Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells
Open accessAbstract
Tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber, and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen-based extracellular matrix hydrogel, we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Transcript and RNA-seq analyses revealed upregulation of key Ca 2+-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells. Clinically-important, physiologically complex contractile parameters such as ejection fraction, developed pressure, and stroke work, as well as electrophysiological properties including action potential and conduction velocity were measured: hvCOC displayed key molecular and physiological characteristics of the native ventricle, and showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes). We conclude that such "human-heart-in-a-jar" technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development.
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Claims the paper makes
52 of 74 cited sources checked · 30 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Engineered cardiac thin films, micro-tissues, and strips permit measurement of twitch force.
“engineered cardiac thin films, micro-tissues and strips allow the assessment of twitch force [9,12–19]”
Quote in the paperSubstantial claim7 of 9 sources checked- cites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. sourceExperimental — accuracy not yet measured
- cites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- cites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
- cites [15] Huang, 2007, Contractile three-dimensional bioengineered heart muscle for myocardial regeneration, J. Biomed. Mater. Res. sourceExperimental — accuracy not yet measured
- cites [16] Schaaf, 2011, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PLoS One sourceExperimental — accuracy not yet measured
- cites [17] Wang, 2014, Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies, Nat. Med. source
The Abstract (page unavailable) describes engineered muscular thin films and calculates twitch stress from their contraction, supporting the thin-film part of the claim. The passages do not establish that this paper used micro-tissues or strips to assess twitch force. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
The Methods section on microtissue force quantification describes measuring forces from engineered cardiac microtissues, and the Results report their measured twitch tension. The Results also describe twitch-force measurements in engineered cardiac tissue strips. Our copy does not address cardiac thin films, so it supports only two of the three formats listed. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [19] Kensah, 2013, Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro, Eur. Heart J. sourceExperimental — accuracy not yet measured
- Premisecitation
Those constructs do not permit pressure- and volume-based measures that directly reflect pump performance.
“but not pressure- and volume-based metrics directly representing pump performance of the heart”
Quote in the paperSubstantial claim7 of 9 sources checked- cites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. sourceExperimental — accuracy not yet measured
- cites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- cites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
Materials and Methods and Results describe force and twitch-stress measurements on engineered cardiac tissues, rather than pressure–volume measures of heart-pump performance. The paper does not explicitly establish that these constructs cannot permit pressure- or volume-based measurements, so the categorical limitation goes beyond what our copy states. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [15] Huang, 2007, Contractile three-dimensional bioengineered heart muscle for myocardial regeneration, J. Biomed. Mater. Res. sourceExperimental — accuracy not yet measured
- cites [16] Schaaf, 2011, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PLoS One source
The Discussion (page unavailable) says the hEHT assay measures contraction frequency, force, timing and velocity, rather than pressure or volume. It does not establish the stronger claim that the constructs cannot permit pressure- or volume-based measures of pump performance. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [17] Wang, 2014, Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies, Nat. Med. source
The Abstract and the MTF stress-quantitation passage (no page given) describe laminar thin-film constructs whose curvature is used to calculate contractile stress, rather than pressure or volume. The paper does not explicitly state that these constructs cannot provide pressure- and volume-based measures of cardiac pump performance. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. sourceExperimental — accuracy not yet measured
- cites [19] Kensah, 2013, Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro, Eur. Heart J. sourceExperimental — accuracy not yet measured
- Findingcitation
Upon 1-Hz electrical stimulation, AP initiation was followed by Ca2+ transient initiation after a systematic and reproducible delay.
“Furthermore, Fig. 5c shows the immediate initiation of an AP (black tracing) upon 1-Hz electrical stimulation (black arrows at 0 and 1000 ms) followed by Ca2+ transient initiation (blue tracing) after a systematic and reproducible delay, as anticipated from Ca2+-induced-Ca2+-release upon Ca2+ influx via L-type Ca2+ channels [28] that subsequently lead to cardiac contractions.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Li, 2014, Mechanistic basis of excitation-contraction coupling in human pluripotent stem cell-derived ventricular cardiomyocytes revealed by Ca2+ spark characteristics: direct evidence of functional Ca2+-induced Ca2+ release, Heart Rhythm source
- Findingown data
As pacing frequency increased, APD50 and conduction velocity decreased in hvCOC, indicating rate-adaptation.
“As the pacing frequency was increased (Fig. 5c) (i.e., shorter basic cycle length, BCL), the AP duration at 50% amplitude (APD50) (Fig. 5d) and the conduction velocity (CV) (Fig. 5e) decreased, indicating the ability of hvCOC to rate-adapt, another key physiological feature of native cardiac cells and tissues [40,41].”
Quote in the paperSubstantial claim1 of 2 sources checked - Findingown data
Transcript analysis of hvCOC and other engineered constructs showed changes consistent with prior maturation studies.
“Transcript analysis of 2D-cultured clusters [24] and alternative engineered constructs, including human ventricular cardiac micro-tissues (hvCMT; ~1000 cells) [18], tissue strips (hvCTS; ~106 cells) [14] and hvCOC made of identical constituent hPSC-vCMs, revealed changes consistent with our previous maturation studies [18,24–28].”
Quote in the paperSubstantial claim4 of 6 sources checked- cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
The Results identify hvCMTs as engineered microtissues of approximately 1,000 ventricular cardiomyocytes, so the source supports that part of the citing sentence. The Transcriptomic Analysis methods describe RNA analysis of hES2-vCMs, not of hvCMTs; the Discussion says their global transcriptome was unchanged after PLB overexpression. This source therefore does not establish transcript changes in the engineered constructs consistent with maturation studies. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [24] Li, 2013, Calcium signalling of human pluripotent stem cell-derived cardiomyocytes, J. Physiol. source
- cites [25] Liu, 2007, Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation, Stem Cell. source
- cites [26] Liu, 2009, Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression, Am. J. Physiol. Cell Physiol. source
- cites [27] Lieu, 2009, Absence of transverse tubules contributes to non-uniform Ca(2+) wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes, Stem Cell. Dev. source
- cites [28] Li, 2014, Mechanistic basis of excitation-contraction coupling in human pluripotent stem cell-derived ventricular cardiomyocytes revealed by Ca2+ spark characteristics: direct evidence of functional Ca2+-induced Ca2+ release, Heart Rhythm source
The Conclusions (page unavailable) describe developmentally immature hESC-derived ventricular cardiomyocytes and suggest that the findings may inform maturation strategies. But this paper studies calcium sparks and excitation–contraction coupling; it does not report transcript changes in hvCOC or the other engineered constructs, so it cannot establish the claimed consistency at the transcript level. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Findingown data
KCNJ2 (KiR2.1) was upregulated in hvCOC by up to about 5-fold.
“Electrophysiologically, KiR2.1 (KCNJ2), which mediates the inwardly rectifying potassium current important for electrical stability of hPSC-CMs [5,29], was upregulated in hvCOC by up to about 5-fold.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Lieu, 2013, Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes, Circ. Arrhyth. Electrophysiol. sourceExperimental — accuracy not yet measured
- cites [29] Liao, 2013, Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction, Heart Rhythm source
- Premisecitation
Prior cardiac tissue engineering studies have shown predictive utility in arrhythmogenicity, contractility and disease phenotype recapitulation.
“Prior cardiac tissue engineering studies have shown this in the context of arrhythmogenicity [33], contractility [14,34] and recapitulation of disease phenotypes [12,48].”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [33] Shum, 2017, A micropatterned human pluripotent stem cell-based ventricular cardiac anisotropic sheet for visualizing drug-induced arrhythmogenicity, Adv. Mater. source
- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
- cites [34] Mannhardt, 2017, Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: comparison with human atrial trabeculae, Toxicol. Sci. source
- cites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- cites [48] Stillitano, 2016, Genomic correction of familial cardiomyopathy in human engineered cardiac tissues, Eur. Heart J source
- Interpretationcitation
Engineered tissues for in vitro use may not need physiologic function levels to be predictive, if they recapitulate cardiac-appropriate responses to treatments.
“However, in contrast to constructs designed for surgical implantation [8], engineered tissues designed for in vitro applications, such as our organoids, may not require physiologic levels of function to be predictive and impactful, provided they can recapitulate cardiac-appropriate responses to treatments and interventions of interest.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials source
The Conclusion (page unavailable) identifies the engineered cardiac patch as a platform for future cell-based cardiac therapies, supporting its use as an example of a therapeutically oriented construct. It does not say the patch was designed for surgical implantation. The sentence’s assertion that in vitro tissues may be predictive without physiologic function levels is the citing authors’ contrast, not a finding attributed to this source by the placement of [8]. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
2D hPSC-vCMs, 3D hvCMTs and hvCTSs have been reported to show positive chronotropic but weak or null inotropic responses to β-adrenergic stimulation.
“Pharmacologically, 2D-cultured hPSC-vCMs [18], as well as 3D hvCMTs [21] and hvCTSs [14] created from such cells, have been reported to display positive chronotropic but weak or even null inotropic responses to b-adrenergic stimulation (Supplemental Fig. 5).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
- cites [21] Boudou, 2012, A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues, Tissue Eng. Part A source
The Results (Drug testing; page unavailable) report a strong positive chronotropic response to the β-adrenergic agonist isoproterenol, with only slight inotropic effects. But Materials and Methods (Cell culture and reagents; page unavailable) states that the CMTs were made from neonatal rat cardiomyocytes, not human pluripotent stem cell-derived ventricular cardiomyocytes. The response is supported; its attribution to 3D hvCMTs is not. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
- Findingown data
Developed pressure exhibited a negative pressure-frequency relationship in hvCOC.
“Developed pressure exhibited a negative pressure-frequency relationship (Fig. 3f), similar to the negative Ca2+ transient-frequency data in hvCMs [24] and negative force-frequency relationships observed for hvCMT [18], hvCTS [14] and newborn human heart muscle [30], as commonly seen with engineered heart tissues.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [24] Li, 2013, Calcium signalling of human pluripotent stem cell-derived cardiomyocytes, J. Physiol. source
The citation [24] is attached to the comparison with negative Ca²⁺ transient–frequency data in hvCMs, not to the citing paper’s own developed-pressure result in hvCOC. The cited paper’s Abstract reports a negative force–frequency relationship in immature cardiomyocytes, but the passages found do not establish a negative Ca²⁺ transient–frequency relationship or measure developed pressure in hvCOC. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
The citation is attached to the comparison with a negative force–frequency relationship in hvCMT, not to the hvCOC pressure result, which the citing sentence assigns to its own Figure 3f. The source’s Results section on hvCMT responses reports beating frequency and twitch tension under isoproterenol and notes that frequency can affect force, but it does not establish a negative force–frequency relationship. Searches for that relationship and for pacing-rate effects found no decisive passage; page numbers were unavailable. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
- Interpretationcitation
Because hvCOC size is significantly smaller than native human heart and closer to mouse heart, it may have limitations for modeling sustained reentrant arrhythmia and fibrillation.
“Finally, because the size of the hvCOC is significantly smaller than the native human heart and closer to the size of a mouse heart, it may have limitations for modeling sustained reentrant arrhythmia and fibrillation, which are known to be less prevalent in rodents [47].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [47] Kaese, 2012, Cardiac electrophysiology in mice: a matter of size, Front. Physiol. source
The Reentry section (page unavailable) says the small mouse heart may limit coexisting fibrillation waves, making multiple-wavelet reentry less likely. That supports a possible size-related modeling limitation, but the paper does not establish that sustained reentrant arrhythmia or fibrillation is generally less prevalent in rodents; it also describes stable ventricular fibrillation in mouse hearts. The paper does not assess hvCOC size or performance. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
Transcript and RNA-seq analyses found increased expression of key calcium-handling, ion channel, and cardiac-specific proteins in hvCOC relative to lower-order 2D and 3D cultures of the same cells.
“Transcript and RNA-seq analyses revealed upregulation of key Ca2+-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells.”
Quote in the paperSubstantial claim - Findingown data
Structural analysis revealed organized sarcomeres and myofibrillar microstructures.
“Structural characterization showed organized sarcomeres with myofibrillar microstructures.”
Quote in the paperSubstantial claim - Findingown data
Baseline stroke volume of hvCOCs (n=25) was 4.82 ± 0.63 μl.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperSubstantial claim - Findingown data
Average maximum pressure points followed a linear ESPVR (R2 = 0.98) with slope 0.28 mmH2O•mm−3 representing Ees.
“The average maximum pressure points followed a linear end-systolic pressure-volume relation (ESPVR) (R2 = 0.98) with a slope of 0.28 mmH2O•mm−3 representing the end-systolic elastance (Ees), a clinically valuable index of ventricular contractility.”
Quote in the paperSubstantial claim - Findingown data
Ejection fraction, pressure-volume relationships, stroke work, and electrophysiology were measured quantitatively from one engineered construct.
“We demonstrated direct quantitative measurement of a variety of physiologically-integrated and clinically-familiar parameters such as ejection fraction, pressure-volume relationships, stroke work and electrophysiology all from a single engineered construct”
Quote in the paperSubstantial claim- The authors state this as an assumption: Chamber volume can be estimated by treating the chamber as a sphere with the same cross-sectional area.
- Findingown data
Exponential regression of average minimum pressure points (R2 = 0.99) yielded an EDPVR with diastolic stiffness constant 0.012 μl−1.
“An exponential regression fit the average minimum pressure points (R2 = 0.99) yielding an end-diastolic pressure-volume relation (EDPVR) with a diastolic stiffness constant of 0.012 μl−1 reflecting the passive compliance of the hvCOC.”
Quote in the paperSubstantial claim - Findingown data
Immunostaining detected α-actinin and mitochondrial COX IV in hvCOC.
“Immunostaining showed positive expression of α-actinin and the mitochondrial protein COX IV (Fig. 1h)”
Quote in the paperNot a substantial claim - Findingown data
MYH6 and MYH7 contractile transcripts were upregulated by more than 20-fold in hvCOC.
“Cardiac contractile transcripts MYH6 and MYH7 were upregulated by > 20-fold.”
Quote in the paperSubstantial claim - Findingown data
Isoproterenol (1 μM) significantly increased spontaneous beating rate of hvCOCs by >200% (n=5, p<0.05).
“When exposed to isoproterenol (n = 5), the spontaneous beating rate of hvCOCs significantly increased by >200% at 1 μM, (p < 0.05; Fig. 4a), consistent with a positive chronotropic response.”
Quote in the paperSubstantial claim - Findingown data
The representative P-V loop showed increased peak systolic pressure and stroke work with isoproterenol.
“In addition, the representative P-V loop showed an increase in peak systolic pressure and stroke work with isoproterenol, consistent with a positive inotropic effect (Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data
The hvCOC responded as expected mechanically and electrophysiologically to various pharmacological agents, including positive and negative inotropes.
“showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes).”
Quote in the paperSubstantial claim - Findingown data
PLN and RYR, Ca2+-handling transcripts lowly expressed in hPSC-CMs, were significantly upregulated in hvCOC.
“As shown in Fig. 2a, several key Ca2+-handling transcripts such as PLN and RYR that are lowly expressed in hPSC-CMs became significantly upregulated in hvCOC.”
Quote in the paperSubstantial claim - Findingown data
Baseline ejection fraction of hvCOCs (n=25) was 2.44 ± 0.27%.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperSubstantial claim - Findingown data
Isochronal conduction mapping revealed systematic propagation of depolarizing signals originating from the pacing site.
“An isochronal conduction map of the hvCOC surface by high-resolution optical mapping during point stimulation revealed systematic propagation of depolarizing signals originating from the pacing site (Fig. 5a).”
Quote in the paperSubstantial claim - Findingown data
Baseline spontaneous beating frequency of hvCOCs (n=25) was 0.76 ± 0.06 Hz.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperNot a substantial claim - Findingown data
Baseline cardiac output of hvCOCs (n=25) was 212.9 ± 28.6 μl/min.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperSubstantial claim - Findingown data
Digoxin (0.1 μM) significantly increased pressure, stroke volume, stroke work, cardiac output and ejection fraction without significantly affecting frequency in hvCOCs (n=5).
“Digoxin (n = 5), another positive inotrope, significantly increased pressure, stroke volume, stroke work and cardiac output as well as the ejection fraction without significantly affecting the frequency at0.1 μM (Fig. 4a–b).”
Quote in the paperNot a substantial claim - Findingown data
Principal-component analysis placed hvCOC on one extreme, followed by hvCTS and hvCMT, with 2D hPSC-vCM clusters on the opposite extreme.
“Accordingly, principal-component analysis of the global transcriptomic signatures showed hvCOC positioned on one extreme, followed by lower-ordered hvCTS and hvCMT, with randomly oriented 2D hPSC-vCM clusters on the opposite extreme (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Baseline developed pressure of hvCOCs (n=25) was 1.26 ± 0.12 mmH2O.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperNot a substantial claim - Findingown data
Organoid pump performance was significantly attenuated by verapamil, nifedipine and disopyramide.
“Conversely, organoid pump performance was significantly attenuated when treated with the well-defined negative inotropes verapamil (n = 3), nifedipine (n = 3) and disopyramide (n 3) (Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data
Desmosomes and gap junctions were identified in hvCOC.
“Cell junctions including desmosomes and gap junctions were also identified (Supplemental Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Upon electrical pacing, hvCOC synchronously responded to frequencies from 0.5 to 3.0 Hz.
“Upon electrical pacing, hvCOC synchronously responded to a physiological range of frequencies from 0.5 to 3.0 Hz (Fig. 3e–f; Movie S1).”
Quote in the paperSubstantial claim - Findingown data
Adrenergic signaling, cGMP-PKG signaling and Ca2+ signaling were among the top four upregulated pathways in hvCOC.
“When the differentially regulated transcripts were examined and ranked by the percent of genes changed in their corresponding biological pathways, adrenergic signaling, cGMP-PKG signaling and Ca2+ signaling stood out among the top four upregulated pathways in hvCOC (see also Supplemental Fig. 4a).”
Quote in the paperNot a substantial claim - Findingown data
Developed pressure increased with increasing external Ca2+ concentration, demonstrating positive inotropy.
“As anticipated for an operating ventricular preparation, the developed pressure increased with increasing external Ca2+ concentration, demonstrating positive inotropy (Fig. 3i).”
Quote in the paperSubstantial claim - Findingown data
The hvCOC sarcomere length was approximately 1.6 μm, attributed to partial tissue contracture.
“with a sarcomere length of about 1.6 μm due to partial contracture of the tissue.”
Quote in the paperNot a substantial claim - Findingown data
Baseline stroke work of hvCOCs (n=25) was 5.832 ± 1.267 mmH2O μl.
“Further detailed analysis revealed the following baseline properties averaged from 25 hvCOCs (Fig. 3d): spontaneous beating frequency, 0.76 ± 0.06 Hz; developed (max-min) pressure, 1.26 ± 0.12 mmH2O; stroke volume, 4.82 ± 0.63 μl; stroke work, 5.832 ± 1.267 mmH2O μl; ejection fraction, 2.44 ± 0.27%; cardiac output, 212.9 ± 28.6 μl/min.”
Quote in the paperNot a substantial claim - Findingown data
A linear relationship between developed pressure and mean pressure load was observed in hvCOCs at 1 Hz (R2 = 0.99).
“Consistent with a functional Frank-Starling mechanism [36] and similar to the load-dependent contractile reserve in native myocardium, a linear relationship between developed pressure and the mean pressure load was observed in hvCOCs pumping at a controlled pacing frequency of 1 Hz (R2 = 0.99, Fig. 3g).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Sarnoff, 1954, Ventricular function. I. Starling's law of the heart studied by means of simultaneous right and left ventricular function curves in the dog, Circulation source
- Findingown data
Cardiac output-based EC50 for digoxin was 34.9 ± 26.3 nM.
“Cardiac output-based EC50 was 34.9 ± 26.3 nM for digoxin treatment.”
Quote in the paperNot a substantial claim - Findingown data
The EC50 for cardiac output response to isoproterenol was 231.7 ± 16.8 nM.
“When we examined the dose-response relationship for the calculated cardiac output with both chronotropic and inotropic responses taken into consideration, the half maximal effective concentration (EC50) was 231.7 ± 16.8 nM (Supplemental Fig. 6), comparable to a value of 800 nM tested in human non-failing heart muscle [37].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Hasenfuss, 1994, Influence of isoproterenol on contractile protein function, excitation-contraction coupling, and energy turnover of isolated nonfailing human myocardium, J. Mol. Cell. Cardiol. source
- Findingown data
In isoproterenol-treated hvCOCs paced at 1 Hz, developed pressure, stroke volume, and stroke work significantly increased by approximately 25-50% (p<0.05).
“When isoproterenol (1 μM)-treated hvCOCs were paced at 1 Hz (so as to control frequency-dependent effects on contractility), the developed pressure, stroke volume, and stroke work likewise significantly increased by approximately 25–50%, (p < 0.05) indicating a positive inotropic effect.”
Quote in the paperSubstantial claim - Findingown data
RNA-sequencing data showed increases in expression of cardiac contractile proteins including myosin, cardiac troponin T and cardiac troponin I.
“In addition, consistent with the observed increase in expression of cardiac proteins including MHCα (MYH6) and MHCβ (MYH7) with qPCR, RNA-sequencing data also showed increases in the expression of cardiac contractile proteins including myosin, cardiac troponin T and cardiac troponin I.”
Quote in the paperNot a substantial claim - Findingown data
At 30 μM flecainide, all electrical activity was abolished.
“At 30 μM flecainide, all electrical activity was abolished.”
Quote in the paperNot a substantial claim - Findingown data
Contractions and developed pressures were completely abolished at 10 μM verapamil.
“Contractions and developed pressures were completely abolished at 10 μM verapamil.”
Quote in the paperSubstantial claim - Findingown data
The roughly 4-fold increase and 5-fold decrease in CV of hvCOC after isoproterenol and flecainide treatments, respectively, suggests such effects can be readily captured.
“Indeed, the roughly 4-fold increase and 5-fold decrease in CV of hvCOC after isoproterenol and flecainide treatments, respectively, suggests such effects can be readily captured in our system.”
Quote in the paperSubstantial claim - Findingown data
GO enrichment analysis revealed top 10 over-represented Biological Processes terms were all related to cardiovascular system and muscle biology.
“Gene Ontology (GO) Enrichment Analysis also revealed that the top 10 GO terms in Biological Processes that are over-represented are all related to the cardiovascular system and muscle biology.”
Quote in the paperNot a substantial claim - Findingown data
The pathway with the highest enrichment score was 'Adrenergic signaling in cardiomyocytes'.
“The pathway with the highest enrichment score was ‘Adrenergic signaling in cardiomyocytes’ (Supplemental Fig. 4b).”
Quote in the paperNot a substantial claim - Findingown data
Despite sub-physiologic function, the hvCOC system was able to distinguish dose responses of positive and negative inotropes.
“Despite the sub-physiologic function, the hvCOC system was able to distinguish dose responses of positive and negative inotropes.”
Quote in the paperSubstantial claim - Findingown data
Flecainide potently and dose-dependently reduced firing frequency and CV primarily by prolonging APD50 as a result of decreased upstroke velocity and reduced amplitudes.
“In stark contrast, the voltage-gated Na+ channel blocker flecainide potently and dose-dependently reduced the firing frequency and CV primarily by prolonging APD50 as a result of decreased upstroke velocity and reduced amplitudes (Fig. 6a, c).”
Quote in the paperNot a substantial claim - Findingown data
9 out of 10 top over-represented Cellular Components GO terms were related to cardiomyocytes.
“Similarly, 9 out of the 10 top over-represented GO terms in Cellular Components are related to cardiomyocytes (Supplemental Fig. 4c).”
Quote in the paperNot a substantial claim - Premisenone given
The physical form of those constructs restricts their use in electrophysiological studies because of boundary effects.
“their physical forms limit utility for electrophysiological studies due to boundary effects”
Quote in the paperSubstantial claim - Premisecitation
Adverse cardiac effects are a leading cause of drug candidate failure.
“Cardiac side effects have been a dominant reason for attrition of newly developed drugs, underscoring an urgent need for developing effective screening models that can help improve the success of costly clinical trials [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Braam, 2009, Cardiomyocytes from human pluripotent stem cells in regenerative medicine and drug discovery, Trends Pharmacol. Sci. source
- Interpretationreasoning
The technology could aid drug discovery by supplying human-specific preclinical data in early drug development.
“We conclude that such “human-heart-in-a-jar” technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development.”
Quote in the paperSubstantial claim - Interpretationnone given
These hvCOCs are the first human engineered cardiac tissue constructs allowing direct measurement of multiple cardiac pump performance metrics of primary cardiology interest.
“To our knowledge, these hvCOCs represent the first human engineered cardiac tissue constructs that allow direct measurement of multiple metrics of cardiac pump performance that are of primary interest in cardiology.”
Quote in the paperSubstantial claim - Interpretationown data
The hvCOC exhibited key molecular and physiological traits of the native ventricle.
“hvCOC displayed key molecular and physiological characteristics of the native ventricle”
Quote in the paperSubstantial claim- The authors state this as an assumption: Chamber volume can be estimated by treating the chamber as a sphere with the same cross-sectional area.
- Interpretationown data
The experimental design for testing hvCOC responses consistently parallels responses expected in native heart function, as demonstrated using five drugs with known inotropic effects.
“Nevertheless, our experimental design for testing hvCOC responses consistently parallels the responses expected in native heart function, as demonstrated using five drugs with known inotropic effects.”
Quote in the paperSubstantial claim - Interpretationreasoning
The signal-to-noise ratio due to small EFs could limit the sensitivity of hvCOC-based assays.
“The signal-to-noise ratio due to small EFs could limit the sensitivity of hvCOC-based assays.”
Quote in the paperNot a substantial claim - Interpretationnone given
The hvCOC platform allows clinically relevant and physiologically complex parameters such as pressure-volume relationships, ejection fraction and cardiac output to be measured from a single engineered construct.
“In this study, we report a new platform, namely hvCOC, that allows clinically relevant and physiologically complex parameters such as pressure-volume relationships, ejection fraction and cardiac output to be measured from a single engineered construct.”
Quote in the paperSubstantial claim - Interpretationreasoning
For the first time, clinically-meaningful parameters such as ejection fraction, pressure-volume relationships, cardiac output, stroke work, EDPVR, ESPVR, PV loops and electrophysiological mapping under multiple loading conditions or drug interventions could be measured from a single human cardiac tissue construct.
“For the first time, clinically-meaningful parameters such as ejection fraction, pressure-volume relationships, cardiac output, stroke work, EDPVR, ESPVR, PV loops as well as electrophysiological mapping under multiple loading conditions or drug interventions could now be measured from a single human cardiac tissue construct.”
Quote in the paperSubstantial claim - Premisenone given
The propensity for arrhythmia formation is related to functional and/or structural heterogeneities that can cause variable conduction velocities across a cardiac surface, detectable by optical mapping.
“However, the propensity for arrhythmia formation is also related to functional and/or structural heterogeneities that can cause variable conduction velocities across a cardiac surface, which can be detected by optical mapping as locally hastened or slowed CVs.”
Quote in the paperSubstantial claim - Interpretationnone given
The generation of physiological parameters extends measurements of contractility and electrophysiology to the organ level, unprecedented by any existing human in vitro systems.
“The generation of physiological parameters extends the measurements of contractility and electrophysiology to the organ level, unprecedented by any existing human in vitro systems.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The fluid-ejecting hvCOC system recapitulates critical physiological and pharmacological features of the native human heart.
“To conclude, the fluid-ejecting hvCOC system recapitulates critical physiological and pharmacological features of the native human heart.”
Quote in the paperSubstantial claim - Interpretationreasoning
The small EF was primarily attributed to the thin wall (relative to diameter, indicating high wall stress) and other factors including random cell alignment and limited cellular maturity.
“This small EF was primarily attributed to the thin wall (relative to the diameter, indicating high wall stress) and other contributing factors including random cell alignment and limited cellular maturity common in most other stem-cell derived systems.”
Quote in the paperSubstantial claim - Interpretationown data
These data demonstrate functional electro-mechanical coupling of hvCOC.
“Taken together, these data demonstrate functional electro-mechanical coupling of hvCOC.”
Quote in the paperSubstantial claim - Interpretationreasoning
Achieving large EF likely requires specialized multi-layered helically aligned hierarchical muscle fiber organization of native adult heart, with integrated vasculature.
“Achieving large EF likely requires the specialized multi-layered helically aligned hierarchical muscle fiber organization of the native adult heart, with integrated vasculature to support viability of the thick-walled tissue.”
Quote in the paperSubstantial claim - Premisecitation
In the day 10.5e11 embryonic mouse LV, the reported EF is only about 27%.
“Considering these simplifications, it is noteworthy that in the day 10.5e11 embryonic mouse LV, in which the heart muscle also has a random organization, the reported EF is only about 27% [46], which may be a more appropriate comparison for our hvCOC than an adult EF of 70%.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Tanaka, 1997, Left ventricular volumes and function in the embryonic mouse heart, Am. J. Physiol. source
- Classified as probably not a substantial claim. 15
- May combine two claims. 17
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPrior studies have arranged hPSC-derived ventricular cardiomyocytes as monolayers and patches for electrophysiology and for surgical implantation.
“Although hPSC-vCMs have been organized as monolayers and patches for electrophysiological assessment [6–8] and even surgical engraftment [9–11]”
Quote in the paperSubstantial claim5 of 6 sources checked- cites [6] Chen, 2011, Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives, Adv. Mater. source
The paper’s Experimental Section reports optical mapping of action-potential propagation in aligned hESC-derived cardiomyocyte monolayers, supporting the electrophysiology portion. It does not identify those cells specifically as ventricular cardiomyocytes or report patches or surgical implantation. The citing sentence assigns surgical engraftment to a separate citation group [9–11]. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [7] Wang, 2013, Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias, Biomaterials source
- cites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials source
- cites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. source
- cites [10] Caspi, 2007, Tissue engineering of vascularized cardiac muscle from human embryonic stem cells, Circ. Res. source
The Generation of the Engineered Human Cardiac Tissue section describes hESC-derived cardiomyocytes seeded on three-dimensional scaffolds, and Impulse Propagation reports electrical activity in those constructs. The paper does not report surgical implantation or engraftment; it presents tissue replacement as a potential application. It also does not describe its constructs as monolayers. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [11] Wendel, 2015, Functional effects of a tissue-engineered cardiac patch from human induced pluripotent stem cell-derived cardiomyocytes in a rat infarct model, Stem Cells Trans. Med. source
Classified as probably not a substantial claim.
PremisecitationHuman pluripotent stem cells can be differentiated into ventricular cardiomyocytes that prior work has characterized thoroughly at the single-cell level.
“Human pluripotent stem cells (hPSC) can be specified into ventricular cardiomyocytes (vCM) that have been robustly characterized at the single-cell level [2–5].”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [2] Mummery, 2003, Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells, Circulation source
- cites [3] He, 2003, Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization, Circ. Res. source
- cites [4] Xue, 2005, Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers, Circulation source
- cites [5] Lieu, 2013, Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes, Circ. Arrhyth. Electrophysiol. source
May combine two claims.
Findingown dataThe sarcomeric organization of hvCOC resembled other human engineered cardiac tissue constructs and differed from random clusters.
“with sarcomeric arrangements similar to other human engineered cardiac tissue constructs [14,21–23] but distinct from random clusters.”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
- cites [21] Boudou, 2012, A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues, Tissue Eng. Part A source
The Results (page not provided) describe engineered cardiac microtissues developing aligned, parallel cross-striations after an initially almost random cellular arrangement. That supports the contrast with random clusters, but this paper used neonatal rat heart cells and does not establish a comparison with human engineered cardiac tissue constructs. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [22] Kerscher, 2016, Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues, Biomaterials source
- cites [23] Nunes, 2013, Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes, Nat. Methods source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe weak β-adrenergic response is thought to result from immature adrenergic and Ca2+ signaling pathways, such as lowered phospholamban expression.
“The weak response is thought to be due to immature adrenergic and Ca2+ signaling pathways such as lowered phospholamban expression compared to their adult counterparts [14].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The Results report a weak sustained inotropic response to β-adrenergic stimulation and suggest immature sarcoplasmic-reticulum function or reduced β-receptor sensitivity as possible explanations. The Discussion also raises differences in β-signaling maturity. Our copy does not support the specific example of lowered phospholamban expression compared with adult tissue. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationWe previously reported a linear relationship between developed stress and axial stretch in hvCTS.
“Similarly, we have reported a linear relationship between the developed stress and axial stretch in hvCTS [14].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The Results (page not provided) report that developed stress increased with axial stretch in hECTs, supporting the relationship's direction. They do not describe it as linear and say stress reached a plateau at Lmax; the Methods specify linear regression for the force-frequency relationship, not the stretch relationship. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEngineered tissues with contractile forces and conduction properties approaching native myocardium have been reported by several groups.
“A number of groups have reported engineered tissues with contractile forces and conduction properties approaching physiologic levels observed in native myocardium [8,13,31,32].”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials source
- cites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- cites [31] Guyette, 2016, Bioengineering human myocardium on native extracellular matrix, Circ. Res. source
The Results (Recellularization of myocardial slices and fibers; page unavailable) report contractile force and a conduction velocity of 32 ± 56 cm/s in engineered tissue. But the reported slice force reached 33.8% of native murine embryonic heart tissue, slice strain was below normal adult myocardium, and the copy gives no native-myocardium benchmark for conduction velocity. It therefore supports the presence of mechanical and electrical function, but not the full claim that both properties approached physiologic levels. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [32] Herron, 2016, Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function, Circ Arrhythm. Electrophysiol source
The Results (ECM Effects on iCell hiPSC-CM Monolayer Impulse Propagation; page unavailable) report engineered cardiac monolayers with conduction velocities as high as 55 cm/s, approaching the adult-heart range described in the Introduction. The Discussion says their myofilament changes may promote greater tension development, but the paper does not report contractile-force measurements approaching native myocardium. This citation therefore supports the conduction part, not the force part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown datahvCOC showed augmented sensitivity to adrenergic stimulation and both chronotropic and inotropic effects compared with hvCTS and hvCMT systems constructed with the same hPSC-vCMs.
“Functionally, we observed an augmented sensitivity of the hvCOC to adrenergic stimulation and the presence of both chronotropic and inotropic effects when compared with the hvCTS and hvCMT systems constructed with the same hPSC-vCMs [14,18].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The Results (page not provided) report a strong chronotropic response but a negligible sustained inotropic response to isoproterenol in the paper’s hECTs. This supports part of the comparison, but the paper does not assess hvCOC or establish that its tissues were made from the same cardiomyocytes as the citing authors’ systems, so it cannot substantiate the claimed relative sensitivity. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
The Results section reports that β-adrenergic stimulation increased beating frequency but not twitch tension in hvCMTs, and says cardiac tissue strips likewise showed a positive chronotropic but negligible inotropic response. The paper therefore supports the comparator response described in the citing sentence, but it does not assess hvCOC or establish its greater sensitivity; the citing authors present that as their own observation. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataVerapamil decreased stroke volume, cardiac output, and developed pressure, with P-V loops showing decreases in end-systolic pressure and stroke work.
“Consistent with a negative inotropic effect resulting from reduced Ca2+ entry that we reported in our previous studies with hvCTS and hvCMT [14,18], the stroke volume, cardiac output, and developed pressure decreased (shown in Fig. 4a) with the P-V loops likewise exhibiting decreases in end-systolic pressure and stroke work (Fig. 4b).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
- cites [18] Chen, 2015, Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs, Circ. Arrhythm. Electrophysiol. source
The Results section reports reduced twitch tension in hvCMTs after PLB transduction, supporting a negative inotropic effect. But the Results on Ca²⁺ transients say PLB transduction did not alter L-type Ca²⁺ current; the paper does not report verapamil treatment or the cited pressure–volume measures. In the citing sentence, those measures are presented as the citing authors’ own Fig. 4 results, while the citation is attached to the prior-study comparison. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataElectron microscopy showed Z-lines, other sub-sarcomeric structures, and myofibrils interspersed with mitochondria in hvCOC.
“Electron microscopy further revealed clearly visible Z-lines and other sub-sarcomeric structures and myofibrils intercalated with mitochondria (Fig. 1i)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter 10 days of incubation, hvCOCs had a hollow chamber shape and a wall thickness of about 100 μm.
“Following incubation for 10 days, the resulting hvCOCs exhibited a hollow chamber geometry (Fig. 1f) with cells distributed across a wall thickness of approximately 100 μm (Fig. 1g).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationVerapamil initially increased and then at higher concentrations decreased APD50, with shortened plateau phase and reduced amplitudes, secondarily increasing firing frequency.
“As described in guinea pig ventricular myocytes [42], the L-type Ca2+ channel blocker verapamil initially increased and then at higher concentrations decreased the APD50, with a shortened plateau phase and reduced amplitudes, thereby secondarily increasing the firing frequency (Fig. 6a, d).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Zhang, 1997, Multiple modulations of action potential duration by different calcium channel blocking agents in Guinea pig ventricular myocytes, J. Cardiovasc. Pharmacol. source
Classified as probably not a substantial claim.
Findingown dataOver 10 days, the tissue compacted around the balloon core to form a human engineered cardiac organoid.
“during which time the tissue compacted around the balloon core to form a human engineered cardiac organoid.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn hvCOC, cyclical pressure and volume changes were out-of-phase, and reconstructed PV loops progressed counter-clockwise.
“Mechanically, cyclical changes in pressure (P) and volume (V) were out-of-phase such that an increase in chamber pressure was accompanied by a decrease in volume, and vice versa; as a result, the reconstructed PV loops exhibited a counter-clockwise progression throughout the beating cycle (see Fig. 3b–c for a representative experiment).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt selected loading pressures, reconstructed P-V loops progressed counter-clockwise, indicating positive stroke work that increased with mean pressure.
“At selected loading pressures the reconstructed P-V loops progressed counter-clockwise (Fig. 3h), indicating positive stroke work that increased with mean pressure.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEC50 values for cardiac output were 61.7 ± 6.6 nM for verapamil, 15.4 ± 9.4 nM for nifedipine, and 354.5 ± 42.7 nM for disopyramide.
“The EC50 values for their cardiac outputs were 61.7 ± 6.6 nM, 15.4 ± 9.4 nM and 354.5 ± 42.7 nM, respectively, which are in the range of those previously reported with Langendorff heart experiments [38,39].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [38] Hugtenburg, 1989, The differential effect of calcium antagonists on the positive inotropic effects induced by calcium and monensin in cardiac preparations of rats and Guinea-pigs, Naunyn-Schmiedeberg’s Arch. Pharmacol. source
- cites [39] Matsumoto, 1993, Relationship between negative inotropic and chronotropic effects of tocainide and five class I antiarrhythmic drugs in the coronary perfused Guinea-pig heart, Gen. Pharmacol. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe tissue mixture contained about 90% cTNT+MLC2v+ cells and 1 million cells/mL human dermal fibroblasts.
“10 million cells/mL tissue mixture of which about 90% were cTNT+MLC2v+ (Supplemental Fig. 1), with an additional 1 million cells/mL human dermal fibroblasts to aid in tissue compaction”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataConnexin-43 was elevated in hvCOC compared to other engineered constructs, but not different from 2D culture.
“Connexin-43 was elevated in hvCOC compared to the other engineered constructs, though not different from 2D culture.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThis observation was consistent with upregulation of PLB as demonstrated by qPCR and ranking of cGMP-PKG and calcium signaling pathways among top 10 upregulated pathways.
“This observation was consistent with an upregulation of PLB as demonstrated by our qPCR and the ranking of the pathways ‘cGMP-PKG signaling pathway’ and ‘calcium signaling pathway’ among the top 10 pathways with the highest number of upregulated genes in KEGG pathway analysis of the RNA-sequencing data (Supplemental Fig. 4a).”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningThe bioreactor design enables a single researcher to assemble 8-10 hvCOCs per week with a success rate of about 70-80%.
“in particular, our bioreactor design enables a single researcher to assemble 8–10 hvCOCs per week with a success rate of about 70–80%.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIsoproterenol dose-dependently increased spontaneous AP firing with concomitant increases in CV and decreases in APD50.
“As for positive inotropic interventions, the addition of isoproterenol dose-dependently increased spontaneous AP firing with concomitant increases in CV and decreases in APD50 (Fig. 6a and b), consistent with an intact chronotropic response and mirroring the increased spontaneous beating rate already presented in Fig. 4a.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingown dataApproximately 50% increase in pressure and ejection fraction and 100% increase in stroke work could be achieved by prolonging culture time to Day 20.
“Indeed, approximately 50% increase in pressure and ejection fraction and 100% increase in stroke work could be achieved by prolonging the culture time to Day 20 (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe authors created a 3D miniature ventricle-like cardiac organoid chamber (hvCOC) that is electro-mechanically coupled and ejects fluid, and that reproduces key molecular, physiological, and pharmacological features of the native ventricle.
“we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC).”
- Also stated in: § Introduction · plain
“herein we describe the engineering of a 3D electro-mechanically coupled, fluid-ejecting human ventricle-like cardiac organoid chamber (hvCOC) that recapitulates key molecular, physiological and pharmacological features of the native ventricle.”
Quote in the paperSubstantial claim- Rests on an assumption: Existing human in vitro systems do not directly measure how the heart performs as a pump.
- Rests on an assumption: Monolayer and patch constructs are not intended for contractile characterization.
- Also stated in: § Introduction · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDuring optical mapping, the silicone balloon inside the hvCOC stayed inflated to prevent spontaneous movement and motion artifacts.
“Throughout the optical mapping experiment, the silicone balloon inside the hvCOC remained inflated to impede spontaneous movement of the hvCOC to avoid motion artifacts.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThe study included only hPSC-CM batches in which more than 70% of cells expressed cardiac troponin-T.
“Only batches of hPSC-CMs with >70% of cells positively expressing cardiac troponin-T (cTnT) were included in the study.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAt least three hvCOC were analyzed for each pharmacological intervention.
“data from at least n = 3 hvCOC were collected for each intervention.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe Frank-Starling mechanism is a hallmark of cardiac physiology: ventricular stroke volume increases with filling blood volume.
“A hallmark characteristic of cardiac physiology is the Frank-Starling mechanism by which the ventricular stroke volume increases as the volume of filling blood increases. In native cardiac muscle experiments, this translates into the generation of stronger twitch forces with increasing preload or stretch [35].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Allen, 1985, The cellular basis of the length-tension relation in cardiac muscle, J. Mol. Cell. Cardiol. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenPreparations with spontaneous reentrant arrhythmia at baseline, about 20% of the total, were excluded from further analysis.
“preparations demonstrating spontaneous reentrant arrhythmia in baseline condition (~20% of total preparations) were excluded from further analysis.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe hvCOC system is complementary to other existing tools for drug discovery and disease modeling, and allows organ-level measurements of cardiac pump performance not previously possible with human in vitro systems.
“The hvCOC system is complementary to other existing tools for drug discovery and disease modeling, and allows organ-level measurements of cardiac pump performance that have not been previously possible with human in vitro systems.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningIn combination with somatic reprogramming of induced hPSC and control of cellular composition and external milieu, the 'human-heart-in-a-jar' system offers an advanced biomaterial platform for next-generation drug discovery, cardiotoxicity screening, disease modeling and other applications.
“In combination with somatic reprogramming of induced hPSC and the control of cellular composition as well as the external milieu, such a “human-heart-in-a-jar” system offers an advanced biomaterial platform representing the upper end of a tiered screening approach for next-generation drug discovery, cardiotoxicity screening, disease modeling and other ethnicity-, sex- and patient-specific”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe ability to measure both mechanical and electrical properties in a simplified yet biomimetic model of a human ventricle offers new avenues to bridge the gap between traditional cell culture systems, in vivo animal models and clinical trials.
“Combined, the ability to measure both mechanical and electrical properties in a simplified yet biomimetic model of a human ventricle offers new avenues to help bridge the longstanding gap between traditional cell culture systems, in vivo animal models and clinical trials.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Existing human in vitro systems do not directly measure how the heart performs as a pump.
“However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump.”
The paper relies on this without support.
Monolayer and patch constructs are not intended for contractile characterization.
“such constructs are not designed for contractile characterization”
The authors state this as an assumption.
Chamber volume can be estimated by treating the chamber as a sphere with the same cross-sectional area.
“Chamber volume was estimated by assuming an equivalent sphere with the same cross-sectional area.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Engineered cardiac organoid chambers made of cardiomyocytes in isotropic hydrogels showed promise for intra-ventricular pressure measurements, but lack of scaffold hampers formation of organized tissues recapitulating native myocardial laminar architecture.
“Engineered cardiac organoid chambers comprised of cardiomyocytes embedded in isotropic hydrogels showed significant promise for obtaining intra-ventricular pressure measurements26–29 but the lack of a scaffold to guide cell assembly hampers the formation of organized tissues that recapitulate the laminar architecture30,31 of the native myocardium.”
From A tissue-engineered scale model of the heart ventricle (2018) · cites this paper as [29]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMethods such as microcontact printing, photolithography, directional freeze drying, fiber spinning, and microphysiological chip fabrication are limited in producing tissues on complex geometries that fully replicate cardiac function.
“These methods are however limited in their ability to produce tissues on complex geometries that fully replicate cardiac function.”
From Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles (2023) · cites this paper as [10]
The Introduction (page not provided) says earlier cardiac monolayers, patches, thin films, micro-tissues and strips could not provide direct pressure- and volume-based measures of heart-pump performance. It does not assess the five named fabrication methods or establish that they are limited in producing tissues on complex geometries. The paper discusses recapitulating key cardiac features, not fully replicating cardiac function. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThese volume-handling models are limited to a single ventricle and lack perfusion capacity.
“However, these tissues are limited to a single ventricle model and thus lack the capacity for perfusion.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
The Introduction and Discussion describe a simplified, single ventricle-like chamber, supporting the single-ventricle part of the claim. The Discussion contrasts the model with native heart tissue that has integrated vasculature, but the paper does not establish that being a single-ventricle model causes a lack of perfusion capacity. The Results also report that the chamber pumps fluid, so lack of perfusion should not be read as lack of fluid movement. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe thinnest hChaMP walls match prior literature values, while the thickest walls greatly exceed existing tissue models.
“Wall thicknesses on the low end of this spectrum match what has been previously demonstrated in the literature, and the high end of the spectrum far exceeds existing tissue models6–8.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
The Results section (Bioengineering hvCOC; page unavailable) reports a wall thickness of approximately 100 μm. It does not compare that thickness with prior wall-thickness values or establish that thicker hChaMP walls exceed existing tissue models. The cited paper also studies hvCOCs, not the citing document’s hChaMPs. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe hChaMP maintained its functions for at least six weeks, whereas most comparable models have been characterized only up to two weeks after fabrication.
“Notably, we show that the hChaMP can maintain these functions for at least 6 weeks, while most similar models have been characterized only up to 2 weeks after fabrication6–8, 18.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
The Materials and methods describe functional testing of this paper’s ventricular chamber after 10–12 days in culture, which supports it as an example of a model characterized around two weeks. The Discussion also describes improved function with culture extended to day 20. Neither passage establishes that most comparable models were characterized only up to two weeks; the six-week result is the citing authors’ own finding, not a claim attributed to this source. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Construction of engineered 3D mimics often necessitates addition of stromal cells to facilitate proper formation of tissue constructs.
“the construction of tissues, specifically engineered 3D mimics, often necessitates the addition of stromal cells to facilitate proper formation of these tissue constructs.32,33”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [33]
The Materials and methods section says human dermal fibroblasts were added to aid compaction of this 3D cardiac construct, and the Results section describes its formation. This supports the use of stromal cells to facilitate formation in this example, but does not establish that engineered 3D mimics often require them. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe hvCTS and hvCOC human mini-heart models have proven effective for modeling different cardiovascular disease states and testing of drugs and biologics.
“Despite the sub-physiologic levels of function typical of engineered tissue constructs for in vitro studies, the hvCTS and hvCOC human mini-heart models used in this study have proven effective for modeling different cardiovascular disease states and testing of drugs and biologics.17,18,22,23”
From Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial (2024) · cites this paper as [22]
The Results section on pump performance reports that hvCOC responded to several drugs, and the Discussion says it distinguished dose responses to positive and negative inotropes. The paper compares hvCOC with hvCTS and describes disease modeling as a potential application, but it does not establish that both models have proven effective for modeling different cardiovascular disease states or for testing biologics. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredContractile work in our ventricle models was measured using conductance catheters and was smaller than reported for cardiac organoid chambers based on NRVM or pluripotent hES2 human embryonic stem cell-derived cardiomyocytes, where volume changes were indirectly assessed from video recordings.
“Contractile work in our ventricle models was measured using conductance catheters and was smaller than reported for cardiac organoid chambers based on NRVM26 or pluripotent hES2 human embryonic stem cell-derived cardiomyocytes29, where volume changes were indirectly assessed from video recordings.”
From A tissue-engineered scale model of the heart ventricle (2018) · cites this paper as [29]
In spontaneously beating tissue-engineered model ventricles, isoproterenol did not produce the positive inotropic effects that others have reported during electrical pacing.
“the positive inotropic effects of isoproterenol observed by others during electrical pacing29 was not observed by us when isoproterenol was administered to spontaneously beating model ventricles (Fig. 3b, right panels).”
From A tissue-engineered scale model of the heart ventricle (2018) · cites this paper as [29]
Researchers have generated volume-handling cardiac tissue models that recapitulate pressure-volume dynamics of the heart.
“To address this issue, researchers have made strides in the generation of volume-handling cardiac tissue models capable of recapitulating pressure-volume dynamics of the heart6–8.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
Existing single ventricle models use simple cup-like geometry for casting cardiomyocyte-laden gel or seeding cardiomyocytes after fabrication.
“Indeed, multiple existing single ventricle models rely on their simple cup-like geometry to enable casting of a cardiomyocyte-laden gel6 or seeding of cardiomyocytes after fabrication7.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
The hChaMP generated a low pressure of 0.23 mmHg, which is higher than other reported values.
“the pressure generated by the hChaMP, while low (0.23 mmHg), is higher than other reported values6, 7.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
The hChaMP ejection fraction measurements are comparable to those reported for single ventricle models.
“These measurements are on par with data shown in single ventricle models6, 7.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [6]
Pressure-volume parameters in hvCOC were measured to ensure viability and normal function before collection for scRNA-seq.
“Pressure-volume parameters in hvCOC were measured via video recording and a custom analysis software according to Li et al.33 to ensure viability and normal function before collection of tissue construct for scRNA-seq.”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [33]
Tissue fabrication of hvCAS, hvCTS and hvCOC follows previously published reports without deviations.
“The tissue fabrication of hvCAS, hvCTS and hvCOC follows our previously published reports without deviations.28,32,33”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [33]
The finding that CMs from CS were less mature than those from hvCTS and hvCOC corroborates previous bulk RNA-sequencing findings.
“which corroborates with findings from our previous study using bulk RNA-sequencing analysis.33”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [33]
Prior hydrogel tissue engineering approaches have had limited capacity to create the microstructural features required for cells to self-organize into hierarchical three-dimensional organ models.
“Hydrogels are attractive materials for tissue engineering, but efforts to date have shown limited ability to produce the microstructural features necessary to promote cellular self-organization into hierarchical 3D organ models.”
From Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles (2023) · cites this paper as [10]
The Introduction describes limitations of earlier cardiac constructs in measuring pump performance, not an inability of hydrogels to produce microstructural features. The Results describe self-assembly of the authors’ hydrogel-based chamber, while the Discussion notes that their simplified chamber lacks the native heart’s hierarchical muscle-fiber organization. Neither passage establishes the claimed general limitation of prior hydrogel approaches; searches for microstructural features and hierarchical self-organization found no such statement. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Stimulus strength does not match the stated voltage and electrode spacing
MajorThe field strength and hardware values given here are not mutually consistent. A 10 V stimulus across 19 cm corresponds to about 52.6 mV/mm, not 63 mV/mm.
Reported 63 · recomputed 0.526316
“Functional pump analysis was performed under field stimulation at 63 mV/mm with a GRASS S88x stimulator (Astro-Med) at specified frequencies. Where required, electrical field stimulation was induced with a pair of carbon electrodes 19 cm apart and a stimulation pulse length of 50 ms at 10 V.”
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- Authors
- Li, R. A., Keung, W., Cashman, T. J., Backeris, P. C., Johnson, B. V., Bardot, E. S., Wong, A. O. T., Chan, P. K. W., Chan, C. W. Y., & Costa, K. D.
- Affiliations
- Karolinska Institutet (SE)
- Icahn School of Medicine at Mount Sinai (US)
- University of Hong Kong (HK)
- Corresponding author
- Li, Ronald A.
- Costa, Kevin D.
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 163
- Pages
- 116-127
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC6561506
- OpenAlex
- W2791886935
- Cited by
- 175
- References
- 51
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 14 · 2023: 23 · 2022: 30 · 2021: 23 · 2020: 32 · 2019: 20 · 2018: 8
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F30HL118923, HHSN268201000045C)
- National Institute of General Medical Sciences (T32GM008553)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD075735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- human pluripotent stem cells, ventricular myocytes, collagen gel, extracellular matrix, cardiac contractility, ejection fraction, action potential, conduction velocity, inotropic agents, drug screening, cardiac electrophysiology
- MeSH terms
- Action Potentials, Cell Differentiation, Collagen, Heart Ventricles, Humans, Myocardial Contraction, Myocardium, Ventricular Function, Cell Culture Techniques, Hydrogels, Tissue Engineering, Myocytes, Cardiac, Pluripotent Stem Cells, Biomimetic Materials, Electrophysiological Phenomena
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