Human disease models in drug development

May combine two claims.

Non-human primates are frequently the sole species with pharmacological relevance, raising ethical and economic concerns.

“Non-human primates are often the only pharmacologically relevant species, whose use has ethical and economic implications7.”

• cites [7] Brennan, F. R. et al. Safety testing of monoclonal antibodies in non-human primates: case studies highlighting their impact on human risk assessment. mAbs 10, 1–17 (2018). sourcePartly supported

  The Discussion (page not specified) says that, for many monoclonal antibodies, non-human primates are the only pharmacologically relevant species. The Introduction calls for ethically justified use and reduced NHP use, but the passages do not address economic implications. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Human disease models for liver, pancreas, CNS, skin, lung, intestine, musculoskeletal system and heart exist, yet whether they equal or surpass animal models remains unproven.

“Promising disease models of the liver65,66, pancreas67,68, central nervous system35,69,70, skin71, lung72,73, intestine72–76, musculoskeletal system77 and heart78–81 have been developed, but their equivalence or superiority over their animal models needs to be demonstrated.”

• cites [65] Nawroth, J. C. et al. Modeling alcohol-associated liver disease in a human liver-chip. Cell Rep. 36, 109393 (2021). sourceSupported
• cites [67] Bauer, S. et al. Functional coupling of human pancreatic islets and liver spheroids on-a-chip: towards a novel human ex vivo type 2 diabetes model. Sci. Rep. 7, 14620 (2017). sourcePartly supported

  The Discussion describes a developed human pancreatic-islet–liver chip that models glucose regulation, supporting its citation as a promising pancreatic platform. But it says inducing type 2 diabetes conditions is a next step; the paper does not establish that this chip already models the disease. The source does not compare its performance with animal models. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [35] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). sourceSupported

May combine two claims.

Most animal models resemble human conditions poorly and therefore predict poorly.

“most animal models poorly resemble human conditions and thus have low predictive values.”

• cites [6] Ingber, D. E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat. Rev. Genet. 23, 467–491 (2022). sourcePartly supported

  The Introduction says animal-study results often fail to predict human results and that animal disease models can have molecular and cellular mechanisms distinct from those in humans. It does not establish that most animal models poorly resemble human conditions; it notes that some may appear phenotypically similar. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Organs-on-chips are perfused microfluidic devices with engineered or miniaturized tissues linked by 3D microchannels to mimic organ functions, biomechanics and pathophysiological responses.

“OoCs are perfused microfluidic platforms that contain bioengineered or miniaturized tissues or organs interconnected by 3D microchannels to simulate the in vivo functions, biomechanics and (patho)physiological responses of organs6,52–54.”

• cites [6] Ingber, D. E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat. Rev. Genet. 23, 467–491 (2022). sourcePartly supported

  The Introduction describes organ chips as microfluidic devices with living cells and tissues in channels under dynamic fluid flow, designed to model organ functions and disease states. But it says only some recreate mechanical cues, while the Microfluidic organ chips section includes single-channel devices; interconnected tissues and 3D channels are therefore not defining features of all organ chips. The supplied passages have no page numbers. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [52] Low, L. A., Mummery, C., Berridge, B. R., Austin, C. P. & Tagle, D. A. Organs-on-chips: into the next decade. Nat. Rev. Drug Discov. 20, 345–361 (2021). sourceCould not verify

  The passages available from our copy are bibliographic metadata, not a description of how organs-on-chips are constructed or what they simulate. Searches for microfluidic devices, 3D microchannels, biomechanics, and pathophysiological responses found no passage addressing the claim. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [53] Vunjak-Novakovic, G., Ronaldson-Bouchard, K. & Radisic, M. Organs-on-a-chip models for biological research. Cell 184, 4597–4611 (2021). sourcePartly supported

  The Introduction describes organs-on-chips as engineered tissue constructs that reproduce selected organ functions using physical signals and fabricated channels. But it says these constructs are not mini-organs, and the section on combining single-organ models describes several ways to connect them—not necessarily 3D microchannels. The claim therefore overstates what all organs-on-chips contain. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

To date, human-based models have mainly served toxicity testing, with preclinical and clinical use still nascent.

“human-based models have so far been primarily used for toxicity testing61–64, and their application in preclinical and clinical research is still in its infancy.”

• cites [61] Marx, U. et al. Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. Altex 33, 272–321 (2016). sourcePartly supported

  Section 5.5 describes chemical safety testing as a major driver of human-based alternative methods. Section 3.1 presents wider pharmaceutical adoption of microphysiological systems, including use during clinical development, as prospective. The paper does not establish that human-based models have been used primarily for toxicity testing or that preclinical and clinical research applications as a whole remain in their infancy; it also describes existing disease-modeling and drug-development applications. Page numbers were not available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [62] Matsui, T. & Shinozawa, T. Human organoids for predictive toxicology research and drug development. Front. Genet. 12, 767621 (2021). sourcePartly supported

  The Introduction describes toxicity assays using human cells, and the Concluding Remarks discuss human organoids as potential tools for toxicity evaluation. Neither section establishes that human-based models have been used primarily for toxicity testing; the review also says reports of organoid toxicity studies remain very limited. It does not assess whether their preclinical or clinical use is still in its infancy. (LLM, conf=0.77)

  Experimental — accuracy not yet measured
• cites [63] Li, M. et al. Advanced human developmental toxicity and teratogenicity assessment using human organoid models. Ecotoxicol. Environ. Saf. 235, 113429 (2022). sourceSupported

May combine two claims.

Biomedical research is shifting toward human disease models because current drug development has high failure rates.

“Biomedical research is undergoing a paradigm shift towards approaches centred on human disease models owing to the notoriously high failure rates of the current drug development process.”

• Also stated in: § Introduction · plain

  “Biomedical research is currently undergoing a paradigm shift towards approaches centred on human disease models1. This shift has been driven by the notoriously high failure rates of the current drug development process.”

• cites [1] Adhikary, P. P., Ul Ain, Q., Hocke, A. C. & Hedtrich, S. COVID-19 highlights the model dilemma in biomedical research. Nat. Rev. Mater. 6, 374–376 (2021). sourcePartly supported

  The Abstract links poorly predictive animal models to high clinical-trial failure rates and says researchers are calling for a shift toward human-centred approaches. It does not establish that biomedical research is already undergoing that shift; the section on available preclinical models says the impact of human-based models remains low. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Adult stem cells and induced pluripotent stem cells can multiply indefinitely and become any somatic cell type, alleviating primary-cell shortages.

“Multipotent adult stem cells (ASCs) and induced pluripotent stem (iPS) cells can help overcome this shortage, as they can readily and indefinitely propagate and convert into any somatic cell10.”

• cites [10] Brooks, I. R. et al. Functional genomics and the future of iPSCs in disease modeling. Stem Cell Rep. 17, 1033–1047 (2022). sourcePartly supported

  The Introduction says primary patient cells are scarce because they proliferate poorly, and describes hiPSCs as having high proliferative capacity and the potential to yield multiple cell types. It does not extend those properties to adult stem cells or say that either cell type propagates indefinitely or can become any somatic cell type. No page numbers are provided in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Organs-on-chips allow automation of biophysical processes like perfusion, enabling real-time in situ monitoring of tissue function and responses.

“biophysical processes, such as chip perfusion, can be easily automated using OoCs, which allows monitoring of tissue function and responses in situ and in real time52.”

• cites [52] Low, L. A., Mummery, C., Berridge, B. R., Austin, C. P. & Tagle, D. A. Organs-on-chips: into the next decade. Nat. Rev. Drug Discov. 20, 345–361 (2021). sourceCould not verify

  The supplied passages contain bibliographic metadata, not discussion of organ-on-chip capabilities. Searches of our copy for automated chip perfusion and real-time, in situ monitoring of tissue function returned no substantive passage, so the claim cannot be assessed from the available text. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

May combine two claims.

Organoids measure about 100 μm for lung to 2 mm for brain and can be grown in small wells, making them suitable for high-throughput screening.

“The size of these organ-like structures ranges from 100 µm (lung organoid) to 2 mm (brain organoid) and they can be cultivated in small dimensions (for example, 96-well or 384-well plates25,26), thereby being suitable for high-throughput screening.”

• cites [25] Du, Y. et al. Development of a miniaturized 3D organoid culture platform for ultra-high-throughput screening. J. Mol. Cell Biol. 12, 630–643 (2020). sourceSupported
• cites [26] Vonk, A. M. et al. Protocol for application, standardization and validation of the forskolin-induced swelling assay in cystic fibrosis human colon organoids. STAR Protoc. 1, 100019 (2020). sourcePartly supported

  The Forskolin Induced Swelling (FIS) Assay methods describe seeding human colon organoids in 96-well plates, supporting the small-well part of the claim. They do not give the stated 100 µm lung-to-2 mm brain size range or describe cultivation in 384-well plates, and the protocol does not establish high-throughput screening across organoid types. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Early in the COVID-19 pandemic, species susceptibility to SARS-CoV-2 was unknown and no ready model existed.

“At the beginning of the pandemic, it was unclear which species were susceptible to SARS-CoV-2 and no model was readily available to study the course of the disease and identify druggable targets against the unknown pathogen9.”

• cites [9] Muñoz-Fontela, C. et al. Animal models for COVID-19. Nature 586, 509–515 (2020). sourcePartly supported

  The Abstract says the WHO convened experts in February 2020 to develop COVID-19 animal models, and the Conclusions describe efforts to determine which species are susceptible. These passages support the early uncertainty and need for models, but they do not establish that models were needed specifically to identify druggable targets. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Gene and protein expression, as well as cellular responses, vary substantially between 2D and 3D systems.

“cell responses and gene and/or protein expression patterns greatly differ between 2D and three-dimensional (3D) models11.”

• cites [11] Jensen, C. & Teng, Y. Is it time to start transitioning from 2D to 3D cell culture? Front. Mol. Biosci. 7, 33 (2020). sourceSupported

May combine two claims.

Kidney organoid scRNA-seq showed direct SARS-CoV-2 infection of kidney cells, causing pro-fibrotic changes and polycystic kidney disease features similar to those in severe COVID-19.

“single-cell RNA sequencing (scRNA-seq) of kidney organoids showed that SARS-CoV-2 directly infects kidney cells, triggering pro-fibrotic events and features of polycystic kidney disease, closely resembling renal processes observed in individuals who are critically ill with COVID-19 (refs. 89,90).”

• cites [89] Jansen, J. et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 29, 217–231.e8 (2022). sourcePartly supported

  The Results and discussion sections on kidney organoids report scRNA-seq evidence of infection and profibrotic signaling; the patient-tissue results also report infection and increased fibrosis in COVID-19 kidneys. Our copy does not report polycystic kidney disease features in the organoids or in critically ill patients, so that part of the claimed resemblance is unsupported (pages not provided). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [90] Helms, L. et al. Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations. JCI Insight 6, e154882 (2021). sourcePartly supported

  The Results section, ‘SARS-CoV-2 infects organoid proximal tubules with pathogenic effects,’ supports direct infection of kidney organoid cells. But the paper used pre-existing PKD2–/– cystic organoids to test infection; it does not show that infection caused polycystic kidney disease features. The Methods describe using previously available organoid scRNA-seq data, while the patient comparison in Results concerns urinary proteins and interferon-response signatures—not scRNA-seq evidence of pro-fibrotic changes resembling renal processes in critically ill patients. Page numbers were not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

CDK4/6 inhibitors promote T cell activation and increase tumour-infiltrating T cells in PDOs grown in a microfluidic 3D chip.

“cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6) facilitate T cell activation, resulting in a higher number of tumour-infiltrating T cells in PDOs, cultivated over several days in a microfluidic 3D chip setup.”

• cites [129] Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018). sourcePartly supported

  The Results section reports that CDK4/6 inhibitors increased cytokines associated with T-cell responses in patient-derived tumor spheroids cultured in 3D microfluidic devices. The Introduction places the increase in tumor-infiltrating T cells in vivo, not in those spheroids. The cited paper therefore supports T-cell activation and the chip model, but not the claimed higher number of infiltrating T cells in that model. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Targeted RNA sequencing of nearly 1,600 molecules found an oestrogen-related receptor-α inverse agonist that corrected CAVD gene dysregulation in patient valve endothelial cells and modified mice.

“Almost 1,600 molecules were screened using targeted RNA sequencing, resulting in the identification of an inverse agonist of oestrogen-related receptor-α as the lead compound, which proved effective in correcting dysregulated CAVD-relevant genes in primary aortic valve endothelial cells from individuals with CAVD and in genetically modified mice.”

• cites [108] Theodoris, C. V. et al. Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease. Science 371, eabd0724 (2021). sourceSupported

May combine two claims.

Clinical trials have begun for amodiaquine and imatinib.

“amodiaquine (for example, NCT04532931, NCT04502342)51 and imatinib111 (for example, NCT04394416) have entered clinical trials.”

• cites [51] Si, L. et al. A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nat. Biomed. Eng. 5, 815–829 (2021). sourceSupported
• cites [111] Han, Y. et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589, 270–275 (2021). sourceCould not verify

  The citation to this paper is attached to imatinib, not amodiaquine. The ‘Drugs block SARS-CoV-2 infection’ section reports imatinib experiments in organoids and Vero cells, but our copy does not say that imatinib entered a clinical trial or mention NCT04394416 (searched: clinical trials and the trial identifier). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

Brain organoids showed SARS-CoV-2 targets neurons and cortical astrocytes, favors mature cells, and has distinct neurotoxic effects.

“SARS-CoV-2 tropism for neurons87 and cortical astrocytes88 or its preference for mature cell types and distinct neurotoxic effects were demonstrated in brain organoids.”

• cites [87] Ramani, A. et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 39, e106230 (2020). sourceSupported
• cites [88] Andrews, M. G. et al. Tropism of SARS-CoV-2 for human cortical astrocytes. Proc. Natl Acad. Sci. USA 119, e2122236119 (2022). sourcePartly supported

  The Results section on gliogenic cortical organoids (page unavailable) reports robust infection of astrocytes in week-22 organoids, but only rare infection of neurons. The paper supports astrocyte tropism and greater infection at a later organoid stage; it does not establish a general preference for mature cell types. The neuron-tropism claim is attached to citation 87, not this source, and the supplied organoid results do not establish the claimed distinct neurotoxic effects. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Infected kidney organoid transcriptomes matched urine proteomes from severe COVID-19 patients, supporting the model's validity.

“transcriptomic profiling of infected kidney organoids aligned with the proteomic profile of the urine of individuals who were critically ill with COVID-19, further validating the findings of the model.”

• cites [89] Jansen, J. et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 29, 217–231.e8 (2022). sourceCould not verify

  The Results section reports RNA sequencing of infected kidney organoids and analysis of COVID-19 patient kidney tissue, but no passage reports comparing organoid transcriptomes with patients’ urine proteomes. Searches for “urine,” “proteomics,” and “urine proteome” found no such comparison in our copy, so the claimed alignment and resulting validation cannot be verified. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [90] Helms, L. et al. Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations. JCI Insight 6, e154882 (2021). sourceSupported

May combine two claims.

In a human lung-on-chip model, chloroquine and hydroxychloroquine were ineffective, matching clinical results.

“the antimalarial drugs chloroquine and hydroxychloroquine, which received controversial attention during the COVID-19 pandemic, proved non-effective in a human lung-on-chip disease model, similar to clinical findings51.”

• cites [51] Si, L. et al. A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nat. Biomed. Eng. 5, 815–829 (2021). sourceSupported

May combine two claims.

SARS-CoV-2 infection in organoids produced weak interferon responses, and infected bioengineered lung models shared interferon signatures with native human lungs.

“Organoids demonstrated the induction of inefficient interferon responses in SARS-CoV-2 infections84,85, revealing similar interferon signatures between SARS-CoV-2-infected bioengineered lung models and native human lungs”

• cites [84] Katsura, H. et al. Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Cell Stem Cell 27, 890–904.e8 (2020). sourcePartly supported

  The Results sections on IFN pathways and transcriptome-wide similarities report that infected alveolospheres activated interferon pathways and had strikingly similar IFN signatures to AT2 cells from COVID-19 patient lungs (page unavailable). The paper does not characterize the organoids’ interferon response as weak or inefficient; it reports significant upregulation of IFN-related transcripts, with inflammatory responses emerging at later times. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [85] Lamers, M. M. et al. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J. 40, e105912 (2021). sourcePartly supported

  The Host responses section reports that SARS-CoV-2 infection induced a broad type I/III interferon-stimulated gene signature in the organoid-derived cultures. It does not characterize that response as weak or inefficient. The section compares the induction with a report on human bronchial epithelial cells, not with interferon signatures in native human lungs; no page number is available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

In the CIDP organ-on-chip model, TNT005 suppressed immune reaction and restored function, leading the FDA to approve trials.

“Treatment with the antibody TNT005, a specific complement component 1s inhibitor, inhibited the immune reaction and rescued the functional deficits, prompting the FDA to approve clinical trials (NCT04658472).”

• cites [116] Rumsey, J. W. et al. Classical complement pathway inhibition in a “human-on-a-chip” model of autoimmune demyelinating neuropathies. Adv. Ther. 5, 2200030 (2022). sourcePartly supported

  The Results (page unavailable) report that TNT005 inhibited patient-serum-mediated complement deposition and rescued motoneuron functional deficits in the CIDP and MMN chip models. The Abstract says the efficacy data were included in an investigational new drug application, and the Introduction links the model to clinical testing (NCT04658472). Neither passage says the FDA approved trials because of these findings. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Adding peripheral blood mononuclear cells worsens endothelial dysfunction and causes excessive inflammation.

“This endothelial dysfunction is exacerbated after the introduction of peripheral blood mononuclear cells, resulting in excessive inflammation82.”

• cites [82] Lu, R. X. Z. et al. Vasculature-on-a-chip platform with innate immunity enables identification of angiopoietin-1 derived peptide as a therapeutic for SARS-CoV-2 induced inflammation. Lab Chip 22, 1171–1186 (2022). sourceSupported

May combine two claims.

Some OoC models have been maintained for up to 3 months, but the effective lifetime of most disease models spans only a few days.

“Although some OoC models have been maintained for up to 3 months55, the effective lifetime of most disease models spans over a few days”

• cites [55] Maschmeyer, I. et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15, 2688–2699 (2015). sourcePartly supported

  The citation follows the three-month claim. The Abstract and Introduction report that this four-organ-chip maintained functional co-cultures for at least 28 days, supporting long-term maintenance but not the stated three-month duration. The later claim about most disease models is not attached to this citation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Similarity scaling adapts dimensional analysis and similitude to OoCs and accounts for different similarity criteria simultaneously in a systematic framework.

“the similarity scaling approach140 adapts engineering techniques of dimensional analysis and similitude to OoCs. This strategy accounts for different similarity criteria (Box 1) simultaneously in a systematic framework”

• cites [140] Feng, J. J. & Hedtrich, S. A similarity scaling approach for organ-on-chip devices. Lab Chip 22, 3663–3667 (2022). sourceSupported

May combine two claims.

Microfabricated array devices using organoids at passage 0 provide drug screening results within a week without compromising the predictivity of patient responses to anticancer drugs.

“microfabricated array devices using organoids at passage 0 provide drug screening results within a week without compromising the predictivity of patient responses to anticancer drugs152”

• cites [152] Hu, Y. et al. Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week. Nat. Commun. 12, 2581 (2021). sourceSupported

May combine two claims.

Mass spectrometry-based proteomics measures protein abundance and dynamics, identifies subcellular protein localization and post-transcriptional modifications, and facilitates generation of interaction networks.

“Mass spectrometry-based proteomics measures protein abundance and dynamics, identifies subcellular protein localization and post-transcriptional modifications, and facilitates the generation of interaction networks162”

• cites [162] Kip, A. M. et al. Proteomics analysis of human intestinal organoids during hypoxia and reoxygenation as a model to study ischemia-reperfusion injury. Cell Death Dis. 12, 95 (2021). sourcePartly supported

  The Methods (Liquid chromatography mass spectrometry proteomics analysis; page unavailable) describe mass-spectrometry-based protein identification, and the Results (Differentiation of human small intestinal organoids; page unavailable) report protein abundance ratios. The Results (Temporal protein profiles; page unavailable) also track changes over time. Our copy does not show this approach identifying subcellular protein localization or post-transcriptional modifications, or generating protein interaction networks. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

The medium circulation rate in tissue models is disproportionately slow compared to physiological blood flow, which slows nutrient transport and metabolic processes.

“the medium circulation rate is disproportionately slow compared to physiological blood flow, which in turn slows down the transport of nutrients and metabolic processes in tissue models138”

• cites [138] Sung, J. H., Wang, Y. & Shuler, M. L. Strategies for using mathematical modeling approaches to design and interpret multi-organ microphysiological systems (MPS). APL Bioeng. 3, 021501 (2019). sourcePartly supported

  In “Scaling methods” (page not provided), the paper describes one liver–skin model whose medium recirculated more slowly than blood in the human body: 15 minutes versus about 5 minutes. In “Considerations for designing MPSs” (page not provided), it says perfusion affects nutrient supply and could alter biochemical reaction kinetics, but it does not establish that slow circulation generally slows nutrient transport and metabolic processes across tissue models. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

It is difficult to balance competing key functional indices in multi-OoC setups; for a gut-liver system, a perfusion rate chosen for the gut to yield proper metabolic rates might result in drug exposure times in the liver that are too short.

“it has proven difficult to balance competing key indices in multi-OoC setups; for a gut–liver system139, for example, a perfusion rate chosen for the gut to yield proper metabolic rates might result in drug exposure times in the liver that are too short”

• cites [139] Maass, C., Stokes, C. L., Griffith, L. G. & Cirit, M. Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS). Integr. Biol. 9, 290–302 (2017). sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

CDK4/6 inhibition was highly active in vitro and in vivo and synergized with anti-PD-1 antibodies.

“CDK4/6 inhibition also showed high in vitro and in vivo activity and synergy with anti-PD-1 blocking antibodies129.”

• cites [129] Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018). sourceSupported

May combine two claims.

Organoids can be cultivated over months and probably even years, enabling investigation of tissue maturation in a disease context, as shown for SARS-CoV-2 infections in brain organoids.

“Notably, organoids can be cultivated over months and probably even years, thus enabling the investigation of tissue maturation in a disease context as shown for SARS-CoV-2 infections in brain organoids87”

• cites [87] Ramani, A. et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 39, e106230 (2020). sourcePartly supported

  The Results section reports that 60-day-old brain organoids showed signs of maturation and had more SARS-CoV-2-positive cells than 15-day-old organoids. This supports using organoids of different maturities to study infection, but the paper does not establish cultivation over years or investigation of tissue maturation during a prolonged infection; the Discussion says experiments with more mature organoids are still needed. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Commercially available bioengineered disease models mainly focus on preclinical safety testing and not disease modelling, and are not customizable.

“these models mainly focus on preclinical safety testing and not disease modelling and are not customizable169”

• cites [169] Busek, M., Aizenshtadt, A., Amirola-Martinez, M., Delon, L. & Krauss, S. Academic user view: organ-on-a-chip technology. Biosensors 12, 126 (2022). sourcePartly supported

  The Discussion (p. 7) says most commercial organ-on-chip platforms are tailored for pharmaceutical testing and only a few are suitable for disease modelling. The paper does not narrow that focus to preclinical safety testing: the Overview (p. 3) discusses both safety and efficacy. The opening summary (p. 1) says self-made systems offer opportunities for customized models, but does not establish that commercial systems cannot be customized. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Broad clinical implementation of patient-specific disease models such as PDOs is hindered by low efficiencies in PDO establishment (60-70% success rate on average, up to 90% for intestinal organoids) and lengthy generation times and expansion procedures.

“broad clinical implementation of patient-specific disease models, such as PDOs, is currently hindered by low efficiencies in PDO establishment (60–70% success rate on average although, for some tissues, up to 90% have been reported for intestinal organoids151) as well as lengthy generation times and expansion procedures”

• cites [151] van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015). sourceSupported

May combine two claims.

Spatial profiling provides information on tissue organization and three-dimensional architecture, which is essential for model validation.

“Spatial profiling provides further information on tissue organization and three-dimensional architecture, thereby being essential for model validation186,187”

• cites [186] Fleck, J. S. et al. Resolving organoid brain region identities by mapping single-cell genomic data to reference atlases. Cell Stem Cell 28, 1148–1159.e8 (2021). sourcePartly supported

  The Results ('Spatial projection of organoid cell transcriptomes'; page not available) show that mapping organoid cells to a spatial brain atlas helps assess regional identity and can be visualized in three dimensions. The paper does not show that this profiling reveals the organoid tissue’s own three-dimensional architecture, or establish that it is essential for model validation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [187] Rodriques, S. G. et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463–1467 (2019). sourcePartly supported

  The paper’s main text (page unavailable in our copy) shows that Slide-seq resolves tissue organization and that co-registered hippocampal sections allow three-dimensional visualization. It does not say that spatial profiling is essential for model validation. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Most disease models rely on the integration of only a few pre-defined immune cell types, which does not emulate the complexity of in vivo immunoregulation.

“most models rely on the integration of only a few, pre-defined immune cell types, which, however, does not emulate the complexity of in vivo immunoregulation”

• cites [143] Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010). sourcePartly supported

  The Abstract (page not provided) says existing models fail to recreate an interface important for immune-cell transport. The Biomimetic Microsystems section (page not provided) acknowledges that this lung chip lacks alveolar macrophages. These passages support a limitation in modeling immune responses, but do not establish that most disease models integrate only a few pre-defined immune cell types. (LLM, conf=0.80)

  Experimental — accuracy not yet measured
• cites [145] Bein, A. et al. Enteric coronavirus infection and treatment modeled with an immunocompetent human intestine-on-a-chip. Front. Pharmacol. 12, 718484 (2021). sourcePartly supported

  The Introduction (page unavailable) says patient-derived intestinal organoids lack circulating immune cells and other features of the in vivo organ environment, supporting the concern that such models miss physiological complexity. It does not say that most disease models integrate only a few predefined immune cell types. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [154] Wallmeyer, L. et al. TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents. Sci. Rep. 7, 774 (2017). sourcePartly supported

  The Introduction says some earlier inflammatory-skin models used disease-associated cytokines but lacked actual immune cells, so they could not fully reflect complex skin–immune interactions. It does not establish that most disease models integrate a few pre-defined immune cell types; the examples it describes contain no immune cells. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [155] Maharjan, S., Cecen, B. & Zhang, Y. S. 3D immunocompetent organ-on-a-chip models. Small Methods 4, 2000235 (2020). sourceSupported
• cites [156] Kerns, S. J. et al. Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies. eLife 10, e67106 (2021). sourcePartly supported

  The Introduction says conventional 2D models lack the complexity needed to model immunotherapeutic effects and omit essential cellular factors. The Discussion says accurately modeling multifactorial immune-related toxicities would likely require resident immune cells and lymphoid structures. Neither passage establishes that most disease models integrate only a few pre-defined immune cell types. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Living biobanks can provide access to patient-derived cells and organoids from large patient cohorts, and have already been established for different cancers, genetic diseases such as cystic fibrosis, infectious diseases, chronic obstructive pulmonary disease and inflammatory bowel diseases.

“‘living biobanks’ can provide access to patient-derived cells and organoids from large patient cohorts, and have already been established for different cancers124,151,176–178, genetic diseases such as cystic fibrosis, infectious diseases, chronic obstructive pulmonary disease and inflammatory bowel diseases179”

• cites [124] Lee, S. H. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–528.e17 (2018). sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [151] van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015). sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [176] Yan, H. H. N. et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 23, 882–897.e11 (2018). sourceNot checked — no full text of the source
• cites [177] Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2018). sourceNot checked — no full text of the source
• cites [178] Jacob, F. et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 180, 188–204.e22 (2020). sourceSupported
• cites [179] Ramalho, A. S. et al. Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis. Eur. Respir. J. 57, 1902426 (2021). sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

A ClinicalTrials.gov search for 'organoids' returns 131 studies, mostly cancer-related.

“ClinicalTrials.gov currently lists 131 studies for the search term ‘organoids’, most of which focus on cancer.”

May combine two claims.

Non-stem-cell-based tissue models show limited cell variety and no self-renewal.

“they have limited cell diversity and lack self-renewal capacity in non-stem cell-based models.”

Classified as probably not a substantial claim.

Work continues on bioengineered human disease models with high clinical mimicry to bridge the translational gap.

“efforts are ongoing to develop bioengineered human-based (disease) models of high clinical biomimicry to close this translational gap.”

May combine two claims.

Animal models differ from humans in anatomical layouts, biological barriers, receptor expression, immune responses, host specificities of microorganisms, and pathomechanisms.

“The discrepancies derive from different anatomical layouts and biological barriers, divergent receptor expression and immune responses, host specificities of microorganisms, and distinct pathomechanisms.”

May combine two claims.

These tissue models have a short lifespan and cannot be propagated or cryopreserved.

“these tissue models cannot be cryopreserved or propagated and therefore have a limited lifespan.”

May combine two claims.

Adult-stem-cell organoids usually are smaller than iPS-cell organoids and lack ectodermal and mesenchymal cells.

“ASC-derived organoids lack cells from the ectodermal and mesenchymal germ layer and are usually smaller than iPS cell-derived counterparts.”

May combine two claims.

Reporter cell lines and similar engineered cells suit high-throughput production, are reproducible, and cost less than stem-cell methods.

“Engineered cells, such as reporter cell lines, are also commonly used as they are amenable to high-throughput manufacturing and have high reproducibility and lower costs relative to stem cell-based methods.”

May combine two claims.

Primary cells are favored for their greater genetic heterogeneity than cell lines, yet scarce availability or limited in vitro growth limits their use.

“Primary cells are the preferred option owing to their higher genetic heterogeneity compared to cell lines, but their limited availability or in vitro proliferation capacity restricts their use.”

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

40% of drugs in clinical trials are antibodies.

“Currently, 40% of the drugs undergoing clinical trials are antibodies3.”

• cites [3] IQVIA Institute. Global Trends in R&D 2022 (IQVIA Institute, 2021).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Intestinal organoids from human adult stem cells mimic the host environment by forming active, multicellular epithelium, enabling norovirus infection research.

“Infection studies using human ASC-derived intestinal organoids provided the solution as they closely emulate the host environment by differentiating into physiologically active, multicellular epithelial tissues.”

• cites [96] Ettayebi, K. et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387–1393 (2016). sourceNot checked — no full text of the source

May combine two claims.

Lead compounds for spinal muscular atrophy were tested in iPS-derived motor neurons, where they corrected splicing and restored protein levels.

“The efficacy of the lead compounds was assessed in iPS cell-derived motor neurons showing splice correction and restored protein levels.”

May combine two claims.

Rectal organoids from 71 cystic fibrosis patients carrying 28 CFTR mutations showed residual CFTR function and helped identify effective drug combinations.

“rectal organoids from 71 individuals with cystic fibrosis that harboured 28 different CFTR mutations revealed residual CFTR function and identified effective drug combinations.”

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

Risdiplam was authorized in the EU in 2021 as the first oral drug for spinal muscular atrophy.

“Risdiplam received its marketing authorization in the EU in 2021 and became the first orally available medication for spinal muscular atrophy.”

May combine two claims.

A neurovascular-unit organ-on-chip infected with Cryptococcus neoformans showed the fungus crosses the blood-brain barrier by transcytosis, suggesting a therapeutic target.

“This system revealed that C. neoformans trespasses the blood–brain barrier through transcytosis, providing a potential therapeutic target to inhibit this process104.”

• cites [104] Kim, J. et al. Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier. Nat. Biomed. Eng. 5, 830–846 (2021). sourceNot checked — no full text of the source

May combine two claims.

The MCLA-158 results came solely from human cancer organoids and reached clinical use within three years.

“These findings relied entirely on human-derived cancer organoids and went from bench to bedside in just 3 years (NCT03526835)114.”

• cites [114] Herpers, B. et al. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nat. Cancer 3, 418–436 (2022). sourceNot checked — no full text of the source

May combine two claims.

Organoid lumen area measurement enabled CFTR function comparison across patients and gave clinicians a reliable predictive tool.

“measuring the lumen area of the organoids allowed comparison of CFTR function among patients, thereby providing physicians with a reliable predicting tool for clinical decision-making.”

May combine two claims.

Clinical trials reproduced the amivantamab findings, and the EMA approved it for non-small cell lung cancer.

“These results were replicated in clinical trials (for example, NCT04538664), eventually leading to the approval of amivantamab by the EMA for the treatment of non-small cell lung cancer.”

• cites [115] Yun, J. et al. Antitumor activity of Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20 insertion-driven NSCLC. Cancer Discov. 10, 1194–1209 (2020). sourceNot checked — no full text of the source

May combine two claims.

Brain organoid studies found Zika mainly infects neural progenitor cells, raising cell death and lowering proliferation, which impairs neurogenesis and causes microcephaly.

“infection studies in brain organoids showed that the Zika virus primarily infects neural progenitor cells, which increases neural cell death and reduces proliferation, thereby hampering neurogenesis and causing microcephaly99,100.”

• cites [99] Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016). sourceNot checked — no full text of the source
• cites [100] Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016). sourceNot checked — no full text of the source

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

For unraveling disease mechanisms or studying drug efficacy and safety, models with higher biomimicry and complexity are required.

“If the goal is to unravel disease mechanisms or study drug efficacy and safety, disease models with higher biomimicry and complexity are required”

Classified as probably not a substantial claim.

Patient-specific disease models are promising for personalized and precision medicine.

“Patient-specific disease models hold great potential for personalized and precision medicine”

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

Variabilities in model composition, complexity and experimental protocols aggravate the problem of disease model validation.

“The problem is further aggravated by variabilities in model composition, complexity and experimental protocols”

May combine two claims.

Commercially available setups for bioengineered disease models are often very expensive and not affordable for many laboratories.

“commercially available setups are often still very expensive and therefore not affordable for many laboratories”

May combine two claims.

Single-cell proteomics is still in its infancy; measurements are time consuming, expensive, have limited dynamic range, and are low throughput.

“single-cell proteomics is still in its infancy; measurements are time consuming, expensive and have a limited dynamic range of measurements, rendering it low throughput”

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

Rigorous disease model validation is essential but often neglected.

“rigorous disease model validation is essential but often neglected”

May combine two claims.

Including putative key components in bioengineered models based on existing knowledge risks overlooking and excluding disease-relevant contributors, which bears the risk of false-positive or false-negative results.

“Putative key components, such as cells or biomechanical cues relevant to the disease of interest, are included based on existing knowledge, yet the possibility to overlook and thus exclude disease-relevant contributors remains. This biased approach bears the risk of false-positive or false-negative results”

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

Models derived from both sexes and diverse ethnic groups could reveal inter-individual differences and improve therapy assessment.

“Human-based models from both sexes and different ethnicities could help pinpoint these inter-individual differences, thereby improving therapeutic assessment.”

May combine two claims.

Media mixtures used in multi-organ models could reverse tissue maturation because cells from different germ layers are exposed to unspecific factors, potentially resulting in gene and protein expression levels atypical for the tissue of interest.

“Media mixtures are typically used in these models, which, however, could reverse tissue maturation because cells from different germ layers are exposed to unspecific factors. This mismatch could result in gene and protein expression levels that are atypical for the tissue of interest”

May combine two claims.

Direct and allometric scaling account for length and mass scales but not time scale, and are often inaccurate.

“These two methods account for length and mass scales but not the time scale, and are often inaccurate”

May combine two claims.

Miniaturized models typically carry fewer cells and lack a pervasive vasculature to perfuse tissue compared to actual organs.

“Miniaturized models typically carry fewer cells and lack a pervasive vasculature to perfuse the tissue compared to actual organs”

May combine two claims.

Developing and maintaining bioengineered disease models require high-level expertise and costly infrastructures.

“Developing and maintaining bioengineered disease models require high-level expertise and costly infrastructures”

Classified as probably not a substantial claim.

Providing a universal disease model design is challenging because model usefulness depends on context, intended use, and relevant readout parameters.

“providing a universal disease model design is challenging because their usefulness is strongly context dependent and influenced by the intended use and relevant readout parameters”

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

For systemic conditions such as inflammation or metastatic cancer, complex multi-OoC setups are superior to single-tissue or organ models.

“when studying systemic conditions such as inflammation or metastatic cancer, complex multi-OoC setups are superior to single-tissue or organ models”

Classified as probably not a substantial claim.

Similar to bulk RNA-seq, proteomic analysis at the bulk level provides a population average and obscures cellular heterogeneities.

“Similar to bulk RNA-seq, proteomic analysis at the bulk level provides a population average and obscures cellular heterogeneities”

May combine two claims.

Phase I trials often underrepresent women, partly because of reproductive toxicity concerns.

“Women are often underrepresented, partly owing to the risk of reproductive toxicity.”

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

For drug screening, 2D high-throughput methods using patient-specific or genetically engineered cells allow testing many compounds quickly.

“2D high-throughput methods using patient-specific or genetically engineered cells are most suitable as they allow testing of a large number of compounds in a short time”

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

These combinatorial approaches could help identify effective drugs more reliably, although their actual impact has yet to be proven.

“These combinatorial approaches could help identify effective drugs more reliably, although their actual impact has yet to be proven”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

It is unrealistic to assume that the complexity of a human can be fully recapitulated in vitro.

“It is unrealistic to assume that the complexity of a human can be fully recapitulated in vitro”

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

Personalized disease models are well suited for clinical decision-making and in clinical trials to diversify patient cohorts with respect to ethnicity, sex or age.

“personalized disease models are well suited for clinical decision-making and in clinical trials to diversify the patient cohorts with respect to ethnicity, sex or age”

May combine two claims.

Some OoC setups have the size of a coin or even smaller, making it difficult to cultivate actual 3D tissue models.

“Some OoC setups have the size of a coin (or even smaller), thereby making it difficult to cultivate actual 3D tissue models”

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

Initial drawbacks such as the lack of cell diversity, vascularization and the ability to study tissue crosstalk have already been largely overcome.

“initial drawbacks, such as the lack of cell diversity, vascularization and the ability to study tissue crosstalk, have already been largely overcome”

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

Animal models are still considered the gold standard and are often requested by default by grant review panels or reviewers.

“animal models are still considered the gold standard and therefore are often requested by default by grant review panels or reviewers”

May combine two claims.

Animal testing is not going to be completely replaced in the near future, partly because toxicity testing in animals is legally mandated before entering clinical trials.

“Animal testing is not going to be completely replaced in the near future for several reasons, one of them being that toxicity testing in animals is legally mandated before entering clinical trials”

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

Different disease models are suitable for different applications; organoids are useful for high-throughput drug screenings, whereas OoCs are more applicable for drug safety and efficacy testing.

“different disease models are suitable for different applications; organoids, for example, are useful for high-throughput drug screenings, whereas OoCs are more applicable for drug safety and efficacy testing”

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

Personalized disease models are poorly suited for high-throughput screenings.

“they are poorly suited for high-throughput screenings”