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Cited by 223Tissue Engineering and Regenerative MedicineAnimal testing and alternativesCardiac electrophysiology and arrhythmias

Cardiovascular disease models: A game changing paradigm in drug discovery and screening

Open access
Savoji, Houman, Mohammadi, Mohammad Hossein, Rafatian, Naimeh, Toroghi, Masood Khaksar, Wang, Erika Yan, Zhao, Yimu, Korolj, Anastasia, Ahadian, Samad +1 more·2019·Biomaterials
DOI 10.1016/j.biomaterials.2018.09.036PMC PMC6397087
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Abstract

Cardiovascular disease is the leading cause of death worldwide. Although investment in drug discovery and development has been sky-rocketing, the number of approved drugs has been declining. Cardiovascular toxicity due to therapeutic drug use claims the highest incidence and severity of adverse drug reactions in late-stage clinical development. Therefore, to address this issue, new, additional, replacement and combinatorial approaches are needed to fill the gap in effective drug discovery and screening. The motivation for developing accurate, predictive models is twofold: first, to study and discover new treatments for cardiac pathologies which are leading in worldwide morbidity and mortality rates; and second, to screen for adverse drug reactions on the heart, a primary risk in drug development. In addition to in vivo animal models, in vitro and in silico models have been recently proposed to mimic the physiological conditions of heart and vasculature. Here, we describe current in vitro, in vivo, and in silico platforms for modelling healthy and pathological cardiac tissues and their advantages and disadvantages for drug screening and discovery applications. We review the pathophysiology and the underlying pathways of different cardiac diseases, as well as the new tools being developed to facilitate their study. We finally suggest a roadmap for employing these non-animal platforms in assessing drug cardiotoxicity and safety.

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  • Premisecitation

    TGF-β is the critical mediator of pathological fibrosis after myocardial injury.

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  • Interpretationreasoning

    Identifying biomarkers that signal both acute and long-term toxicities before irreversible organ damage remains a challenge with current technologies.

    “Identifying biomarkers that can signal both acute and long-term toxicities before irreversible organ damage is incurred would be ideal, but how to do this with current technologies remains a challenge, suggesting a need for new technologies.”
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    A high-fat diet in animals is a well-established way to create atherosclerosis models.

    “Although the use of the high-fat diet in animals (e.g. atherosclerosis models) has been a well-established method to generate these models”
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    Atherosclerosis is the most likely cause of myocardial infarction and stroke.

    “Atherosclerosis is the most likely cause of MI and stroke [12–15].”
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    The main disadvantage of small animal models (mice, rats, rabbits, and cats) is the relevance of obtained results to humans due to distinct physiological differences.

    “However, the main disadvantage of these small animal models (i.e. mice, rats, rabbits, and cats) is the relevance of the obtained results to humans due to the distinct physiological differences between these species and humans [84–86].”
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    Premisecitation

    Vioxx (Rofecoxib) was linked to over 27,000 cardiovascular-related deaths and myocardial infarctions.

    “Vioxx (Rofecoxib), originally designed to treat pain related to osteoarthritis and approved by the Food and Drug Administration (FDA) in 1999, was linked to over 27,000 cardiovascular-related deaths and myocardial infarctions (MI).”
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    Genetically modified mice have been extensively used for feasibility and proof-of-concept studies, but translational aspects need careful addressing due to differences in heart function and size between mice and humans.

    “For example, genetically modified mice have been extensively used for feasibility and proof-of-concept studies. However, translational aspects need to be more carefully addressed due to the enormous differences in the heart function and size between mice and humans [93].”
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    Biomarkers used in clinical trials often reflect already serious and acute toxicities, with limited insight into long-term damage.

    “Although non-invasive, biomarkers assessed via biochemical assays, genomic markers, antibody-based methods and imaging techniques [9], often yield information that reflects already serious and acute toxicities, with limited insight available for long-term damage [8].”
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    Clinical trials have relatively small sample sizes, narrow patient demographics, and require non-invasive endpoints for monitoring.

    “Clinical trials have relatively small sample sizes, narrow subgroups of patient demographics, and require non-invasive endpoints for study monitoring [8].”
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    • cites [8] Li, 2004, Accurate prediction of human drug toxicity: a major challenge in drug development, Chem. Biol. Interact. source

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    The spontaneously hypertensive rat has been the animal of choice for screening antihypertensive compounds.

    “The spontaneously hypertensive rat (SHR), a transgenic line of hypertensive rats, have been the animal of choice for screening antihypertensive compounds [109].”
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    Premisecitation

    Reperfusion after ischemia restores blood flow, but over-oxygenation induces reactive oxygen species that cause further damage to cardiac tissue through necrosis, apoptosis, autophagy, and secondary necrosis.

    “Reperfusion after ischemia restores blood flow; but over-oxygenation after ischemia, with the induction of reactive oxygen species (ROS), induces further damage to cardiac tissue by necrosis, apoptosis, autophagy, and secondary necrosis [40].”
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    Cardiac fibrosis is characterized by cardiac fibroblast over-proliferation, myofibroblast activation, and increased deposition of fibrous extracellular matrix proteins.

    “Cardiac fibrosis is the scarring process that is characterized by cardiac fibroblast (CF) over-proliferation, myoFB activation, and increased deposition of fibrous ECM proteins [56].”
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    Extensive cardiac fibrosis causes electro-mechanical disturbances and decreases cardiac contractile reserve, leading to heart failure.

    “However, extensive cardiac fibrosis causes electro-mechanical disturbances in the heart and decreases the cardiac contractile reserve, which results in an attenuated ability of the heart to maintain cellular perfusion under normal cardiac filling pressure, eventually leading to HF [46].”
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    Premisecitation

    Up to 70% of human toxicity can be approximated in preclinical studies, but subtler higher-risk cardiovascular events emerge only when drugs are administered to humans for longer periods and in larger populations.

    “While up to 70% of human toxicity may be approximated in the preclinical stage, there are other subtler and higher-risk cardiovascular events that only emerge when drugs are administered to humans for longer periods of time and in larger populations [7].”
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    Dilated cardiomyopathy is defined by an enlarged and poorly contractile left ventricle and is the major cause of heart failure.

    “Dilated cardiomyopathy (DCM) is defined by an enlarged and poorly contractile LV. Genetic or non-genetic causes, including hypertension and valve diseases, may lead to dilated cardiomyopathy. This type of heart disease is the major cause of HF [51,53].”
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    Doxorubicin-induced heart failure is a suitable model for mechanistic evaluation of non-ischemic cardiovascular disease, mimicking severe non-ischemic human cardiomyopathy and left ventricular dysfunction.

    “Doxorubicin (DOX)-induced HF is a suitable model to perform mechanistic evaluation of non-ischemic CVD. It mimics severe non-ischemic human cardiomyopathy and LV dysfunction. It is achieved by giving a single dose of DOX (20 mg/kg) to the animal, causing clinical symptoms reminiscent of non-ischemic HF [90].”
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    Hypertrophic cardiomyopathy is characterized by cardiac hypertrophy, a non-dilated left ventricle, and a normal or increased ejection fraction.

    “Hypertrophic cardiomyopathy (HCM) is characterized by cardiac hypertrophy, a non-dilated left ventricle (LV), and a normal or increased EF.”
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    Genetically modified ApoE-deficient mice have plasma cholesterol about five times higher than controls, and Ldlr-deficient mice have levels two to three times higher.

    “genetically modified ApoE- and Ldlr-deficient mice have higher plasma cholesterol levels (5 times and 2–3 times higher than controls, respectively) [114]”
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    Mice and rats are not all suitable for atherosclerosis research because of intrinsic genetic differences, greater resistance to atherogenesis, and the high-cholesterol diet.

    “not all experimental models (i.e. mice and rats) are acceptable for atherosclerosis due to intrinsic genetic differences, their higher resistance to atherogenesis and the high cholesterol diet [112,113]”
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    • cites [112] Badimon, 2001, Atherosclerosis and thrombosis: lessons from animal models, Thromb. Haemostasis

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    • cites [113] Vilahur, 2011, Atherosclerosis and thrombosis: insights from large animal models, BioMed Res. Int. source

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    Transgenic lines are relatively costly, which limits researchers from using optimal numbers of subjects.

    “However, the transgenic lines are relatively costly, limiting researchers from using optimal numbers of subjects in their studies [119].”
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    • cites [119] Pinkert, 2014

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    Animal models have historically been used to study the etiology, pathogenesis, pathophysiology, progression, and mechanisms of cardiovascular diseases, and offer tools in disease modelling, drug discovery, and therapeutic interventions.

    “Various animal models have historically been used to further our knowledge on the etiology, pathogenesis, pathophysiology, progression, and underlying mechanisms of CVDs. They offer valuable tools in disease modelling, drug discovery and therapeutic interventions [76,77].”
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    Genetically modified animal models capture some features of the human cardiovascular disease phenotype but typically do not resemble all aspects of cardiovascular diseases in humans.

    “Although these genetically modified models could capture some of the features of the CVD phenotype in humans, they typically do not resemble all aspects of CVDs in humans [86,87].”
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    • cites [86] Houser, 2012, Animal models of heart failure: a scientific statement from the American Heart Association, Circ. Res. source

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    Premisecitation

    Cardiovascular disease is a leading cause of death globally, with an estimated 17 million deaths annually.

    “Cardiovascular disease is the leading cause of death worldwide.”
    • Also stated in: § Pathophysiology of cardiovascular diseases (CVDs) · hedged
      “Cardiovascular diseases (CVDs) including heart attack, stroke and heart failure (HF) are a leading cause of morbidity and mortality, contributing to an estimated 17 million deaths annually, around the world [12].”
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    • cites [12] Benjamin, 2017, Heart disease and stroke statistics-2017 update: a report from the American Heart Association, Circulation source

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    Human and murine lipid processing differ: humans are LDL-based and mice are HDL-based.

    “differences in human versus murine lipid processing (i.e. LDL-based versus HDL-based, respectively) [113]”
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    • cites [113] Vilahur, 2011, Atherosclerosis and thrombosis: insights from large animal models, BioMed Res. Int. source

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    Rodent models are widely used in cardiovascular research due to easy handling and housing, short gestation time, low maintenance costs, and ability for genetic manipulation.

    “Rodent models are widely used in cardiovascular research due to their easy handling and housing, short gestation time, low maintenance costs, and more importantly ability for genetic manipulation.”
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    • cites [84] Milani-Nejad, 2014, Small and large animal models in cardiac contraction research: advantages and disadvantages, Pharmacol. Therapeut. source

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    Pig arterial anatomy and collateral coronary circulation better mimic human ones.

    “the arterial anatomy and collateral coronary circulation in pigs can better mimic those of humans.”
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    • cites [126] Montgomery, 2017, Flexible shape-memory scaffold for minimally invasive delivery of functional tissues, Nat. Mater. source

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    Premisecitation

    Human primary cell use is restricted by limitations including donor-dependent behavior, low proliferation, limited expansion, and finite lifespan, making broad drug discovery use difficult.

    “The usage of human primary cells is restricted by some important limitations [134].”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “in addition to their low proliferation rate, limited expansion capacity, and finite lifespan, it is difficult to use primary cells more broadly in drug discovery”
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    • cites [134] Eglen, 2011, Primary cells and stem cells in drug discovery: emerging tools for high-throughput screening, Assay Drug Dev. Technol. source

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    • cites [135] Polak, 2006, Stem cells and tissue engineering: past, present, and future, Ann. N. Y. Acad. Sci. source

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    Premisenone given

    Directed differentiation yields heterogeneous populations with average cardiomyocyte purity of 50-90%, so enrichment is necessary for some applications.

    “directed differentiation yields a heterogeneous cell population with purity of CMs between 50 and 90% on average, it is necessary to enrich CMs for some applications.”
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    Premisereasoning

    Primary human cardiomyocytes have extremely limited proliferation and cannot be expanded to appreciable numbers from cardiac biopsies.

    “primary human CMs have an extremely limited ability to proliferate, thus they cannot be expanded to appreciable numbers from cardiac biopsies.”
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    Premisecitation

    Adult cardiomyocytes have an aspect ratio of 7:1 to 9.5:1, while heterogeneous hiPSC-CMs are smaller with aspect ratios of 2-3:1.

    “rod-like adult CMs have an aspect ratio between 7:1 to 9.5:1 [164], heterogeneous hiPSC-CMs are much smaller with lower aspect ratios (2–3:1) [165,166].”
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    • cites [164] Gerdes, 1992, Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy, Circulation source

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    • cites [165] Maillet, 2013, Molecular basis of physiological heart growth: fundamental concepts and new players, Nat. Rev. Mol. Cell Biol. source

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    • cites [166] Denning, 2016, Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform, Biochim. Biophys. Acta Mol. Cell Res. source

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    iPSCs can differentiate into various cell types, overcoming ethical issues associated with human embryonic stem cells.

    “iPSCs have also been demonstrated to differentiate into various cell types, overcoming the ethical issues associated with the use of human ESCs [155].”
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    • cites [155] Lu, 2013, Clinical therapy using iPSCs: hopes and challenges, Dev. Reprod. Biol.

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    Human heart architecture, heart rate, oxygen consumption, contractility, protein expression, and stem cell populations differ from those of rodents.

    “human heart architecture, heart rates, oxygen consumption, contractility, protein expression, and stem cell populations are different from those of rodents [123]”
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    • cites [123] Tsang, 2016, Large animal models of cardiovascular disease, Cell Biochem. Funct. source

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    Interpretationcitation

    Patient-derived iPSCs promise to provide many cells without immune rejection and improved disease models, making them suitable for drug discovery.

    “As they can be patient derived, iPSCs hold a great promise in providing patients with a significant number of cells, without immune rejection as well as providing improved models for disease modelling.”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “This makes them suitable substrates for drug discovery [156].”
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    • cites [156] Avior, 2016, Pluripotent stem cells in disease modelling and drug discovery, Nat. Rev. Mol. Cell Biol. source

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    • Rests on an assumption: Engineered in vitro cardiac tissues can adequately model human heart morphology and function for disease modelling, compound testing, and patient-specific drug screening.

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    Premisecitation

    Primary cardiomyocytes cannot proliferate naturally, but AC16 and HL-1 cell lines can.

    “Primary CMs naturally cannot proliferate; however, there are a few cell lines such as AC16 [137] and HL-1 [138] which can.”
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    • cites [137] Davidson, 2005, Novel cell lines derived from adult human ventricular cardiomyocytes, J. Mol. Cell. Cardiol. source

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    • cites [138] White, 2004, Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function, Am. J. Physiol. Heart Circ. Physiol. source

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    Premisecitation

    Cell lines have issues: responses may change with passage number, behavior depends on culture medium, serum, and immortalization-related genetic manipulation, they differ from primary cells, and many derive from tumors that affect functional properties.

    “there are some issues associated with the use of cell lines in vitro.”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “many cell lines are derived from tumors affecting their functional properties [136].”
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    • cites [136] Pan, 2009, Comparative proteomic phenotyping of cell lines and primary cells to assess preservation of cell type-specific functions, Mol. Cell. Proteomics source

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    Premisecitation

    hiPSC-CMs generally lack T-tubules, are largely mononuclear, and show mainly Z-discs and I-bands; adult cardiomyocytes have prominent T-tubules, are multinuclear, and show H-, A-bands, M-lines, Z-discs, and I-bands.

    “hiPSC-CMs generally exhibit no T-tubules, they largely have a single nucleus and microscopic analysis can detect mainly their Z-discs and I-bands. On the other hand, adult CMs have prominent T-tubules, they are multi-nuclear cells and transmission electron microscopy clearly shows their H-, A-bands, and M-lines in addition to Z-discs and I-bands [166].”
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    • cites [166] Denning, 2016, Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform, Biochim. Biophys. Acta Mol. Cell Res. source

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    Premisecitation

    Large animal models such as dogs, pigs, and sheep more faithfully resemble human physiology, function, and structure and are used to translate murine cellular and biological findings to the clinic.

    “large animal models (e.g. dogs, pigs, and sheep), which more faithfully resemble human physiology, function, and structural features, have been employed as experimental models to translate the cellular and biological findings from murine models into the clinic [123]”
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    • cites [123] Tsang, 2016, Large animal models of cardiovascular disease, Cell Biochem. Funct. source

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    • Rests on an assumption: Similarity to human anatomy and physiology is a valid criterion for selecting a translational CVD model.

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    Premisecitation

    In that study, hiPSC-CMs had sarcomere length 2.2 μm, 30% mitochondrial density, T-tubules, and highly organized ultrastructure, but a less mature phenotype than adult cardiomyocytes.

    “hiPSC-CMs were reported to have a sarcomere length of 2.2 μm, 30% mitochondrial density, the presence of T-tubules and highly organized ultrastructure.”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “a less mature phenotype was observed compare to adult CMs [175].”
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    • cites [175] Ronaldson-Bouchard, 2018, Advanced maturation of human cardiac tissue grown from pluripotent stem cells, Nature

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    Premisecitation

    Most in vitro models use cell lines because of their availability and unlimited expansion capacity.

    “Most in vitro models use cell lines due to their availability and unlimited expansion capacity [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Pan, 2009, Comparative proteomic phenotyping of cell lines and primary cells to assess preservation of cell type-specific functions, Mol. Cell. Proteomics source

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    Premisecitation

    HL-1, derived from atrial sarcoma, has organized sarcomeres, maintains contractile function after passaging, has gene expression similar to adult cardiomyocytes, spontaneous depolarization, and good ion channel expression.

    “The HL-1 cardiac cell line, derived from atrial sarcoma, exhibits a well-organized sarcomere structure and the ability to maintain contractile function after passaging, similar gene expression to the adult CMs, spontaneous depolarization and good ion channel expression [138,139].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] White, 2004, Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function, Am. J. Physiol. Heart Circ. Physiol. source

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    • cites [139] Claycomb, 1998, HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte, Proc. Natl. Acad. Sci. U. S. A. source

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    Premisereasoning

    There are no abundant sources of viable primary human cardiomyocytes because they can only be isolated from small cardiac biopsies that are rarely performed in cardiac disease.

    “There are also no abundant sources of viable primary human CMs, as they can only be isolated from small cardiac biopsies, which are only performed rarely in cardiac disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Cardiac progenitor cells are relatively easy to identify in rodents, but demonstrating their relevance in primates and humans is considerably harder.

    “Although these cells are relatively easy to identify in rodent models, it is considerably more difficult to demonstrate their relevance in primates and humans.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    AC16 is an immortalized human ventricular cell line made by fusing primary ventricular cardiomyocytes with SV40-transformed fibroblasts; it can proliferate, express cardiac markers, and differentiate under specific conditions.

    “AC16 is an immortalized human ventricular cell line, developed by fusing primary ventricular CMs with a simian virus 40 transformed fibroblast cell line.”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “these cells can proliferate, express cardiac-specific markers and differentiate under specific culture conditions [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Davidson, 2005, Novel cell lines derived from adult human ventricular cardiomyocytes, J. Mol. Cell. Cardiol. source

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    Premisecitation

    Adult human cardiomyocyte sarcomeres average about 2.0-2.2 μm, while hiPSC-CM sarcomeres average about 1.6-1.7 μm.

    “The average length for adult human- and hiPSCs-CMs’ sarcomeres is about 2.0–2.2 μm and 1.6–1.7 μm, respectively [169].”
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    • cites [169] Lundy, 2013, Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells, Stem Cell. Dev. source

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    Interpretationnone given

    Large animal models are more physiologically relevant for studying disease phenotypes, but they are costly and ethically restricted.

    “Although large animal models are more physiologically relevant for studying disease phenotypes, they are costly and impose several ethical restrictions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In vitro and in silico CVD models can provide more physiologically and clinically relevant readouts than the animal models they aim to supplement or replace.

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    Premisecitation

    Delivered growth factors restored stable collateral networks and enhanced myocardial perfusion and function in infarcted myocardium.

    “as well as to restore stable collateral networks and enhance myocardial perfusion and function in the infarcted myocardium [129]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Lu, 2007, Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The authors' team developed AngioChip, a multidimensional scaffold with a built-in vascular network using 3D stamping; long-term gravity-driven perfusion improved parenchymal cell viability and enabled vascular sprouting through scaffold micro-holes.

    “our team has developed a multidimensional scaffold with a built-in vascular network using a 3D stamping technique (AngioChip).”
    • Also stated in: § In vitro models in CVD research · plain
      “the system was able to improve the viability of cells embedded in the parenchymal space.”
    • Also stated in: § In vitro models in CVD research · plain
      “enabled vascular sprouting through the micro-holes of the scaffold into the parenchymal spaces”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266] Zhang, 2016, Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis, Nat. Mater. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mechanical stretch of hESC-CMs in gelatin sponge increased cell size, number, and elongation, lowered calcium cycle duration, increased contraction rate, and increased ion channel and gap junction protein expression.

    “This sample exhibited an increase in the size, number and elongation of cells compared to the unstretched sample.”
    • Also stated in: § Cardiac tissue engineering approaches · plain
      “the stretched sample showed a lower calcium cycle duration, higher rate of contraction and increase in the expression of ion channels and gap junctional proteins [177].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Mihic, 2014, The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    3D models have advantages over 2D models including cell-cell and cell-ECM interactions, physiological cues, more complex microenvironments, and higher similarity to native tissue.

    “3D models have several advantages compared to 2D models such as cell-cell, cell-ECM interactions, physiological cues, more complex microenvironments and higher similarity to native tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premiseown data

    In inVADE, immediate increase in tissue contraction frequency was observed after drug perfusion through microvasculature, and electrical stimulation gradually increased contraction under pacing.

    “Immediate increase in tissue contraction frequency was observed after drug perfusion through the microvasculature.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [274] Lai, 2017, InVADE: integrated vasculature for assessing dynamic events, Adv. Funct. Mater. source

      Not checked in the free run.

    • cites [275] Lai, 2017, InVADE: integrated vasculature for assessing dynamic events, Adv. Funct. Mater. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Pharmaceutical companies have used 2D cardiac in vitro models for decades to assess functional properties and test cardiotoxicity in preclinical stages.

    “Pharmaceutical companies have been utilizing 2D cardiac in vitro models to assess functional properties and test cardiotoxicity in preclinical stages for decades.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    It remains a challenge to develop functional evaluations that allow systematic assessment of risks and efficacy of drug candidates in such platforms.

    “it remains a challenge to develop functional evaluations that allow systematic assessment of the risks and efficacy of drug candidates in such platforms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Biowire lacks vasculature, so its tissue diameter was minimized to about 600 μm to allow oxygen and nutrient diffusion.

    “since this model lacks vasculature the tissue diameter was minimized on purpose to ~600 μm to allow for appropriate oxygen and nutrient diffusion [248].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Radisic, 2006, Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue, Biotechnol. Bioeng. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EHTs provide the opportunity to measure contractile function, the Frank-Starling mechanism, and effects of mechanical and electrical stimulation.

    “EHTs provide the opportunity to measure contractile function, Frank-Starling mechanism, and investigate the effects of mechanical and electrical stimulation [233,234].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [233] Hirt, 2012, Increased afterload induces pathological cardiac hypertrophy: a new in vitro model, Basic Res. Cardiol. source

      Not checked in the free run.

    • cites [234] Ralphe, 2013, 3D engineered cardiac tissue models of human heart disease: learning more from our mice, Trends Cardiovasc. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sarcomere alignment and organization affect action potential duration, contractile stress, and calcium transient kinetics.

    “sarcomere alignment and organization affect APD, contractile stress, and kinetics of Ca2+ transients (e.g CTD) [195,196].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [195] Ribeiro, 2015, Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro–correlation between contraction force and electrophysiology, Biomaterials source

      Not checked in the free run.

    • cites [196] Feinberg, 2012, Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microfabrication enables biomaterials to support long-lasting open EC lumens for perfusion, define capillary networks mimicking native vascular hierarchy, and guide and support EC growth and function.

    “Microfabrication enables the use of biomaterials to 1) support long-lasting open EC lumens for perfusion; 2) define sophisticated capillary networks to mimic the hierarchy of native vasculature; 3) guide and support EC growth and maintain their cellular functions [259–263].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [259] Zheng, 2012, In vitro microvessels for the study of angiogenesis and thrombosis, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

    • cites [260] Kolesky, 2014, 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs, Adv. Mater. source

      Not checked in the free run.

    • cites [261] Kolesky, 2016, Three-dimensional bioprinting of thick vascularized tissues, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

    • cites [262] Miller, 2012, Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues, Nat. Mater. source

      Not checked in the free run.

    • cites [263] Bertassoni, 2014, Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs, Lab a Chip source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AngioChip, parenchymal cells showed physiological drug responses through the vasculature: epinephrine increased spontaneous beating rate, and engineered tissue metabolized terfenadine to fexofenadine.

    “engineered cardiac tissue perfused with epinephrine increased the spontaneous beating rate, and engineered metabolised terfenadine to fexofenadine [266].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266] Zhang, 2016, Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis, Nat. Mater. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Biowire, cardiomyocytes aligned toward the suture, improving intercellular organization compared with age-matched embryoid bodies.

    “Since CMs were aligned toward the suture, the overall intercellular organization significantly improved compared to the age-matched embryoid bodies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Nunes, 2013, Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes, Nat. Methods source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In inVADE, cardiac tissues were formed from hiPSC-derived cardiomyocytes in fibrin gel, and two cantilevers measured contraction frequency and force non-invasively.

    “cardiac tissues were formed from hiPSCs-derived CMs encapsulated in fibrin gel. Two cantilevers were also used to determine the frequency and force of tissue contraction in a non-invasive way.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [274] Lai, 2017, InVADE: integrated vasculature for assessing dynamic events, Adv. Funct. Mater. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These vasculature-on-a-chip platforms are versatile tools to investigate drug effects on individual tissue models or link multiple tissue types via integrated vasculature, potentially enabling modeling of systemic exposure to drugs and their metabolites.

    “These platforms are versatile tools to investigate specific drug effects on individual tissue models or to link multiple different tissue types together via integrated vasculature, and therefore potentially enable modelling of systemic exposure to either a drug and/or its metabolic by-products.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Engineered in vitro cardiac tissues can adequately model human heart morphology and function for disease modelling, compound testing, and patient-specific drug screening.

  • May combine two claims.

    Premisecitation

    Shadrin et al. combined hydrogel molding and dynamic culture to develop a platform for culturing and maturing hiPSC-CMs to clinically relevant size (7×7 to 40×40 mm); the 50 μm-thick platform grew without exogenous stimulation and had conduction velocity 25.1 cm/s.

    “Shadrin et al. [242] combined hydrogel molding [243,244] and dynamic culture [245] techniques to develop a platform for culturing and maturing hiPSC-CMs to a clinically relevant size (from 7 mm × 7 mm–40 mm × 40 mm).”
    • Also stated in: § In vitro models in CVD research · plain
      “Their 50 μm-thick platform was grown without any exogenous stimulation and exhibited mature functional properties including conduction velocity of 25.1 cm/s [242].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [242] Shadrin, 2017, Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microfluidic and 3D-printed platforms can complement in vivo models, but they may not fully predict biological processes over longer periods because of coagulation problems.

    “Although microfluidic and 3D-printed platforms can complement the use of in vivo models, they may not fully predict biological processes especially in a longer period of time due to the coagulation issue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Increasing fibroblast number significantly reduced contractile force and altered beating frequency.

    “Increased fibroblast number was shown to significantly reduce contractile force and alter beating frequency [308].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [308] van Spreeuwel, 2017, Mimicking Cardiac Fibrosis in a Dish: fibroblast density rather than collagen density weakens cardiomyocyte function, J. Cardiovascular Transl. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The diseased tissues showed asynchronous beating behavior and increased mechanical stiffness.

    “The diseased tissues presented asynchronous beating behavior and increased mechanical stiffness.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [310] Sadeghi, 2017, Engineered 3D cardiac fibrotic tissue to study fibrotic remodeling, Adv. Healthcare Mater. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conant et al. developed an artificial neural network model to analyze experimental results efficiently and without bias, selecting kinase inhibitors with maximum efficacy and minimum side effects on cardiac cell viability and function.

    “For example, Conant et al. [337] have developed an artificial neural network model to analyze the experimental results in an efficient and unbiased manner to select kinase inhibitors with maximum efficacy and minimum side effects on cardiac cell viability and function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [337] Conant, 2017, Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Current animal models, including genetically modified CVD models, cannot fully recapitulate human physiology and pathophysiology and therefore imprecisely predict the biology and mechanisms of human cardiac dysfunction.

    “Current animal models, including genetically modified ones for CVDs, are incapable of fully recapitulating human physiology and pathophysiology, and thus imprecisely predict the biology and mechanisms involved in human cardiac dysfunctions [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Milani-Nejad, 2014, Small and large animal models in cardiac contraction research: advantages and disadvantages, Pharmacol. Therapeut. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    There is a growing need for new therapeutic agents with improved efficacy and safety.

    “Therefore, there is a growing need for new therapeutic agents with improved efficacy and safety.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A high-fidelity human cardiac tissue model using cardiomyocytes derived from hiPSCs would advance human-relevant disease models for personalized medicine and preclinical drug screening.

    “A highfidelity human cardiac tissue model using CMs derived from hiPSCs would be an asset in our progress toward generating human-relevant cardiac disease models enabling personalized medicine and preclinical drug screening.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Long-term studies are needed to systematically evaluate thrombotic processes using whole blood.

    “Long-term studies will inevitably be needed to systematically evaluate thrombotic processes using whole blood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These examples demonstrate the potential of mechanistic and data-driven modelling for dose selection, drug-drug interaction studies, and identifying the most efficient therapies.

    “Overall, these examples demonstrate the potential use of mechanistic and data driven modelling in dose selection, studies of drug-drug interaction, and identification of the most efficient therapies [338].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [338] Fitzgerald, 2006, Systems biology and combination therapy in the quest for clinical efficacy, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmaceutical companies use alternative systems such as simple 2D monolayer cell cultures of cell lines and, more recently, iPSC-derived cardiomyocytes, which cannot accurately mimic the 3D microenvironment of tissues and organs.

    “Therefore, pharmaceutical companies use alternative systems such as the relatively simple 2D monolayer cell cultures of cell lines, and, more recently, CMs derived from iPSCs [350] which are unable to accurately mimic aspects of the 3D microenvironment of tissues and organs of interest [351], where the main functions and physiological features are more complex.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [350] Breslin, 2013, Three-dimensional cell culture: the missing link in drug discovery, Drug Discov. Today source

      Not checked in the free run.

    • cites [351] Edmondson, 2014, Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors, Assay Drug Dev. Technol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although some protocols have reported differentiation of ventricular, atrial, and pacemaker cardiomyocyte subtypes, they still require standardization and harmonization because they produce heterogeneous cell populations.

    “Although few protocols reported differentiation of different subtypes of CMs including the ventricular [399,400], atrial [401,402], and pacemaker cells [172,398,403], they still need standardization and harmonization as they result in heterogeneous cell populations.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [172] Zhu, 2010, Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells novelty and significance, Circ. Res. source

      Not checked in the free run.

    • cites [398] Protze, 2017, Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker, Nat. Biotechnol. source

      Not checked in the free run.

    • cites [403] Kapoor, 2013, Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18, Nat. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is an unmet need for high-throughput toxicity screening for drug testing in which many compounds can be tested with minimized cost and time.

    “Furthermore, there is an unmet need for high throughput toxicity screening for drug testing in which many compounds can be tested with minimized costs and time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The advent of iPSC technology is a landmark breakthrough in regenerative medicine because it enabled acquisition of hiPSCs without ethical concerns and their targeted differentiation into any cell type.

    “The advent of iPSC technology represents a landmark breakthrough in regenerative medicine, as it enabled acquisition of hiPSCs without ethical concerns and their targeted differentiation into any cell type [395,396].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [395] Takahashi, 2006, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell source

      Not checked in the free run.

    • cites [396] Matsa, 2016, Human induced pluripotent stem cells as a platform for personalized and precision cardiovascular medicine, Physiol. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In silico modelling is a low-cost, ethical, and practical way to quickly investigate multiple hypotheses.

    “In silico modelling is a low-cost, ethical and practical way to quickly investigate multiple hypotheses [367].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [367] Kapetanovic, 2008, Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach, Chem. Biol. Interact. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Patient-on-chip platforms with engineered in vitro tissue models and patient-derived cells have the potential to revolutionize drug discovery and bring personalized medicine closer to reality.

    “Patient-on-chip platforms including engineered in vitro tissue models associated with patient derived cells (i.e. individual- and disease-specific hiPSCs) have the potential to revolutionize the drug discovery paradigm, and bring us closer towards the reality of personalized medicine [160,359,412].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [160] Mathur, 2016, In vitro cardiac tissue models: current status and future prospects, Adv. Drug Deliv. Rev. source

      Not checked in the free run.

    • cites [359] Zheng, 2016, Organ-on-a chip systems: microengineering to biomimic living systems, Small source

      Not checked in the free run.

    • cites [412] Zhang, 2017, Cancer-on-a-chip systems at the frontier of nanomedicine, Drug Discov. Today source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Combined human-based in vitro and in silico approaches will complement preclinical in vivo assessments and can fine-tune decision-making in drug discovery and development pipelines.

    “These combined human-based in vitro and in silico approaches will complement preclinical in vivo assessments and can fine-tune decision making steps in drug discovery and development pipelines.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Developing a suitable platform for high-throughput drug screening with reliable, repeatable results and sufficient physiological function to the native cardiac system is challenging because of technical limitations and tissue maturity.

    “However, development of a suitable platform for high-throughput drug screening with reliable, repeatable results and sufficient physiological function to the native cardiac system is challenging, due to the technical limitations as well as the resultant tissue maturity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Synergy between in vitro and in silico CVD models based on individual genomics, environmental factors, and lifestyle choices would lead to more reliable in vivo predictions and benefit CVD patients with safer and more effective drugs.

    “Furthermore, the synergy between in vitro and in silico CVD models based on individual genomics, environmental factors and lifestyle choices would lead to more reliable in vivo predictions, which would benefit CVD patients who would have access to safer and more effective drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Animal models are not entirely capable of representing human disease states, and the phenotypes of isolated primary cells often change drastically during culture.

    “However, animal models are not entirely capable of representing human disease states, and the phenotypes of isolated primary cells often change drastically during culture [115].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] McGonigle, 2014, Animal models of human disease: challenges in enabling translation, Biochem. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Genome editing technology such as CRISPR promises to be the most important translational perspective in the future.

    “Moreover, genome editing technology (e.g. the clustered regularly interspaced short palindromic repeats (CRISPR) technology) promises to be the most important translational perspective in the future [419–421].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [419] Jinek, 2012, A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity, Science

      Not checked in the free run.

    • cites [420] Cong, 2013, Multiplex genome engineering using CRISPR/Cas systems, Science

      Not checked in the free run.

    • cites [421] Ran, 2013, Genome engineering using the CRISPR-Cas9 system, Nat. Protoc. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    In vitro and in silico disease models have so far complemented laboratory animal models, but their combination is foreseen as a promising substitute that could reduce animal consumption and yield high-quality results in the future.

    “The in vitro and in silico disease models have so far been used to complement the use of laboratory animal models, however it is foreseen that the combination of these two fast-growing and emerging platforms with less costly, more ethical and accurate outcomes, would be a promising substitute, which can reduce animal model consumption and acquire high-quality results in the future.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Engineered 3D in vitro disease models using patient-derived cells differentiated to specific fates provide deeper understanding of human disease mechanisms and can test the efficacy and safety of emerging drugs in preclinical testing.

    “Engineered 3D in vitro disease models that use cells from patients differentiated to the specific cell fate under standard culture conditions, provide a deeper understanding of the breadth and complexity of human disease mechanisms, and can be used for testing the efficacy and safety of emerging therapeutic drugs during preclinical testing [156,357].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Avior, 2016, Pluripotent stem cells in disease modelling and drug discovery, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

    • cites [357] Tzatzalos, 2016, Engineered heart tissues and induced pluripotent stem cells: macro-and microstructures for disease modeling, drug screening, and translational studies, Adv. Drug Deliv. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patient-specific genotype can significantly affect disease onset and progression and influence drug responses.

    “It is known that patient-specific genotype can significantly affect disease onset and progression, as well as influence drug responses [211,214,410].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [211] Moretti, 2010, Patient-specific induced pluripotent stem-cell models for long-QT syndrome, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [214] Carvajal-Vergara, 2010, Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome, Nature source

      Not checked in the free run.

    • cites [410] Jung, 2012, Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia, EMBO Mol. Med. source

      Not checked in the free run.

79 of 79

  • The paper relies on this without support.

    In vitro and in silico CVD models can provide more physiologically and clinically relevant readouts than the animal models they aim to supplement or replace.

    “Therefore, the bioengineering and tissue engineering communities have been implementing extensive efforts to develop in vitro and in silico CVD models for more physiologically and clinically relevant readouts of CVDs.”

  • The paper relies on this without support.

    Engineered in vitro cardiac tissues can adequately model human heart morphology and function for disease modelling, compound testing, and patient-specific drug screening.

    “In vitro engineered cardiac tissues were introduced with the ultimate goal of resembling human heart morphology and function for various purposes including disease modelling, compound testing, and patient specific drug screening.”

  • The paper relies on this without support.

    Similarity to human anatomy and physiology is a valid criterion for selecting a translational CVD model.

    “large animal models (e.g. dogs, pigs, and sheep), which more faithfully resemble human physiology, function, and structural features, have been employed as experimental models to translate the cellular and biological findings from murine models into the clinic [123]”

  • The paper relies on this without support.

    Some thrombosis-on-chip devices are now being commercialized and implemented by pharmaceutical companies.

    “Some of these chips are now being commercialized and implemented by pharmaceutical companies.”

  • The paper relies on this without support.

    Johnson & Johnson is validating the thrombosis-on-chip device by Emulate for studies of pulmonary thrombosis.

    “For example, Johnson & Johnson is validating the thrombosis-on-chip device by Emulate for the studies of pulmonary thrombosis.”

  • The paper relies on this without support.

    In silico approaches have been implemented by both regulatory agencies and pharmaceutical companies.

    “In silico approaches have been implemented by both regulatory agencies as well as pharmaceutical companies.”

  • The paper relies on this without support.

    Many FDA-approved drugs, such as TKI-related cancer drugs, were developed based on high-throughput screening technologies.

    “There are many drugs that have received U.S. FDA approval, such as TKI-related drugs for cancer, that were developed based on high-throughput screening technologies.”

  • The paper relies on this without support.

    The FDA has requested companies to investigate inhibition of the cardiac hERG gene to assess in vitro cardiotoxicity of new drugs.

    “To assess in vitro cardiotoxicity of a new drug, the FDA has requested companies to investigate inhibition of the cardiac hERG gene that encodes a potassium ion channel of cardiac cells.”

  • The paper relies on this without support.

    TKIs are cancer therapeutics that often exhibit cardiotoxic effects, including LV malfunction and HF.

    “TKIs are cancer therapeutics that often exhibit cardiotoxic effects, including LV malfunction and HF.”
9 of 9

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References 413 · Cited by 223

Research works printed but not linked: 10

  1. Tavares, 2018, Chapter 14 - adhesion molecules and endothelium, 189
  2. Ronaldson-Bouchard, 2018, Advanced maturation of human cardiac tissue grown from pluripotent stem cells, Nature, 1
  3. Yazawa, 2011, Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome, Nature, 471, 230, 10.1038/nature09855 · DOI · Paper page
  4. Stoehr, 2014, Automated analysis of contractile force and Ca 2+ transients in engineered heart tissue, Am. J. Physiol. Heart Circ. Physiol., 306, H1353, 10.1152/ajpheart.00705.2013 · DOI · Paper page
  5. Zimmermann, 2002, Tissue engineering of a differentiated cardiac muscle construct, Circ. Res., 90, 223, 10.1161/hh0202.103644 · DOI · Paper page
  6. Schaaf, 2011, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PloS One, 6, 10.1371/journal.pone.0026397 · DOI · Paper page
  7. Nunes, 2013, Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes, Nat. Methods, 10, 781, 10.1038/nmeth.2524 · DOI · Paper page
  8. Kolesky, 2014, 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs, Adv. Mater., 26, 3124, 10.1002/adma.201305506 · DOI · Paper page
  9. Lai, 2017, InVADE: integrated vasculature for assessing dynamic events, Adv. Funct. Mater., 27, 1703524, 10.1002/adfm.201703524 · DOI · Paper page
  10. Zheng, 2012, In vitro microvessels for the study of angiogenesis and thrombosis, Proc. Natl. Acad. Sci. U. S. A., 109, 9342, 10.1073/pnas.1201240109 · DOI · Paper page

Authors
Savoji, H., Mohammadi, M. H., Rafatian, N., Toroghi, M. K., Wang, E. Y., Zhao, Y., Korolj, A., Ahadian, S., & Radisic, M.
Affiliations
  • University Health Network (CA)
  • University of Toronto (CA)
Corresponding author
Radisic, Milica
ORCID
Venue
Biomaterials
Publisher
Elsevier BV
Published
2019-04
Volume
198
Pages
3-26
ISSN
0142-9612 (ISSN-L)
DOI
10.1016/j.biomaterials.2018.09.036
PMC
PMC6397087
OpenAlex
W2895717498
Semantic Scholar
27c2053c2505f17f12f75d731b304ff3645b0a53
Cited by
223
References
413
Citations by year
2026: 9 · 2025: 32 · 2024: 37 · 2023: 31 · 2022: 40 · 2021: 34 · 2020: 21 · 2019: 17 · 2018: 1 · 2017: 1
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomaterials (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • PolyPublie (École Polytechnique de Montréal) (submittedVersion)
Funders
  • CIHR (MOP-126027, MOP-137107)
  • NSERC (RGPIN-2015-05952)
  • NSERC Steacie Fellowship (SMFSU 4620)
  • Heart and Stroke Foundation Grant-in-Aid (G-16-00012)
  • NSERC-CIHR Collaborative Health Research Grant (CHRPJ 4937)
  • M.R. and National Institutes of Health Grant (2R01 HL076485)
  • Fonds de Recherche du Québec - Nature et Technologies
  • Canadian Institutes of Health Research
  • Humane Society International
  • Humane Society of the United States
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
cardiovascular disease, drug discovery, drug screening, cardiotoxicity, adverse drug reactions, in vitro cardiac models, in silico models, in vivo animal models, cardiac pathophysiology, non-animal models, drug safety assessment
MeSH terms
Animals, Cardiovascular Diseases, Computer Simulation, Disease Models, Animal, Drug Evaluation, Preclinical, Equipment Design, Humans, Models, Cardiovascular, Myocytes, Cardiac, Drug Discovery, Induced Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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