scholarly journals Microphysiological Systems: Stakeholder Challenges to Adoption in Drug Development

2021 ◽  
pp. 1-13
Author(s):  
Passley Hargrove-Grimes ◽  
Lucie A. Low ◽  
Danilo A. Tagle
Keyword(s):  
Human Physiology ◽  
Pharmaceutical Industry ◽  
Drug Development ◽  
End Users ◽  
Regulatory Agencies ◽  
Functional Level ◽  
Multiple Stakeholder ◽  
Widespread Adoption ◽  
Microphysiological Systems

Microphysiological systems (MPS) or tissue chips/organs-on-chips are novel <i>in vitro</i> models that emulate human physiology at the most basic functional level. In this review, we discuss various hurdles to widespread adoption of MPS technology focusing on issues from multiple stakeholder sectors, e.g., academic MPS developers, commercial suppliers of platforms, the pharmaceutical and biotechnology industries, and regulatory organizations. Broad adoption of MPS technology has thus far been limited by a gap in translation between platform developers, end-users, regulatory agencies, and the pharmaceutical industry. In this brief review, we offer a perspective on the existing barriers and how end-users may help surmount these obstacles to achieve broader adoption of MPS technology.

scholarly journals Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

2021 ◽  
Vol 12 ◽  
Author(s):  
Felipe T. Lee-Montiel ◽  
Alexander Laemmle ◽  
Verena Charwat ◽  
Laure Dumont ◽  
Caleb S. Lee ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Development ◽  
Induced Pluripotent Stem Cell ◽  
Study Drug ◽  
Cytochrome P450 Enzyme ◽  
Human Organ ◽  
Microphysiological Systems ◽  
Drug Drug Interaction ◽  
Induced Pluripotent

Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.

ECVAM and Pharmaceuticals

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 221-223 ◽  
Author(s):  
Philippe Vanparys
Keyword(s):  
Pharmaceutical Industry ◽  
Drug Development ◽  
Toxicity Tests ◽  
Development Phase ◽  
Use Of Resources ◽  
Discovery Phase ◽  
Test Models ◽  
New Chemical Entities ◽  
Phase Medium

In the pharmaceutical industry, toxicology testing is normally done by preclinical scientists during the Development phase. In the last decade, the implementation of high-throughput screens during the Discovery phase has resulted in an ever-increasing number of lead candidates to be selected for drug development. The low throughput of the conventional safety tests is a bottleneck in the drug-development process. The pharmaceutical industry needs new techniques, down-scaled tests and in vitro alternative test models to determine the absorption, distribution, metabolism, and excretion (ADME) and toxicology profiles of compounds in the late-Discovery phase and/or early in the Development phase. Medium-throughput ADME and toxicity tests will enhance the selection of safer new chemical entities for animals and/or humans. Consequently, this testing strategy will not only reduce the use of resources and the overall development time, but will also result in a substantial decrease in animal use.

scholarly journals Application of lung microphysiological systems to COVID-19 modeling and drug discovery: a review

2021 ◽  
Author(s):  
Argus M. Sun ◽  
Tyler Hoffman ◽  
Bao Q. Luu ◽  
Nureddin Ashammakhi ◽  
Song Li
Keyword(s):  
Drug Development ◽  
High Throughput Screening ◽  
Current Model ◽  
3D Structure ◽  
Three Dimensional ◽  
Cell Types ◽  
Model Systems ◽  
Biological Interactions ◽  
Microphysiological Systems

AbstractThere is a pressing need for effective therapeutics for coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The process of drug development is a costly and meticulously paced process, where progress is often hindered by the failure of initially promising leads. To aid this challenge, in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening, thereby saving valuable time and resources during a pandemic crisis. The SARS-CoV-2 virus attacks the lung, an organ where the unique three-dimensional (3D) structure of its functional units is critical for proper respiratory function. The in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell types. Current model systems include Transwell, organoid and organ-on-a-chip or microphysiological systems (MPSs). We review models that have direct relevance toward modeling the pathology of COVID-19, including the processes of inflammation, edema, coagulation, as well as lung immune function. We also consider the practical issues that may influence the design and fabrication of MPS. The role of lung MPS is addressed in the context of multi-organ models, and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung MPS to accelerate drug development for COVID-19 and other infectious diseases.

Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry

Lab on a Chip ◽  
2020 ◽  
Vol 20 (2) ◽  
pp. 215-225 ◽  
Author(s):  
Andreas R. Baudy ◽  
Monicah A. Otieno ◽  
Philip Hewitt ◽  
Jinping Gan ◽  
Adrian Roth ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Pharmaceutical Industry ◽  
Systems Development ◽  
End Users ◽  
Safety Risk ◽  
Microphysiological Systems

This pharmaceutical industry guidance based on a 3-staged benchmarking strategy aims to help MPS developers and end users identify what could be the most valuable models for safety risk assessment, as well as provide an overview of contexts of use.

scholarly journals Integrated hiPSC-based liver and heart microphysiological systems predict unsafe drug-drug interaction

2020 ◽  
Author(s):  
Felipe T. Lee-Montiel ◽  
Alexander Laemmle ◽  
Laure Dumont ◽  
Caleb S. Lee ◽  
Nathaniel Huebsch ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Development ◽  
Human Genetics ◽  
Functional Integration ◽  
Study Drug ◽  
Cytochrome P450 Enzyme ◽  
Human Organ ◽  
Microphysiological Systems ◽  
Drug Drug Interaction

AbstractMicrophysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both built with the same hiPSC line—to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish functional integration of isogenic hiPSC-based liver and cardiac MPSs, which allows screening for DDI, and thus drug efficacy and toxicity, in the same genetic background.

scholarly journals Integrating Biosensors in Organs-on-Chip Devices: A Perspective on Current Strategies to Monitor Microphysiological Systems

Biosensors ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 110 ◽  
Author(s):  
Erika Ferrari ◽  
Cecilia Palma ◽  
Simone Vesentini ◽  
Paola Occhetta ◽  
Marco Rasponi
Keyword(s):  
Imaging Techniques ◽  
Biological Models ◽  
Electromechanical Properties ◽  
Human Organs ◽  
Tissue Constructs ◽  
Microphysiological Systems ◽  
Metabolic Activities ◽  
On Chip ◽  
Chip Analysis

Organs-on-chip (OoC), often referred to as microphysiological systems (MPS), are advanced in vitro tools able to replicate essential functions of human organs. Owing to their unprecedented ability to recapitulate key features of the native cellular environments, they represent promising tools for tissue engineering and drug screening applications. The achievement of proper functionalities within OoC is crucial; to this purpose, several parameters (e.g., chemical, physical) need to be assessed. Currently, most approaches rely on off-chip analysis and imaging techniques. However, the urgent demand for continuous, noninvasive, and real-time monitoring of tissue constructs requires the direct integration of biosensors. In this review, we focus on recent strategies to miniaturize and embed biosensing systems into organs-on-chip platforms. Biosensors for monitoring biological models with metabolic activities, models with tissue barrier functions, as well as models with electromechanical properties will be described and critically evaluated. In addition, multisensor integration within multiorgan platforms will be further reviewed and discussed.

scholarly journals Qualification of translational safety biomarkers

2021 ◽  
pp. 153537022110021
Author(s):  
John-Michael Sauer ◽  
Amy C Porter
Keyword(s):  
Skeletal Muscle ◽  
Drug Development ◽  
Vascular Injury ◽  
Validation Studies ◽  
Safety Assessment ◽  
Regulatory Agencies ◽  
Development Studies ◽  
Clinical Validation ◽  
Development Tools ◽  
Important Drug

Safety biomarkers are important drug development tools, both preclinically and clinically. It is a straightforward process to correlate the performance of nonclinical safety biomarkers with histopathology, and ideally, the biomarker is useful in all species commonly used in safety assessment. In clinical validation studies, where histopathology is not feasible, safety biomarkers are compared to the response of standard biomarkers and/or to clinical adjudication. Worldwide, regulatory agencies have put in place processes to qualify biomarkers to provide confidence in the manner of use and interpretation of biomarker data in drug development studies. This paper describes currently qualified safety biomarkers which can be utilized to monitor for nephrotoxicity and cardiotoxicity and ongoing projects to qualify safety biomarkers for liver, skeletal muscle, and vascular injury. In many cases, the development and use of these critical drug development tools is dependent upon partnerships and the precompetitive sharing of data to support qualification efforts.

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