Lee
Coculturing multiple cell types together in 3-dimensional (3D) cultures better mimics the in vivo microphysiological environment, and has become widely adopted in recent years with the development of organ-on-chip systems. However, a bottleneck in set-up of these devices arises as a result of the delivery of the gel into the microfluidic chip being sensitive to pressure fluctuations, making gel confinement at a specific region challenging, especially when manual operation is performed. In this paper, we present a novel design of an on-chip regulator module with pressure-releasing safety microvalves that can facilitate stable gel delivery into designated microchannel regions while maintaining well-controlled, non-bursting gel interfaces...
March 7, 2016: Lab on a Chip
S Eggert, F A Alexander, J Wiest
Screening a newly developed drug, food additive or cosmetic ingredient for toxicity is a critical preliminary step before it can move forward in the development pipeline. Due to the sometimes dire consequences when a harmful agent is overlooked, toxicologists work under strict guidelines to effectively catalogue and classify new chemical agents. Conventional assays involve long experimental hours and many manual steps that increase the probability of user error; errors that can potentially manifest as inaccurate toxicology results...
August 2015: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
Richard A Thompson, Emre M Isin, Monday O Ogese, Jerome T Mettetal, Dominic P Williams
Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites...
April 18, 2016: Chemical Research in Toxicology
Giovanni Ligresti, Ryan J Nagao, Jun Xue, Yoon Jung Choi, Jin Xu, Shuyu Ren, Takahide Aburatani, Susan K Anderson, James W MacDonald, Theo K Bammler, Stephen M Schwartz, Kimberly A Muczynski, Jeremy S Duffield, Jonathan Himmelfarb, Ying Zheng
Human kidney peritubular capillaries are particularly susceptible to injury, resulting in dysregulated angiogenesis, capillary rarefaction and regression, and progressive loss of kidney function. However, little is known about the structure and function of human kidney microvasculature. Here, we isolated, purified, and characterized human kidney peritubular microvascular endothelial cells (HKMECs) and reconstituted a three-dimensional human kidney microvasculature in a flow-directed microphysiologic system...
August 2016: Journal of the American Society of Nephrology: JASN
J Yu, N A Cilfone, E M Large, U Sarkar, J S Wishnok, S R Tannenbaum, D J Hughes, D A Lauffenburger, L G Griffith, C L Stokes, M Cirit
Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models...
October 2015: CPT: Pharmacometrics & Systems Pharmacology
C L Stokes, M Cirit, D A Lauffenburger
Scaling of a microphysiological system (MPS) or physiome-on-a-chip is arguably two interrelated, modeling-based activities: on-platform scaling and in vitro-in vivo translation. This dual approach reduces the need to perfectly rescale and mimic in vivo physiology, an aspiration that is both extremely challenging and not substantively meaningful because of uncertain relevance of any specific physiological condition. Accordingly, this perspective offers a tractable approach for designing interacting MPSs and relating in vitro results to analogous context in vivo...
October 2015: CPT: Pharmacometrics & Systems Pharmacology
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