The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index; 52 of the 74 sources its claims cite were checked for support.
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
47 Own result · 16 Own interpretation · 14 Partly supported · 7 No full text of the sources · 4 Supported so far · 4 Own method · 3 No basis given · 1 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“engineered cardiac thin films, micro-tissues and strips allow the assessment of twitch force [9,12–19]”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Introduction
What the sources say
- Supportedcites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. sourceExperimental — accuracy not yet measured
The Methods section describes an elongated engineered cardiac tissue construct. The Results section reports mounting these constructs on a force transducer and measuring their active twitch force, supporting this paper as an example of the force-measurable constructs cited in the multi-source sentence. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- Not checked — no full text of the sourcecites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
The Materials and Methods section describes calculating twitch force in engineered human cardiac tissues from flexible-post deflection and measuring it with a force transducer. The Abstract also identifies muscular thin films and microfabricated tissue gauges as related platforms. Together, these passages support the cited sentence’s general point that engineered tissue formats permit twitch-force assessment. (LLM, conf=0.89)
- Supportedcites [15] Huang, 2007, Contractile three-dimensional bioengineered heart muscle for myocardial regeneration, J. Biomed. Mater. Res. sourceExperimental — accuracy not yet measured
The Evaluation of contractility section (page not provided) describes measuring the electrically stimulated twitch force of three-dimensional bioengineered heart-muscle constructs with a force transducer. This paper supports the claim as one example within the grouped citations, rather than as evidence for every listed format. (LLM, conf=0.88)
- Supportedcites [16] Schaaf, 2011, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PLoS One sourceExperimental — accuracy not yet measured
The Introduction identifies strip-format fibrin-based engineered heart tissues. Figure 1 in the Results describes calculating their force development from silicone-post deflection over time, supporting this paper as an example of strips used to assess twitch force. The citation is one of a group accompanying the list of formats; this paper need not establish the thin-film and micro-tissue examples. (LLM, conf=0.91)
- Partly supportedcites [17] Wang, 2014, Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies, Nat. Med. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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
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)
- Supportedcites [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
The Bioartificial cardiac tissue preparation and cultivation section (page not supplied) describes engineered tissue constructs fixed at both ends and direct measurement of active contraction force with bioreactor sensors. This paper therefore supports the citation as an example of an engineered cardiac tissue format that permits twitch-force assessment. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“but not pressure- and volume-based metrics directly representing pump performance of the heart”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Introduction
What the sources say
- Supportedcites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. sourceExperimental — accuracy not yet measured
The Materials and Methods section describes solid tissue constructs held by tabs for uniaxial loading, while the Results section measures force as construct length changes. These are not chamber-like constructs that yield pressure–volume measures of pumping performance; the claim accurately distinguishes their force–length measurements from those metrics. Page numbers are unavailable in our copy. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- Not checked — no full text of the sourcecites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- Partly supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [15] Huang, 2007, Contractile three-dimensional bioengineered heart muscle for myocardial regeneration, J. Biomed. Mater. Res. sourceExperimental — accuracy not yet measured
The Evaluation of contractility section describes a construct attached to a force transducer and assessed by twitch force, rather than by pressure or displaced volume. The Results describe a tensioned muscle construct anchored between sutures, while the Introduction distinguishes these patches from bioartificial ventricles. Together, these passages support the distinction between the constructs’ contractility measurements and pressure–volume measures of pump performance. (LLM, conf=0.84)
- Partly supportedcites [16] Schaaf, 2011, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PLoS One sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [17] Wang, 2014, Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies, Nat. Med. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The Methods section (page unavailable) describes measuring microtissue force from cantilever displacement, and the Results section (page unavailable) reports beating rate and twitch tension. These constructs are assessed by force rather than the pressure- and volume-based measures of heart pump performance named in the claim. (LLM, conf=0.84)
- Supportedcites [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
The Bioartificial cardiac tissue preparation and cultivation section describes constructs fixed at both ends and measured with force sensors. The Discussion reports contraction forces as the measure of function. These are tissue-force measurements, not pressure- or volume-based measures of heart pump performance. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Electrophysiological function of hvCOC
What the sources say
- Supportedcites [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 Results section, under “L-type Ca2+ channels but not the NCX modulate Ca2+ sparks in hESC-VCMs” (page unavailable), reports that depolarization rapidly generated Ca2+ sparks and that L-type-channel-mediated Ca2+ influx activates RyRs. This supports the Ca2+-induced Ca2+ release mechanism for which the citation is supplied; the citing authors describe the 1-Hz tracing and its delay as their own Fig. 5c observation. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Electrophysiological function of hvCOC
What the sources say
- Not checked — no full text of the sourcecites [40] Bass, 1975, Some electrical and mechanical effects of strontium on toad ventricular muscle: comparison to calcium, J. Physiol. source
- Supportedcites [41] Boyett, 1980, Analysis of the effects of changes in rate and rhythm upon electrical activity in the heart, Prog. Biophys. Mol. Biol. source
The citation supports the sentence’s background point about rate adaptation in native cardiac tissue, not the citing authors’ hvCOC measurements. In “Description of Changes,” the review says Purkinje and ventricular action potentials shorten at higher stimulation rates; its discussion of steady-state action potentials reports reduced conduction velocity at higher rates in rabbit atrium. It does not claim to have studied hvCOC. (LLM, conf=0.90)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
What the sources say
- Partly supportedcites [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
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)
- Supportedcites [24] Li, 2013, Calcium signalling of human pluripotent stem cell-derived cardiomyocytes, J. Physiol. source
The passage on in vitro electrical conditioning (labelled Abstract in our copy; page unavailable) reports maturation of hESC-derived cardiomyocytes alongside increased expression of several calcium-handling and T-tubule-related genes. That supports this citation’s role as a prior maturation study with which the citing authors compare their transcript results. (LLM, conf=0.86)
- Supportedcites [25] Liu, 2007, Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation, Stem Cell. source
The citation is attached to “previous maturation studies,” not to the transcript analysis of the engineered constructs. In the section on Ca²⁺-handling proteins (page unavailable), this paper compares embryonic-stem-cell-derived, fetal, and adult cardiomyocytes and reports developmental changes in SR-related proteins, making it a relevant prior maturation study. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
What the sources say
- Supportedcites [5] Lieu, 2013, Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes, Circ. Arrhyth. Electrophysiol. sourceExperimental — accuracy not yet measured
The Results section identifies Kir2.1 as a channel underlying the inwardly rectifying potassium current IK1 and reports that adding it stabilized the electrical behavior of hESC-derived cardiomyocytes. The Discussion likewise identifies IK1 as important for electrical stability. The citation attaches to that background point; the approximately fivefold increase in hvCOC is presented as the citing authors’ own finding. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [29] Liao, 2013, Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction, Heart Rhythm source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Prior cardiac tissue engineering studies have shown this in the context of arrhythmogenicity [33], contractility [14,34] and recapitulation of disease phenotypes [12,48].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Not checked — no full text of the sourcecites [33] Shum, 2017, A micropatterned human pluripotent stem cell-based ventricular cardiac anisotropic sheet for visualizing drug-induced arrhythmogenicity, Adv. Mater. source
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The Results section reports dose-dependent changes in twitch force in engineered human cardiac tissues exposed to calcium chloride, consistent in direction with natural myocardium. The paper also tests other inotropic agents and notes that its isoproterenol response differs from natural myocardium; the citation supports the contractility part of the citing sentence, not the separately cited arrhythmogenicity or disease-phenotype parts. (LLM, conf=0.86)
- Supportedcites [34] Mannhardt, 2017, Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: comparison with human atrial trabeculae, Toxicol. Sci. source
The citation is attached to contractility, not arrhythmogenicity or disease-phenotype recapitulation. The Conclusion (page unavailable) states that hiPSC engineered heart tissue detected drug-induced inotropic effects under blinded conditions, while noting that it failed to detect beta-2 adrenergic or PDE3 effects. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [12] Hansen, 2010, Development of a drug screening platform based on engineered heart tissue, Circ. Res. source
- Supportedcites [48] Stillitano, 2016, Genomic correction of familial cardiomyopathy in human engineered cardiac tissues, Eur. Heart J source
This source is cited for recapitulation of disease phenotypes, rather than for every item in the citing sentence. The Abstract reports that mutant engineered cardiac tissues reproduced a disease-dependent phospholamban distribution observed in patient tissue and showed impaired contractility that was restored by genetic correction. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Partly supportedcites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials sourceExperimental — accuracy not yet measured
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Supportedcites [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 (page not supplied) reports that isoproterenol significantly increased the spontaneous beating frequency of 3D hvCMTs but did not alter their developed twitch tension. This supports the portion of the citing sentence attributed to this source, which is specifically about hvCMTs. (LLM, conf=0.94)
- Partly supportedcites [21] Boudou, 2012, A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues, Tissue Eng. Part A sourceExperimental — accuracy not yet measured
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)
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The citation to this paper is attached to the 3D tissue example, not the separately cited 2D cells or other 3D constructs. The Abstract and Results (pages not provided) report that its hESC-derived engineered cardiac tissues showed a strong positive chronotropic response to isoproterenol but a negligible, statistically nonsignificant sustained inotropic response. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Partly supportedcites [24] Li, 2013, Calcium signalling of human pluripotent stem cell-derived cardiomyocytes, J. Physiol. sourceExperimental — accuracy not yet measured
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)
- Could not verifycites [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
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)
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
The citation to this paper is attached to the comparison with a negative force–frequency relationship in engineered cardiac tissue, not to the citing authors’ hvCOC pressure measurement. The Results report that developed stress in hECTs was relatively uniform below 1.5 Hz but decreased at higher stimulation frequencies; the Discussion characterizes the trend as flat or slightly decreasing. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
- Probably not a substantial claim. 15
- It may state two separate claims as one. 17
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although hPSC-vCMs have been organized as monolayers and patches for electrophysiological assessment [6–8] and even surgical engraftment [9–11]”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Introduction
What the sources say
- Partly supportedcites [6] Chen, 2011, Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives, Adv. Mater. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [7] Wang, 2013, Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias, Biomaterials source
- Supportedcites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials source
The Results sections on structural phenotype and action-potential conduction report hESC-derived cardiomyocytes cultured as both monolayers and 3D patches, with electrical propagation assessed in each. The electrophysiological-properties Results section describes a predominantly ventricular action-potential phenotype. This source supports the electrophysiology portion of the citing sentence; surgical engraftment is attached to a separate citation group. (LLM, conf=0.92)
- Supportedcites [9] Tulloch, 2011, Growth of engineered human myocardium with mechanical loading and vascular coculture, Circ. Res. source
The citation is attached to surgical engraftment. In Results > Cardiac Engraftment, the paper reports implanting human stem-cell-derived cardiac constructs onto rat hearts and identifying the grafts one week later. (LLM, conf=0.92)
- Partly supportedcites [10] Caspi, 2007, Tissue engineering of vascularized cardiac muscle from human embryonic stem cells, Circ. Res. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The citation is attached to surgical engraftment, not to the preceding claim about monolayers used for electrophysiology. The Construction and Culture of Patches section describes patches containing human iPSC-derived cardiomyocytes, and the Patch Engraftment section reports that the implanted patches remained on the rats’ left ventricular surface four weeks after surgery. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Human pluripotent stem cells (hPSC) can be specified into ventricular cardiomyocytes (vCM) that have been robustly characterized at the single-cell level [2–5].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Introduction
What the sources say
- Supportedcites [2] Mummery, 2003, Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells, Circulation source
The Abstract reports that coculture differentiated human embryonic stem cells into cardiomyocytes, most of which resembled human fetal ventricular cells electrophysiologically. The Electrophysiology section reports single-cell patch-clamp characterization: 28 of 33 dissociated cells had ventricular-like action potentials, though other phenotypes were also present. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [3] He, 2003, Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization, Circ. Res. source
- Not checked — no full text of the sourcecites [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
- Supportedcites [5] Lieu, 2013, Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes, Circ. Arrhyth. Electrophysiol. source
The Introduction states that human embryonic stem cells can be differentiated into cardiomyocytes, including ventricular cells. The Methods (Electrophysiology) describe recording from individual cells and identifying ventricular phenotypes; the Results report single-cell action-potential measurements and ionic-current profiling of ventricular derivatives. Page numbers are not available in our copy. (LLM, conf=0.91)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“with sarcomeric arrangements similar to other human engineered cardiac tissue constructs [14,21–23] but distinct from random clusters.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
What the sources say
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The Results section (‘hECT histology reveals features of cardiac microstructure’) describes aligned cardiomyocytes with organized sarcomeres in the paper’s human engineered cardiac tissues. That supports citing this work as an example of the sarcomeric arrangements to which hvCOC is compared; the contrast with random clusters is not presented as a finding of this source. (LLM, conf=0.89)
- Partly supportedcites [21] Boudou, 2012, A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues, Tissue Eng. Part A sourceExperimental — accuracy not yet measured
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)
- Supportedcites [22] Kerscher, 2016, Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues, Biomaterials source
The Results section (‘3D-dhECT CMs develop mature structural features over time’; page unavailable) reports aligned, organized, well-defined sarcomeres in the paper’s engineered human cardiac tissues. The citation is attached to the comparison with other engineered constructs; the subsequent contrast with random clusters is not attributed to this source. (LLM, conf=0.90)
- Supportedcites [23] Nunes, 2013, Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes, Nat. Methods source
The Results sections “Engineering of human cardiac biowires” and “Physiological hypertrophy in stimulated biowires” describe an engineered human cardiac construct with aligned cells, sarcomeric banding, and myofibrillar alignment. This supports the citation as an example of the kind of construct to which the citing authors compare hvCOC; the comparison with random clusters is not attributed specifically to this source. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Partly supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similarly, we have reported a linear relationship between the developed stress and axial stretch in hvCTS [14].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Partly supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Supportedcites [8] Zhang, 2013, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials source
The Discussion (page not supplied) reports that this study’s engineered cardiac patches had high contractile stresses and conduction velocities only 2–3 times lower than adult human myocardium. That supports this paper as one example in the citing sentence’s group of reports. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [13] Thavandiran, 2013, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. source
- Partly supportedcites [31] Guyette, 2016, Bioengineering human myocardium on native extracellular matrix, Circ. Res. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [32] Herron, 2016, Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function, Circ Arrhythm. Electrophysiol sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
What the sources say
- Partly supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Electrophysiological function of hvCOC
What the sources say
- Supportedcites [14] Turnbull, 2014, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, Faseb. J. source
The citation is attached to the prior-study finding of a negative inotropic effect, not to the citing paper’s Fig. 4 measurements. The Results section reports that verapamil, an L-type calcium-channel blocker, reduced systolic force in engineered cardiac tissues. Stroke volume, cardiac output, and P-V-loop changes are presented as the citing paper’s own results. (LLM, conf=0.88)
- Partly supportedcites [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
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Electron microscopy further revealed clearly visible Z-lines and other sub-sarcomeric structures and myofibrils intercalated with mitochondria (Fig. 1i)”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Electrophysiological function of hvCOC
What the sources say
- Not checked — no full text of the sourcecites [42] Zhang, 1997, Multiple modulations of action potential duration by different calcium channel blocking agents in Guinea pig ventricular myocytes, J. Cardiovasc. Pharmacol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“during which time the tissue compacted around the balloon core to form a human engineered cardiac organoid.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Human ventricular cardiac organoid chamber (hvCOC) generation.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At selected loading pressures the reconstructed P-V loops progressed counter-clockwise (Fig. 3h), indicating positive stroke work that increased with mean pressure.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Human ventricular cardiac organoid chamber (hvCOC) generation.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Connexin-43 was elevated in hvCOC compared to the other engineered constructs, though not different from 2D culture.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Bioengineering hvCOC
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“in particular, our bioreactor design enables a single researcher to assemble 8–10 hvCOCs per week with a success rate of about 70–80%.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Electrophysiological function of hvCOC
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Abstract
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Throughout the optical mapping experiment, the silicone balloon inside the hvCOC remained inflated to impede spontaneous movement of the hvCOC to avoid motion artifacts.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Characterization of hvCOC electrophysiological function.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only batches of hPSC-CMs with >70% of cells positively expressing cardiac troponin-T (cTnT) were included in the study.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Experimental design.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“data from at least n = 3 hvCOC were collected for each intervention.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Experimental design.
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Results > Pump performance of hvCOC and their responses to pharmacological interventions
What the sources say
- Not checked — no full text of the sourcecites [35] Allen, 1985, The cellular basis of the length-tension relation in cardiac muscle, J. Mol. Cell. Cardiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“preparations demonstrating spontaneous reentrant arrhythmia in baseline condition (~20% of total preparations) were excluded from further analysis.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Characterization of hvCOC electrophysiological function.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Discussion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“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]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
“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.”
§ Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells > Materials and methods > Characterization of hvCOC contractile function.
Reported 63 · recomputed 0.526316
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Metadata
- 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
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.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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