Tumour-on-a-chip provides an optical window into nanoparticle tissue transport
Open accessAbstract
Nanomaterials are used for numerous biomedical applications, but the selection of optimal properties for maximum delivery remains challenging. Thus, there is a significant interest in elucidating the nano-bio interactions underlying tissue accumulation. To date, researchers have relied on cell culture or animal models to study nano-bio interactions. However, cell cultures lack the complexity of biological tissues and animal models are prohibitively slow and expensive. Here we report a tumour-on-a-chip system where incorporation of tumour-like spheroids into a microfluidic channel permits real-time analysis of nanoparticle (NP) accumulation at physiological flow conditions. We show that penetration of NPs into the tissue is limited by their diameter and that retention can be improved by receptor targeting. NP transport is predominantly diffusion-limited with convection improving accumulation mostly at the tissue perimeter. A murine tumour model confirms these findings and demonstrates that the tumour-on-a-chip can be useful for screening optimal NP designs prior to in vivo studies.
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Nanoparticle transport in tumor spheroids was predominantly dispersion-limited.
“The penetration of NPs into the tissue was mainly influenced by their diameter (Figure 4a-iv–vi) and NP transport was predominantly dispersion-limited.”
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 [27]
The Results section (“Effect of flow rate on tissue accumulation”) says nanoparticles diffuse into spheroid tissue after accumulating at its surface; increased flow did not increase penetration depth. The claim says transport was predominantly dispersion-limited, whereas the paper describes diffusion as the mechanism of penetration. Its separate finding that diameter limits penetration is supported by the Results (“Effect of nanoparticle size on tissue accumulation”). (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredFor nanoparticles larger than 100 μm, inlet flow rate affected their accumulation exclusively at the spheroid perimeter and did not increase their penetration depth.
“For larger particles (i.e., larger than 100 µm), the inlet flow rate affected their accumulation exclusively at the spheroid perimeter and did not increase their penetration depth”
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 [27]
The Results section, “Effect of flow rate on tissue accumulation” (page unavailable), reports greater accumulation at the spheroid’s outer layer with no detectable change in average penetration depth. But it also reports more nanoparticles diffusing into the tissue, so “exclusively” at the perimeter overstates the finding. The separate size experiment tested particles measured in nanometres, not particles larger than 100 µm; the flow-rate result is not established for the size stated in the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn a microfluidic configuration with a perfused microchannel adjacent to a cavity containing multicellular tumor spheroids embedded in polydimethylsiloxane, nanoparticle transport was size-dependent, with smaller particles penetrating more deeply into the spheroid.
“Nanoparticles of varying sizes were introduced into the flow channel, and their transport was found to be size-dependent, with smaller particles penetrating more deeply into the spheroid [230].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [230]
Ligand functionalization of nanoparticles enhanced their retention at the spheroid surface through receptor-mediated interactions.
“Ligand functionalization of nanoparticles further enhanced their retention at the spheroid surface through receptor-mediated interactions [230].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [230]
In vivo xenograft models using the same tumor cells showed comparable nanoparticle distribution patterns, reinforcing the predictive utility of the in vitro platform.
“When tested in vivo using the same tumor cells in xenograft models, comparable distribution patterns were observed, reinforcing the predictive utility of the in vitro platform [230].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [230]
The penetration of nanoparticles into tumor spheroids was mainly influenced by their diameter.
“The penetration of NPs into the tissue was mainly influenced by their diameter (Figure 4a-iv–vi) and NP transport was predominantly dispersion-limited.”
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 [27]
The tumor-on-chip device developed by Albanese et al. can be used for screening nanoparticle designs prior to in vivo studies.
“Their results showed that this tumor-on-chip can be used for screening NP designs prior to in vivo studies.”
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 [27]
Retention of nanoparticles in tumor spheroids could be improved by specific receptor-targeting.
“However, retention could be improved by specific receptor-targeting.”
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 [27]
Valuable information has been obtained from tumor-on-chip models for studying NP transport and penetration into the tumor niche.
“By contrast, valuable information has been obtained from tumor-on-chip models [21,27,28,47,64] as indicated by the following notable examples of tumor-on-chip platforms used to study NP transport and penetration into the tumor niche.”
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 [27]
Unlike simple two-dimensional cell cultures, the development of biomimetic organ-on-a-chip and tissue-on-a-chip systems may enable researchers to more accurately predict the behaviour of nanomedicines in a controlled setting by considering cell-cell interactions, interstitial flow and nanoparticle transport in three dimensions.
“Unlike simple two-dimensional cell cultures, the development of biomimetic organ-on-a-chip and tissue-on-a-chip systems may enable researchers to more accurately predict the behaviour of nanomedicines in a controlled setting by considering cell-cell interactions, interstitial flow and nanoparticle transport in three dimensions93,94.”
From How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation (2018) · cites this paper as [94]
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InfluentialAdvancing cancer research using bioprinting for tumor-on-a-chip platforms
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- Authors
- Albanese, A., Lam, A. K., Sykes, E. A., Rocheleau, J. V., & Chan, W. C. W.
- Affiliations
- University of Toronto (CA)
- University Health Network (CA)
- Corresponding author
- Rocheleau, Jonathan V.
- Chan, Warren C.W.
- Venue
- Nature Communications
- Published
- 2013-10-31
- Volume
- 4
- Issue
- 1
- Pages
- 2718-2718
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3947376
- OpenAlex
- W1997203755
- Cited by
- 330
- References
- 31
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 25 · 2023: 22 · 2022: 29 · 2021: 27 · 2020: 27 · 2019: 27 · 2018: 32 · 2017: 30 · 2016: 40 · 2015: 14 · 2014: 21
- FWCI
- 9.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- TSpace (University of Toronto) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Canadian Institutes of Health Research (126588_1, MOP93532, 93532_1, COP126588)
- Natural Sciences and Engineering Research Council of Canada (288231, 950-223824, RGPIN-288231, RGPIN371705)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
- Keywords
- tumor spheroids, microfluidics, nanoparticle accumulation, nanoparticle size effects, receptor targeting, diffusion-limited transport, convection, nanoparticle retention, nano-bio interactions, mouse tumor model
- MeSH terms
- Animals, Biological Transport, Collagen, Diffusion, Drug Combinations, Equipment Design, Fluorescent Dyes, Humans, Laminin, Neoplasm Transplantation, Proteoglycans, Silver Staining, Microscopy, Confocal, Nanotechnology, Microfluidics, Cell Line, Tumor, Microfluidic Analytical Techniques, Tissue Array Analysis, Mice, Nanoparticles, Optics and Photonics
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