A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening
Open accessAbstract
Cancer is one of the leading causes of morbidity and mortality around the world. Despite some success, traditional anticancer drugs developed to reduce tumor growth face important limitations primarily due to undesirable bone marrow and cardiovascular toxicity. Many drugs fail in clinical development after showing promise in preclinical trials, suggesting that the available in vitro and animal models are poor predictors of drug efficacy and toxicity in humans. Thus, novel models that more accurately mimic the biology of human organs are necessary for high-throughput drug screening. Three-dimensional (3D) microphysiological systems can utilize induced pluripotent stem cell technology, tissue engineering, and microfabrication techniques to develop tissue models of human tumors, cardiac muscle, and bone marrow on the order of 1 mm 3 in size. A functional network of human capillaries and microvessels to overcome diffusion limitations in nutrient delivery and waste removal can also nourish the 3D microphysiological tissues. Importantly, the 3D microphysiological tissues are grown on optically clear platforms that offer non-invasive and non-destructive image acquisition with subcellular resolution in real time. Such systems offer a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for cancer treatment that minimize cardiac and bone marrow toxicity.
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Less than 10% of anticancer drugs that enter clinical trials ever reach the market.
“Today, less than 10% of the anticancer drugs that enter clinical trials ever reach the market [7,8].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
The Abstract (page not provided) says that many drugs showing promise in preclinical trials fail during clinical development. That supports the general point that anticancer drug development has a high failure rate, but the paper does not give a less-than-10% figure for drugs entering clinical trials or state how many reach the market. (LLM, conf=0.83)
Experimental — accuracy not yet measuredToday, tumor-on-chip systems are the most promising embodiment of in vitro platforms capable of faithfully recapitulating relevant aspects of the biochemical complexity and dynamics of the tumor niche in a controlled environment with much lower variability than in vivo systems.
“Today, tumor-on-chip systems are the most promising embodiment of in vitro platforms capable of faithfully recapitulation of relevant aspects of the biochemical complexity and dynamics of the tumor niche in a controlled environment (i.e., with much lower variability than is associated with in vivo systems [8,54,113]).”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
The Tumor Tissue section argues that tumor-on-chip models can better mimic aspects of the tumor microenvironment and calls for control of interstitial flow and pressure. The Platform design considerations section describes control of vascular flow and identifies reproducibility as a design goal. The paper does not establish that current systems faithfully recapitulate the tumor niche, are the most promising in vitro platform, or have much lower variability than in vivo systems; several features are proposed for future models. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMany aspects of cancer biology have been studied in microfluidic systems in which cancerous cells are cultured under well-controlled conditions.
“Many aspects of the biology of cancer have been studied in microfluidic systems in which cancerous cells (frequently co-cultured with non-cancerous cells) are cultured under well-controlled conditions [8,105,106,107,108].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
The Tumor Tissue section (page unavailable) describes earlier cancer-cell cultures, including spheroids containing both cancer and stromal cells. The Platform design considerations section explains how microfluidic devices can control culture conditions. The paper does not establish the broader claim that many aspects of cancer biology had already been studied in such systems. (LLM, conf=0.77)
Experimental — accuracy not yet measuredVascular transport is particularly required for tissues with diffusional distances greater than 200 μm.
“Indeed, vascular transport is particularly required for tissues with diffusional distances greater than 200 μm [8,182,183], and tumors are not an exception.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
The Vascular System section says vascular transport is particularly necessary when tissue diameter exceeds 200 μm because passive diffusion is inefficient. The claim instead applies the 200 μm threshold to diffusional distance, which is a different measurement; the source does not state that threshold for diffusional distance. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRelevant features of cancer progression and the effectiveness of anticancer pharmaceutical compounds cannot be properly recapitulated in 2D cell culture systems.
“While 2D systems were the first workhorses in cancer research, a vast body of experimental evidence confirms that the relevant features of the cancer progression, and the effectiveness of anticancer pharmaceutical compounds, cannot be properly recapitulated in 2D cell culture systems [8,57,93].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
3D culture systems more closely recapitulate the architecture and physiology of human solid tumors than traditional 2D systems.
“An extensive body of experimental evidence has established that 3D culture systems more closely recapitulate the architecture and the physiology of human solid tumors when compared with traditional 2D systems.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
Current in vitro and preclinical models are not reliable predictors of the actual in vivo efficacy and toxicity of anticancer drugs in humans.
“This strongly suggests that the current in vitro and preclinical models are not reliable predictors of the actual in vivo efficacy and toxicity of anticancer drugs in humans [8] (Figure 1a).”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [8]
Over 80% of anticancer drug candidates fail during clinical screening due to weak efficacy or adverse events.
“However, the success rate of anticancer drugs in clinical trials is very low, with over 80% of drug candidates failing during clinical screening due to weak efficacy or adverse events4–7.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [5]
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Flagged first, then by citations
Research works printed but not linked: 2
- [67]Hsu YH Full range physiological mass transport control in 3D tissue cultures Lab on a chip 2013 13 1 81 9 23090158 PMC3510322
- [68]Moya ML In Vitro Perfused Human Capillary Networks Tissue Eng Part C Methods 2013 PMC3719485 23320912
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Tumor-on-a-chip: from bioinspired design to biomedical application
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“This strongly suggests that the current in vitro and preclinical models are not reliable predictors of the actual in vivo efficacy and toxicity of anticancer drugs in humans [8] (Figure 1a).”
BackgroundInfluentialHachey, S. J., Movsesyan, S., Nguyen, Q. H., Burton-Sojo, G., Tankazyan, A., Wu, J., Hoang, T., Zhao, D., Wang, S., Hatch, M. M., et al. (2021) · Lab on a Chip · doi:10.1039/d0lc01216e · Cited by 124 · see citing works
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Self-citation3D Immunocompetent Organ‐on‐a‐Chip Models
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- Authors
- Heylman, C., Sobrino, A., Shirure, V. S., Hughes, C. C., & George, S. C.
- Affiliations
- University of California, Irvine (US)
- Venue
- Experimental Biology and Medicine
- Publisher
- Frontiers Media SA
- Published
- 2014-04-16
- Volume
- 239
- Issue
- 9
- Pages
- 1240-1254
- ISSN
- 0071-3384 (ISSN-L)
- 1535-3702
- 1535-3699
- PMC
- PMC4156538
- OpenAlex
- W2061614588
- Cited by
- 53
- References
- 130
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 9 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 7 · 2016: 4 · 2015: 7 · 2014: 2
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DigitalCommons - CalPoly (California State Polytechnic University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UH2TR000481)
- National Cancer Institute (R01CA180122, P30CA062203)
- National Center for Advancing Translational Sciences
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- anticancer drug screening, induced pluripotent stem cells, organ-on-a-chip, cardiotoxicity, myelosuppression, high-throughput drug screening, capillary network, tissue engineering, microfabrication, in vitro model, drug toxicity prediction
- MeSH terms
- Drug Screening Assays, Antitumor, Humans, Neoplasms, Cell Culture Techniques, Tissue Engineering, Pluripotent Stem Cells
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