Microfluidic analysis of heterotypic cellular interactions: A review of techniques and applications

Sakthivel, Kabilan; O’Brien, Allen; Kim, Keekyoung; Hoorfar, Mina

doi:10.1016/j.trac.2019.03.026

Cited by 20 publications

(25 citation statements)

References 202 publications

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“…Zhang et al exploited this strategy by creating what the authors referred to as a “3D ossified” tissue (Zhang et al, 2014). This study is highly cited in the field of microfluidics, as reported in many reviews (Bhatia and Ingber, 2014; Carvalho et al, 2015; Fong et al, 2016a; Arrigoni et al, 2017; Peela et al, 2017; Rothbauer et al, 2019; Sakthivel et al, 2019; Sontheimer-Phelps et al, 2019), yet the limitations of the study escaped most of them. The “3D ossified” “tissue” appellation was merely disproportionate; the “tissue” consisted simply of a monolayer of human osteoblasts (hFOB 1.19 cell line) cultured on the flat surface of microfluidic chambers for 4 days prior to the pumping of bone marrow mononuclear cells from MM patients for 4 h, followed by perfused culture for 21 days.…”

Section: Engineering Patient-specific Tumor Microenvironment Modelsmentioning

confidence: 88%

Addressing Patient Specificity in the Engineering of Tumor Models

Bray

Hutmacher

2019

Front. Bioeng. Biotechnol.

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Cancer treatment is challenged by the heterogeneous nature of cancer, where prognosis depends on tumor type and disease stage, as well as previous treatments. Optimal patient stratification is critical for the development and validation of effective treatments, yet pre-clinical model systems are lacking in the delivery of effective individualized platforms that reflect distinct patient-specific clinical situations. Advances in cancer cell biology, biofabrication, and microengineering technologies have led to the development of more complex in vitro three-dimensional (3D) models to act as drug testing platforms and to elucidate novel cancer mechanisms. Mostly, these strategies have enabled researchers to account for the tumor microenvironment context including tumor-stroma interactions, a key factor of heterogeneity that affects both progression and therapeutic resistance. This is aided by state-of-the-art biomaterials and tissue engineering technologies, coupled with reproducible and high-throughput platforms that enable modeling of relevant physical and chemical factors. Yet, the translation of these models and technologies has been impaired by neglecting to incorporate patient-derived cells or tissues, and largely focusing on immortalized cell lines instead, contributing to drug failure rates. While this is a necessary step to establish and validate new models, a paradigm shift is needed to enable the systematic inclusion of patient-derived materials in the design and use of such models. In this review, we first present an overview of the components responsible for heterogeneity in different tumor microenvironments. Next, we introduce the state-of-the-art of current in vitro 3D cancer models employing patient-derived materials in traditional scaffold-free approaches, followed by novel bioengineered scaffold-based approaches, and further supported by dynamic systems such as bioreactors, microfluidics, and tumor-on-a-chip devices. We critically discuss the challenges and clinical prospects of models that have succeeded in providing clinical relevance and impact, and present emerging concepts of novel cancer model systems that are addressing patient specificity, the next frontier to be tackled by the field.

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Section: Engineering Patient-specific Tumor Microenvironment Modelsmentioning

confidence: 88%

Addressing Patient Specificity in the Engineering of Tumor Models

Bray

Hutmacher

2019

Front. Bioeng. Biotechnol.

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“…Therefore, the number of research literatures focusing on cell interaction in tumor microenvironment is growing rapidly . Cell-to-cell interactions are more pronounced in MTSs than that in 2D cell cultures (Sakthivel et al 2019). In 3D spheroids, all cells are in close contact that is necessary for tumor development and progression.…”

Section: Cell-to-cell and Cell-to-ecm Interactionsmentioning

confidence: 94%

“…Further, Lazzari et al developed an MTS model contained PANC-1, MRC-5 and HUVEC, which showed more resistance to drugs than the MTS co-culture tumor cells with fibroblasts or with endothelial cells (Lazzari et al 2018). However, it is generally recommended to use up to three cell types in co-culture, as many cell types would make the system complex and difficult to process (Sakthivel et al 2019). At present, the coculture methods are mainly divided into three types:…”

Section: Co-culture Tumor Spheroid Modelmentioning

confidence: 99%

“…Semi-contact co-culture is advantageous for the study of tumor invasion, which is very similar to the cell structure of tumor tissues, allowing the assessment of the contact interaction between tumor cells and surrounding stromal cells (Horie et al 2015). However, the inoculation process is cumbersome, and it is difficult to control the shape of the spheroid and prevent physical contact of heterogeneous cell populations if the cells are co-cultured for a long period of time (Sakthivel et al 2019). iii.…”

Section: Co-culture Tumor Spheroid Modelmentioning

confidence: 99%

See 1 more Smart Citation

Leveraging and manufacturing in vitro multicellular spheroid-based tumor cell model as a preclinical tool for translating dysregulated tumor metabolism into clinical targets and biomarkers

Wang

et al. 2020

Bioresour. Bioprocess.

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The grand challenge now and in the near future for the pharmaceutical industry is how to efficiently improve R&D productivity. Currently, the approval rate of the entire clinical drug development process is extremely low, and the high attrition in the phase I clinical trial is up to 95%; 67% and 33% of all drugs that enter Phase II and Phase III clinical trials fail to transit into the next stage, respectively. To achieve a higher success rate in clinical trials, developing efficient drug screening method based on more in vivo like tumor tissue is an urgent need to predict the toxicity and efficacy of candidate drugs. In comparison to 2D planar tumor model, the 3D multicellular tumor spheroid (MTS) can better simulate the spatial structure, hypoxia and nutrient gradient, extracellular matrix (ECM) deposition and drug resistance mechanism of tumor in vivo. Thus, such model can be applied for high-throughput drug screening and evaluation, and also can be utilized to initiate a series of fundamental research areas regarding oncogenesis, tumor progression and invasion, pharmacokinetics, drug metabolism, gene therapy and immune mechanism. This review article discusses the abnormal metabolism of cancer cells and highlights the potential role of MTSs as being used as efficient preclinical models. Also, the key features and preparation protocols of MTSs as well as the tools and techniques used for their analysis were summarized and the application of 3D tumor spheroid in specific drug screening and in the elucidation of drug resistance mechanism was also provided. Despite the great knowledge gap within biological sciences and bioengineering, the grand blueprint for adaptable stirred-tank culture strategies for large-scale production of MTSs is envisioned.

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“…[ 29 ] Miniature devices designed for cell communication analyses are broadly separated into methods that permit or restrict direct cell–cell contacts. [ 30 ] The reduction in scale of these devices take advantage of low reagent volume requirements and high‐throughput screening capabilities, making microengineered platforms useful for studying communication in heterotypic and homotypic cocultures. [ 31,32 ] In this section, we discuss the development of microengineered devices designed to examine direct and indirect intercellular communication.…”

Section: Microengineered Approaches To Study Intercellular Communicationmentioning

confidence: 99%

Engineered Tools to Study Intercellular Communication

et al. 2020

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All multicellular organisms rely on intercellular communication networks to coordinate physiological functions. As members of a dynamic social network, each cell receives, processes, and redistributes biological information to define and maintain tissue homeostasis. Uncovering the molecular programs underlying these processes is critical for prevention of disease and aging and development of therapeutics. The study of intercellular communication requires techniques that reduce the scale and complexity of in vivo biological networks while resolving the molecular heterogeneity in “omic” layers that contribute to cell state and function. Recent advances in microengineering and high‐throughput genomics offer unprecedented spatiotemporal control over cellular interactions and the ability to study intercellular communication in a high‐throughput and mechanistic manner. Herein, this review discusses how salient engineered approaches and sequencing techniques can be applied to understand collective cell behavior and tissue functions.

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Microfluidic analysis of heterotypic cellular interactions: A review of techniques and applications

Cited by 20 publications

References 202 publications

Addressing Patient Specificity in the Engineering of Tumor Models

Addressing Patient Specificity in the Engineering of Tumor Models

Leveraging and manufacturing in vitro multicellular spheroid-based tumor cell model as a preclinical tool for translating dysregulated tumor metabolism into clinical targets and biomarkers

Engineered Tools to Study Intercellular Communication

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