The DOI matches its Crossref record; 79 of the 79 references it cites were found in a registry or an index; 16 of the 40 sources its claims cite were checked for support.
A liver-on-a-chip platform with bioprinted hepatic spheroids
Open accessAbstract
The inadequacy of animal models in correctly predicting drug and biothreat agent toxicity in humans has resulted in a pressing need for in vitro models that can recreate the in vivo scenario. One of the most important organs in the assessment of drug toxicity is liver. Here, we report the development of a liver-on-a-chip platform for long-term culture of three-dimensional (3D) human HepG2/C3A spheroids for drug toxicity assessment. The bioreactor design allowed for in situ monitoring of the culture environment by enabling direct access to the hepatic construct during the experiment without compromising the platform operation. The engineered bioreactor could be interfaced with a bioprinter to fabricate 3D hepatic constructs of spheroids encapsulated within photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. The engineered hepatic construct remained functional during the 30 days culture period as assessed by monitoring the secretion rates of albumin, alpha-1 antitrypsin, transferrin, and ceruloplasmin, as well as immunostaining for the hepatocyte markers, cytokeratin 18, MRP2 bile canalicular protein and tight junction protein ZO-1. Treatment with 15 mM acetaminophen induced a toxic response in the hepatic construct that was similar to published studies on animal and other in vitro models, thus providing a proof-of-concept demonstration of the utility of this liver-on-a-chip platform for toxicity assessment.
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Claims the paper makes
16 Own result · 14 Own interpretation · 10 Partly supported · 10 No full text of the sources · 5 No basis given · 4 Own method · 3 Supported · 2 Sources not found · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, hepatic models that utilize conventional 2D mono-and co-cultures of normal and diseased human cells fail to mimic the complex threedimensional (3D) in vivo microenvironment and extracellular matrix (ECM) support [16,19,20].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Introduction
What the sources say
- Not checked — no full text of the sourcecites [16] Khetani, 2008, Microscale culture of human liver cells for drug development, Nat. Biotechnol. source
- Not checked — no full text of the sourcecites [19] Bhatia, 1999, Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells, FASEB J. source
- Partly supportedcites [20] LeCluyse, 2012, Organotypic liver culture models: meeting current challenges in toxicity testing, Crit. Rev. Toxicol. sourceExperimental — accuracy not yet measured
Section 3.3 says traditional 2D monocultures and co-cultures do not typically represent the liver’s three-dimensional cellular configuration or in vivo microenvironments. But Section 2.1 says co-cultures satisfy nearly all biophysical requirements for hepatocytes, including cell–matrix contacts, so the blanket claim that they lack ECM support overstates the source. The cited passages also do not establish the claim specifically for diseased human cells; page numbers were unavailable. (LLM, conf=0.83)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Increased albumin secretion from spheroids compared to cell monolayers, as seen here, is consistent with observations reported in literature, which indicates that culturing the cells as spheroids may enhance homotypic cell-cell interactions within aggregated hepatocytes and improve functional outcomes of the hepatic construct [25,48].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
What the sources say
- Partly supportedcites [25] Li, 2014, Micropatterned cell–cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues, Tissue Eng. A sourceExperimental — accuracy not yet measured
The “Effect of homotypic contacts on 3D albumin secretion” section reports more than threefold greater albumin secretion from hydrogels containing aggregated hepatocyte pucks than from hydrogels containing unpatterned hepatocytes at day 8. This supports the proposed benefit of aggregation, but the measured comparison was between two 3D hydrogel conditions, not spheroids and cell monolayers. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [48] Fraczek, 2013, Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies, Arch. Toxicol. source
hedgedconditional- 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
Every source the paper cites for this claim was checked and supports it.
In the paper
“These cell lines offer a reliable alternative to primary cells by overcoming the above issues, especially for use in proof-of-concept studies in dynamic flow liver-on-achip platforms [20].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Supportedcites [20] LeCluyse, 2012, Organotypic liver culture models: meeting current challenges in toxicity testing, Crit. Rev. Toxicol. source
Section 3.1 says hepatic cell lines can be a reasonable alternative to primary cells in dynamic-flow organotypic devices, especially for initial proof-of-concept studies. It attributes this suitability to their availability, support for long-term culture, and retention of some hepatocyte functions. (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.
- Rests on an assumption: Primary hepatocytes have limited lifespan, difficulty in obtaining the cell source, and large batch-to-batch variability post-isolation.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“By adapting this method, we avoided potentially harsh printing conditions including, low temperature for a prolonged printing period [51] and undesirable shear stress along the length of the nozzle [30].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [51] Billiet, 2014, The 3D printing of gelatin methacrylamide cell-laden tissue-engineered constructs with high cell viability, Biomaterials source
- Partly supportedcites [30] Bertassoni, 2014, Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels, Biofabrication sourceExperimental — accuracy not yet measured
Section 3.3 reports that cell viability was not significantly affected and suggests the hydrogel matrix may protect cells from shear stress during dispensing. It also says dispensing required significant stress, so the source supports protection from its effects, not avoidance of shear stress along the nozzle. The low-temperature condition is attached to a different citation in the citing sentence. (LLM, conf=0.84)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The oxygen consumption of HepG2/C3A cells can be described with the Michaelis-Menten kinetics [41,42]:”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Numerical simulations
What the sources say
- Not checked — no full text of the sourcecites [41] Weise, 2013, Analysis and comparison of oxygen consumption of HepG2 cells in a monolayer and three-dimensional high density cell culture by use of a matrigrid®, Biotechnol. Bioeng. source
- Partly supportedcites [42] Buchwald, 2009, FEM-based oxygen consumption and cell viability models for avascular pancreatic islets, Theor. Biol. Med. Modelling sourceExperimental — accuracy not yet measured
The Methods section assumes a Michaelis–Menten-type rate for oxygen consumption, and the Discussion’s “Oxygen consumption model” section specifies that this assumption applies to pancreatic islet tissue. The cited paper does not establish that the same kinetics describe HepG2/C3A cells; no page numbers are available in our copy. (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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Commercial cell lines including HepG2/C3A provide a more stable, easy-to-handle and readily available source of human cells for in vitro studies on liver function and general mechanisms of toxicity [58,59].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Partly supportedcites [58] Jennen, 2010, Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification, Toxicol. Sci. sourceExperimental — accuracy not yet measured
The paper’s Abstract describes HepG2 as easy to handle compared with primary human hepatocytes and as a frequently used model for toxicogenomics studies. It does not establish that these cell lines are more stable or readily available, and it does not address HepG2/C3A specifically. Page numbers are unavailable in our copy. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [59] Wilkening, 2003, Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties, Drug Metab. Dispos. 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.
- Partly 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
“This value dropped to an average of 38% (minimum 19%) at day 30.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioreactor platform overview
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.
- The authors state this as an assumption: The hydrogels can be modeled as a porous medium with a uniform volumetric oxygen consumption rate associated with the total number of encapsulated cells.
- The authors state this as an assumption: The oxygen concentration at the inlet is constant and uniform.
- The authors state this as an assumption: All boundaries of the bioreactor can be treated as impermeable surfaces for oxygen transport.
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
“A batch of 10 000 spheroids was obtained per mold.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
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.
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
“The engineered bioreactor could be interfaced with a bioprinter to fabricate 3D hepatic constructs of spheroids encapsulated within photocrosslinkable gelatin methacryloyl (GelMA) hydrogel.”
- Also stated in: § Bioreactor platform overview · plain
“The fabricated bioreactor shown in figure 1(c) was interfaced with a bioprinter to incorporate 3D cell-laden hydrogel constructs.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Abstract
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.
- Also stated in: § Bioreactor platform overview · plain
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
“We confirmed the cell viability in the spheroids harvested after 5 days of microwell culture using Live/Dead staining.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
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. 17
- Probably not a substantial claim. 14
- The quote only partly states this claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“These iPSC-derived hepatocyte-like cells are still in nascent stages of development and show characteristics similar to fetal hepatocytes [76].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Supportedcites [76] Bhatia, 2014, Cell and tissue engineering for liver disease, Sci. Translational Med. source
The “Stem cells as sources of hepatocytes for cellular therapies” section identifies iPSC-derived hepatocyte-like cells and says they have characteristics closer to fetal-stage than mature adult hepatocytes. It also describes ongoing efforts to improve their maturation, supporting the claim that their development remains incomplete. (LLM, conf=0.92)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Patient-specific hepatocytes derived from autologous iPSCs have recently emerged as an attractive alternative that can overcome these issues [60].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Partly supportedcites [60] Shan, 2013, Identification of small molecules for human hepatocyte expansion and iPS differentiation, Nat. Chem. Biol. sourceExperimental — accuracy not yet measured
The paper describes stem cells as an attractive alternative to primary hepatocytes and says iPS cells offer the possibility of patient-specific hepatocyte-like cells (opening passage, page unavailable). It does not establish that these cells overcome the issues with primary hepatocytes: the same passage says their immature phenotype and limited function restrict their use as a renewable source of functional hepatocytes. (LLM, conf=0.84)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The metabolic activity and function of cells fluctuate over time and similar observations have been reported in the literature [61,62].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Partly supportedcites [61] Dash, 2013, Hemodynamic flow improves rat hepatocyte morphology, function, and metabolic activity in vitro, Am. J. Physiol. Cell Physiol. sourceExperimental — accuracy not yet measured
The Abstract reports that hepatocyte-specific function and metabolic enzyme activity decline over days in nonflow cultures. The Discussion (Fig. 7A) likewise describes a decline in enzyme expression and activity over 3–7 days, but says the controlled-hemodynamics system maintains stability. The source supports time-dependent changes in cultured hepatocytes, not a general claim that cells’ activity and function fluctuate over time. (LLM, conf=0.85)
- Supportedcites [62] Wagner, 2013, A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture, Lab Chip source
The Performance of fluid flow exposed multi-tissue cultures over 14 days section (p. 6) reports that metabolic activity changed through day 7, then reached a steady state with low fluctuations in glucose consumption and lactate production. The same section (p. 7) describes a changing albumin profile, used to monitor functional liver-cell activity. These observations support the cited sentence in the context of the paper’s liver-and-skin co-cultures. (LLM, conf=0.89)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APAP overdose is a common cause of acute liver failure in the US [71,72].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Could not verifycites [71] Blazer, 2009, Nonprescription use of pain relievers by middle-aged and elderly community-living adults: national survey on drug use and health, J. Am. Geriatrics Soc. sourceExperimental — accuracy not yet measured
The Abstract Results report that acetaminophen-containing pain relievers were commonly used without a prescription in the surveyed group, but do not discuss overdose or liver failure. Searches of the full-text copy for acetaminophen overdose and liver failure found no passage addressing whether overdose is a common cause of acute liver failure in the US. (LLM, conf=0.76)
- Partly supportedcites [72] Davidson, 1966, Acute liver necrosis following overdose of paracetamol, Br. Med. J. sourceExperimental — accuracy not yet measured
The Summary (page unavailable) describes two fatal cases of acute liver necrosis after paracetamol overdose and suggests paracetamol was the chief cause. The paper does not establish that overdose is a common cause of acute liver failure in the US; it provides no US frequency data. (LLM, conf=0.88)
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.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“APAP is a wellcharacterized hepatotoxic drug and its in vivo model data is available in literature [73].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Supportedcites [73] Fey, 2012, Determination of drug toxicity using 3D spheroids constructed from an immortal human hepatocyte cell line, Toxicol. Sci. source
The Discussion (page not supplied) describes numerous published studies of APAP toxicity in hepatocytes and compares the paper’s APAP results with published in vivo plasma concentrations. This supports both its characterization as a well-studied hepatotoxic drug and the availability of in vivo data in the literature. (LLM, conf=0.90)
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.
- 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
“Increased albumin secretion from spheroids compared to cell monolayers, as seen here, is consistent with observations reported in literature, which indicates that culturing the cells as spheroids may enhance homotypic cell-cell interactions within aggregated hepatocytes and improve functional outcomes of the hepatic construct [25,48].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
What the sources say
- Supportedcites [25] Li, 2014, Micropatterned cell–cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues, Tissue Eng. A source
The ‘Control and uniformity of hepatocyte patterning’ section says the authors preaggregated hepatocytes to facilitate cell–cell contacts. In ‘Effect of homotypic contacts on 3D albumin secretion’ (page not available), hydrogels containing those aggregates secreted more albumin than controls containing unpatterned hepatocytes, supporting the proposed functional benefit. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [48] Fraczek, 2013, Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies, Arch. Toxicol. source
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.
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
“HepG2 cells can cluster over time, but dispersed cells take longer to form these cell-cell interactions when encapsulated in a porous scaffold compared to spheroids, which could affect their resistance to drugs [49].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
What the sources say
- Partly supportedcites [49] Ho, 2010, Incorporation of multicellular spheroids into 3D polymeric scaffolds provides an improved tumor model for screening anticancer drugs, Cancer Sci. sourceExperimental — accuracy not yet measured
The section ‘Spheroids remain intact in scaffolds after seeding’ (page unavailable) compares dispersed cells with spheroids in porous scaffolds and reports greater drug resistance for the spheroid-seeded scaffolds. However, the experiments used U251 glioma cells, not HepG2 cells, and the copy does not establish that dispersed cells take longer than spheroids to form cell-cell interactions in scaffolds. (LLM, conf=0.86)
hedgedconditional- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“which is a typical cell density range for hydrogel encapsulation [7]”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Partly supportedcites [7] Akbari, 2014, Composite living fibers for creating tissue constructs using textile techniques, Adv. Funct. Mater. sourceExperimental — accuracy not yet measured
The Experimental Section (Preparation of Cell Suspension in Sodium Alginate; page unavailable) reports using 2–5 × 10^6 cells mL−1 in an alginate suspension for cell-laden hydrogel fibers. This supports the range as an example of hydrogel encapsulation, but the paper does not establish that it is typical across hydrogel encapsulation generally. (LLM, conf=0.82)
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.
- Partly 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
“As seen in the side view micrograph of the bioprinted hydrogel with spheroids in figure S2, the thickness of the bioprinted GelMA dot is ∼800 μm, which is thicker than the average diameter of the spheroids (∼200 μm).”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
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.
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
“Unlike the majority of PDMSbased on-chip systems, which are permanently plasma bonded to seal the compartments, the bioreactor could be unscrewed for disassembly at any time for allowing direct access to the hepatic construct and then resealed.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioreactor design and fabrication
hedged- 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
“Moreover, the dimensions of the bioprinted hydrogel features were much smaller than the 8 mm depth of the chamber.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Literature suggests that a size of 200 μm is suitable to avoid necrosis in the core, while maintaining the functionality of the cells within the spheroids [46,47].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Hepatic spheroid formation
What the sources say
- Not checked — no full text of the sourcecites [46] Fukuda, 2003, Efficacy of a polyurethane foam/spheroid artificial liver by using human hepatoblastoma cell line (Hep G2), Cell Transplant source
- Not checked — no full text of the sourcecites [47] Sakai, 2007, Technique for the control of spheroid diameter using microfabricated chips, Acta. Biomater. source
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 current drug development process suffers from a high failure rate during clinical trials, which is partly due to inadequacy of animal models to accurately predict the toxic side-effects of drugs in humans [1,2].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] van Midwoud, 2011, Microfluidic devices for in vitro studies on liver drug metabolism and toxicity, Integr. Biol. (Camb.) source
- Not checked — no full text of the sourcecites [2] Kaplowitz, 2005, Idiosyncratic drug hepatotoxicity, Nat. Rev. Drug Discovery source
plainconditional- 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
“Ex vivo studies using 3D tissue biopsies or slices have been reported, but they may be difficult to be used for high-throughput studies and show rapid loss of functionality within a few days in vitro, thus limiting their application for long-term studies [21].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Introduction
What the sources say
- Not checked — no full text of the sourcecites [21] van Midwoud, 2010, A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices, Lab Chip source
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.
It may state two separate claims as one.
In the paper
“The metabolic functions of the liver are highly dependent on its microstructural architecture, fluid flow patterns, zonal ECM composition, and biochemical (oxygen concentration) gradients [74].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [74] Allen, 2003, Formation of steady-state oxygen gradients in vitro: application to liver zonation, Biotechnol. Bioeng. source
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.
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 acute hepatotoxic dose of APAP causes apoptosis of HepG2 cells within GelMA encapsulated spheroids, leading to a decrease in the biomarkers secretion levels in the bioreactor system over time”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“This shows that although the relative albumin secreted per cell decreased overtime, the level was sustained within the range (0.6-80 pg/cell/day) reported in the literature for albumin production per cell by HepG2 cells/ spheroids [63,64].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [63] Torisawa, 2007, A multicellular spheroid array to realize spheroid formation, culture, and viability assay on a chip, Biomaterials source
- Not checked — no full text of the sourcecites [64] Kim, 2007, A microfluidic platform for three-dimensional cell culture and cell-based assays, Biomed. Microdevices. 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.
In the paper
“Moreover, supportive interactions with non-parenchymal cells, particularly the vascular, stromal and immune cell types, are important for maintaining the high proliferative capacity of hepatocytes in 3D cultures [75].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [75] Kostadinova, 2013, A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity, Toxicology Appl. Pharmacology source
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.
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
“transferrin (0.1-17.2 pg/cell/day) [65,67,68]”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [65] Bouma, 1989, Further cellular investigation of the human hepatoblastoma-derived cell line HepG2: morphology and immunocytochemical studies of hepatic-secreted proteins., In Vitro Cell. Developmental Biol. : J. Tissue Cult. Assoc. source
- Not checked — no full text of the sourcecites [67] Carraro, 2008, In vitro analysis of a hepatic device with intrinsic microvascular-based channels, Biomed. Microdevices source
- Not checked — no full text of the sourcecites [68] Iwasa, 1990, Phenotypic variation in human HepG2 hepatoma cells: alterations in cell growth, plasma protein synthesis and heme pathway enzymes, Int. J. Biochem. 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.
The quote only partly states this 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
“The proposed concept of a bioreactor interfaced with bioprinters expands the field of organ-on-a-chip and may be a key step towards the fabrication of automated systems for high throughput drug screening.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Conclusion
hedgedconditional- 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. It may state two separate claims as one.
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
“The multilayer design was selected in a way that any introduced bubble would be washed away without getting trapped within the chambers.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioreactor design and fabrication
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. 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
“The successful interfacing of a bioprinting platform with the bioreactor, as reported here, might allow for the creation of advanced biomimetic architectures by precisely mimicking the distribution of different ECM-like biomaterials, key hepatic tissue cell types including hepatocytes, stellate, endothelial, and Kupffer cells, and their ratios.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
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.
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
“Although cell secreted proteins interact with the porous hydrogel scaffold, we used the same encapsulation conditions for control and experimental groups, so that these conditions did not affect the results.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“ceruloplasmin (0.1-0.7 pg/cell/day) [68] secreted by HepG2 cells.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not checked — no full text of the sourcecites [68] Iwasa, 1990, Phenotypic variation in human HepG2 hepatoma cells: alterations in cell growth, plasma protein synthesis and heme pathway enzymes, Int. J. Biochem. source
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: 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.
In the paper
“Freshly isolated or cryopreserved primary hepatocytes are the preferred cell source for drug metabolism studies [54][55][56].”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
What the sources say
- Not matchedcites [54][55][56]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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
“There were no issues encountered while carefully disassembling and reassembling the platform during this assessment.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
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
“Also, this bioprinting approach enabled easy tailoring of other printing parameters such as spheroid concentration per dot and hydrogel composition, as well as controlling multicellular distribution and the geometrical features of the printed construct.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
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
“The response of the liver-on-achip platform to APAP treatment was similar to animal and in vitro models, which confirms the possibility of its application for drug toxicity analysis.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Conclusion
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 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 use of bioprinting in our system not only paved the way for a rapid fabrication of the 3D hepatic construct, but also allowed for a precise control over the thickness of the hydrogel layer encapsulating the spheroids to maintain consistency in mass diffusion through the hydrogel, for all experiments.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting hydrogel-based hepatic constructs in the bioreactor
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.
The authors state this as an assumption.
The hydrogels can be modeled as a porous medium with a uniform volumetric oxygen consumption rate associated with the total number of encapsulated cells.
“The hydrogels were modeled as a porous media with uniform volumetric oxygen consumption rate associated with the total number of encapsulated cells.”
The authors state this as an assumption.
The oxygen concentration at the inlet is constant and uniform.
“The oxygen concentration at the inlet was considered to be constant and uniform.”
The authors state this as an assumption.
All boundaries of the bioreactor can be treated as impermeable surfaces for oxygen transport.
“Although PDMS is oxygen permeable [40], since the bioreactor is covered by a impermeable PMMA layer, we considered the worst case scenario and all boundaries were treated as impermeable surfaces.”
The paper relies on this without support.
Primary hepatocytes have limited lifespan, difficulty in obtaining the cell source, and large batch-to-batch variability post-isolation.
“In addition to their limited lifespan, difficulty in obtaining the cell source and large batch-to-batch variability post-isolation are other important challenges associated with the use of primary hepatocytes.”
The paper relies on this without support.
Immortalized cell lines offer a cheap and robust platform for initial toxicity evaluation of an array of drug candidates.
“The use of immortalized cell lines offers a cheap and robust platform for initial toxicity evaluation of an array of drug candidates.”
The paper relies on this without support.
Issues with cost, availability and batch-to-batch variability make primary hepatocytes a challenging cell source to use.
“However, issues with cost, availability and batch-to-batch variability make primary hepatocytes a challenging cell source to use.”
The paper relies on this without support.
HepG2/C3A cell lines may not express all metabolic enzymes and cannot capture the genetic variability of the patient population.
“Although, these cell lines may not express all metabolic enzymes and cannot capture the genetic variability of the patient population”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
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
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Numerical simulations
“The diffusion coefficient of oxygen in aqueous media at 37 °C was assumed as a reasonable approximation of 3.8×10 -9 m 2 s -1 .”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioreactor platform overview
“oxygen diffusivity=3.8×10-8 m 2 s -1”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioprinting of hepatic constructs containing 3D hepatic spheroids
“A 7×7 array was then printed as liquid droplets from this mixture on a glass slide within the cell culture chamber of the bioreactor”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Conclusion
“case A: 400 000 hepatocytes on day 1 (16 000 cells per dot), and case B: 4000 000 hepatocytes on day 30 (160 000 cells per dot).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Functionality of hepatic spheroids cultured in the bioreactor
“the functionality of the construct was monitored over 6 days of culture at multiple time-points.”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Conclusion
“(c)-(f) The levels of hepatic biomarkers secreted by the hepatic construct treated with 15 mM APAP in the bioreactor platform for a period of 30 days,”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Numerical simulations
“where, V max is the maximum volumetric oxygen consumption rate (mol m -3 s -1 )”
§ A liver-on-a-chip platform with bioprinted hepatic spheroids > Bioreactor platform overview
“V max =4.76×10-16 mol s -1 [43].”
Citations
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Metadata
- Authors
- Bhise, N. S., Manoharan, V., Massa, S., Tamayol, A., Ghaderi, M., Miscuglio, M., Lang, Q., Shrike Zhang, Y., Shin, S. R., Calzone, G., Annabi, N., Shupe, T. D., Bishop, C. E., Atala, A., Dokmeci, M. R., & Khademhosseini, A.
- Affiliations
- Brigham and Women's Hospital (US)
- Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115,
- Wake Forest University Health Sciences (US)
- Corresponding author
- Tamayol, Ali
- Khademhosseini, Ali
- ORCID
- Venue
- Biofabrication
- Publisher
- IOP Publishing
- Published
- 2016-01-12
- Volume
- 8
- Issue
- 1
- Pages
- 014101
- ISSN
- 1758-5082 (ISSN-L)
- 1758-5090
- OpenAlex
- W2232645088
- Cited by
- 615
- References
- 78
- Citations by year
- 2026: 22 · 2025: 45 · 2024: 55 · 2023: 65 · 2022: 76 · 2021: 81 · 2020: 73 · 2019: 73 · 2018: 58 · 2017: 43 · 2016: 23
- FWCI
- 31.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biofabrication (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Science Foundation
- Defense Threat Reduction Agency (DTRA) under Space and Naval Warfare Systems Center Pacific
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- liver-on-a-chip, HepG2/C3A cells, 3D bioreactor, GelMA hydrogel, bioprinting, drug toxicity assessment, acetaminophen toxicity, hepatocyte function, albumin secretion, MRP2, ZO-1 tight junction, in vitro toxicity models
- MeSH terms
- Biological Assay, Equipment Design, Humans, Organ Culture Techniques, Toxicity Tests, Spheroids, Cellular, Liver, Artificial, Equipment Failure Analysis, Chemical and Drug Induced Liver Injury, Lab-On-A-Chip Devices, Hep G2 Cells, Printing, Three-Dimensional
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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.
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