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Cancers
Special Issues
Modeling Cancer in Microfluidic Chips
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Modeling Cancer in Microfluidic Chips

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 30029

Special Issue Editors

Dr. Esak Lee

E-Mail Website
Guest Editor
Meinig School of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, NY 14853, USA
Interests: biomedical engineering; organs-on-chips; immunity; lymphatics; cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Taslim Ahmed Al-Hilal

E-Mail Website
Guest Editor
Assistant Professor, School of Pharmacy, The University of Texas at El Paso, TX 79902, USA
Interests: angiogenesis; biomarkers; tissue-on-a-chip models; drug delivery

Special Issue Information

Dear colleagues,

Tumors are complex three-dimensional (3D) tissues that establish a dynamic cross-talk between multiple cell types (cancer cells, various stromal cells (e.g., cancer-associated fibroblasts), various types of immune cells, and vascular cells) and the surrounding matrix through complex chemical signaling. Conventional 2D or 3D culture systems, although they have the ability to conserve at least some of the acquired phenotypes, cannot imitate the cell–cell interactions and tissue-level functions, and thus fail to recreate the dynamics of the tumor niche. Cancer-on-chip systems, which are microfluidic devices, aim to recapitulate relevant features of the tumor physiology and have emerged as powerful tools in cancer research. Cancer-on-a-chip models add another dimension of physiological mimicry by allowing a perfusable system that can be integrated with vascular or lymphatic networks. In this Issue, Cancers is launching a Special Collection that highlights the contribution of on-chip cancer models for better understating human cancers and studying drugs. The Special issue will consider articles from the full breadth of research in the field: from original research papers to reviews and methods papers. Areas of interest include, but are not limited to:

  • Modeling cancer diseases using “organs-on-chips” for drug discovery;
  • Orthotopic cancer organ chips;
  • Application of on-chip cancer models using organoids and spheroids in drug discovery, screening, and delivery;
  • Cancer-on-a-chip models to share an interface between cancerous and normal microtissues for studying tumor niches;
  • Cancer-on-a-chip models for studying the tumor-associated immunosuppressive microenvironment;
  • Cancer-on-a-chip models for studying neovascularization;
  • Cancer-on-a-chip models for studying metastatic dissemination;
  • Cancer-on-a-chip models for developing personalized medicine;
  • Cancer-on-a-chip models for modelling responses to drug therapies.

Dr. Esak Lee
Dr. Taslim Ahmed Al-Hilal
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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17 pages, 5216 KiB  
Article
Early Predictor Tool of Disease Using Label-Free Liquid Biopsy-Based Platforms for Patient-Centric Healthcare
by Wei Li, Yunlan Zhou, Yanlin Deng and Bee Luan Khoo
Cancers 2022, 14(3), 818; https://doi.org/10.3390/cancers14030818 - 06 Feb 2022
Cited by 7 | Viewed by 2209
Abstract
Cancer cells undergo phenotypic changes or mutations during treatment, making detecting protein-based or gene-based biomarkers challenging. Here, we used algorithmic analysis combined with patient-derived tumor models to derive an early prediction tool using patient-derived cell clusters from liquid biopsy (LIQBP) for cancer prognosis [...] Read more.
Cancer cells undergo phenotypic changes or mutations during treatment, making detecting protein-based or gene-based biomarkers challenging. Here, we used algorithmic analysis combined with patient-derived tumor models to derive an early prediction tool using patient-derived cell clusters from liquid biopsy (LIQBP) for cancer prognosis in a label-free manner. The LIQBP platform incorporated a customized microfluidic biochip that mimicked the tumor microenvironment to establish patient clusters, and extracted physical parameters from images of each sample, including size, thickness, roughness, and thickness per area (n = 31). Samples from healthy volunteers (n = 5) and cancer patients (pretreatment; n = 4) could be easily distinguished with high sensitivity (91.16 ± 1.56%) and specificity (71.01 ± 9.95%). Furthermore, we demonstrated that the multiple unique quantitative parameters reflected patient responses. Among these, the ratio of normalized gray value to cluster size (RGVS) was the most significant parameter correlated with cancer stage and treatment duration. Overall, our work presented a novel and less invasive approach for the label-free prediction of disease prognosis to identify patients who require adjustments to their treatment regime. We envisioned that such efforts would promote the management of personalized patient care conveniently and cost effectively. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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14 pages, 2885 KiB  
Article
Microdissected Tissue vs Tissue Slices—A Comparative Study of Tumor Explant Models Cultured On-Chip and Off-Chip
by Dina Dorrigiv, Kayla Simeone, Laudine Communal, Jennifer Kendall-Dupont, Amélie St-Georges-Robillard, Benjamin Péant, Euridice Carmona, Anne-Marie Mes-Masson and Thomas Gervais
Cancers 2021, 13(16), 4208; https://doi.org/10.3390/cancers13164208 - 21 Aug 2021
Cited by 13 | Viewed by 4063
Abstract
Predicting patient responses to anticancer drugs is a major challenge both at the drug development stage and during cancer treatment. Tumor explant culture platforms (TECPs) preserve the native tissue architecture and are well-suited for drug response assays. However, tissue longevity in these models [...] Read more.
Predicting patient responses to anticancer drugs is a major challenge both at the drug development stage and during cancer treatment. Tumor explant culture platforms (TECPs) preserve the native tissue architecture and are well-suited for drug response assays. However, tissue longevity in these models is relatively low. Several methodologies have been developed to address this issue, although no study has compared their efficacy in a controlled fashion. We investigated the effect of two variables in TECPs, specifically, the tissue size and culture vessel on tissue survival using micro-dissected tumor tissue (MDT) and tissue slices which were cultured in microfluidic chips and plastic well plates. Tumor models were produced from ovarian and prostate cancer cell line xenografts and were matched in terms of the specimen, total volume of tissue, and respective volume of medium in each culture system. We examined morphology, viability, and hypoxia in the various tumor models. Our observations suggest that the viability and proliferative capacity of MDTs were not affected during the time course of the experiments. In contrast, tissue slices had reduced proliferation and showed increased cell death and hypoxia under both culture conditions. Tissue slices cultured in microfluidic devices had a lower degree of hypoxia compared to those in 96-well plates. Globally, our results show that tissue slices have lower survival rates compared to MDTs due to inherent diffusion limitations, and that microfluidic devices may decrease hypoxia in tumor models. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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20 pages, 45648 KiB  
Article
Hypoxic Jumbo Spheroids On-A-Chip (HOnAChip): Insights into Treatment Efficacy
by Elena Refet-Mollof, Ouafa Najyb, Rodin Chermat, Audrey Glory, Julie Lafontaine, Philip Wong and Thomas Gervais
Cancers 2021, 13(16), 4046; https://doi.org/10.3390/cancers13164046 - 11 Aug 2021
Cited by 12 | Viewed by 3282
Abstract
Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture naturally hypoxic 3D tumor models. In this study, we used soft lithography to engineer a microfluidic platform allowing [...] Read more.
Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture naturally hypoxic 3D tumor models. In this study, we used soft lithography to engineer a microfluidic platform allowing the culture of up to 240 naturally hypoxic tumor spheroids within an 80 mm by 82.5 mm chip. These jumbo spheroids on a chip are the largest to date (>750 µm), and express gold-standard hypoxic protein CAIX at their core only, a feature absent from smaller spheroids of the same cell lines. Using histopathology, we investigated response to combined radiotherapy (RT) and hypoxic prodrug Tirapazamine (TPZ) on our jumbo spheroids produced using two sarcoma cell lines (STS117 and SK-LMS-1). Our results demonstrate that TPZ preferentially targets the hypoxic core (STS117: p = 0.0009; SK-LMS-1: p = 0.0038), but the spheroids’ hypoxic core harbored as much DNA damage 24 h after irradiation as normoxic spheroid cells. These results validate our microfluidic device and jumbo spheroids as potent fundamental and pre-clinical tools for the study of hypoxia and its effects on treatment response. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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Review

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23 pages, 14888 KiB  
Review
Cancer-on-a-Chip: Models for Studying Metastasis
by Xiaojun Zhang, Mazharul Karim, Md Mahedi Hasan, Jacob Hooper, Riajul Wahab, Sourav Roy and Taslim A. Al-Hilal
Cancers 2022, 14(3), 648; https://doi.org/10.3390/cancers14030648 - 27 Jan 2022
Cited by 24 | Viewed by 6863
Abstract
The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review [...] Read more.
The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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26 pages, 863 KiB  
Review
Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology
by Hongyan Xie, Jackson W. Appelt and Russell W. Jenkins
Cancers 2021, 13(23), 6052; https://doi.org/10.3390/cancers13236052 - 01 Dec 2021
Cited by 14 | Viewed by 3197
Abstract
Recent advances in cancer immunotherapy have led a paradigm shift in the treatment of multiple malignancies with renewed focus on the host immune system and tumor–immune dynamics. However, intrinsic and acquired resistance to immunotherapy limits patient benefits and wider application. Investigations into the [...] Read more.
Recent advances in cancer immunotherapy have led a paradigm shift in the treatment of multiple malignancies with renewed focus on the host immune system and tumor–immune dynamics. However, intrinsic and acquired resistance to immunotherapy limits patient benefits and wider application. Investigations into the mechanisms of response and resistance to immunotherapy have demonstrated key tumor-intrinsic and tumor-extrinsic factors. Studying complex interactions with multiple cell types is necessary to understand the mechanisms of response and resistance to cancer therapies. The lack of model systems that faithfully recapitulate key features of the tumor microenvironment (TME) remains a challenge for cancer researchers. Here, we review recent advances in TME models focusing on the use of microfluidic technology to study and model the TME, including the application of microfluidic technologies to study tumor–immune dynamics and response to cancer therapeutics. We also discuss the limitations of current systems and suggest future directions to utilize this technology to its highest potential. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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15 pages, 5508 KiB  
Review
Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer
by Muhammad R. Haque, Trevor H. Rempert, Taslim A. Al-Hilal, Chengyao Wang, Abhinav Bhushan and Faraz Bishehsari
Cancers 2021, 13(17), 4487; https://doi.org/10.3390/cancers13174487 - 06 Sep 2021
Cited by 15 | Viewed by 5661
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the [...] Read more.
Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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22 pages, 1848 KiB  
Review
Technological Advances in Tumor-On-Chip Technology: From Bench to Bedside
by Santa Bērziņa, Alexandra Harrison, Valérie Taly and Wenjin Xiao
Cancers 2021, 13(16), 4192; https://doi.org/10.3390/cancers13164192 - 20 Aug 2021
Cited by 13 | Viewed by 3460
Abstract
Tumor-on-chip technology has cemented its importance as an in vitro tumor model for cancer research. Its ability to recapitulate different elements of the in vivo tumor microenvironment makes it promising for translational medicine, with potential application in enabling personalized anti-cancer therapies. Here, we [...] Read more.
Tumor-on-chip technology has cemented its importance as an in vitro tumor model for cancer research. Its ability to recapitulate different elements of the in vivo tumor microenvironment makes it promising for translational medicine, with potential application in enabling personalized anti-cancer therapies. Here, we provide an overview of the current technological advances for tumor-on-chip generation. To further elevate the functionalities of the technology, these approaches need to be coupled with effective analysis tools. This aspect of tumor-on-chip technology is often neglected in the current literature. We address this shortcoming by reviewing state-of-the-art on-chip analysis tools for microfluidic tumor models. Lastly, we focus on the current progress in tumor-on-chip devices using patient-derived samples and evaluate their potential for clinical research and personalized medicine applications. Full article
(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)
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