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. 2024 Jun 17;18(3):031506. doi: 10.1063/5.0206058

Application and prospect of microfluidic devices for rapid assay of cell activities in the tumor microenvironment

Linjing Zhu 1, Xueling Cui 1, Lingling Jiang 2, Fang Fang 1, Boyang Liu 1,3,1,3,a)
PMCID: PMC11185871  PMID: 38899164

Abstract

The global impact of cancer on human health has raised significant concern. In this context, the tumor microenvironment (TME) plays a pivotal role in the tumorigenesis and malignant progression. In order to enhance the accuracy and efficacy of therapeutic outcomes, there is an imminent requirement for in vitro models that can accurately replicate the intricate characteristics and constituents of TME. Microfluidic devices exhibit notable advantages in investigating the progression and treatment of tumors and have the potential to become a novel methodology for evaluating immune cell activities in TME and assist clinicians in assessing the prognosis of patients. In addition, it shows great advantages compared to traditional cell experiments. Therefore, the review first outlines the applications and advantages of microfluidic chips in facilitating tumor cell culture, constructing TME and investigating immune cell activities. Second, the roles of microfluidic devices in the analysis of circulating tumor cells, tumor prognosis, and drug screening have also been mentioned. Moreover, a forward-looking perspective is discussed, anticipating the widespread clinical adoption of microfluidic devices in the future.

I. INTRODUCTION

Tumor has become a global public health issue and ranks as the second most common cause of mortality worldwide, which is characterized by the abnormal proliferation of local tissue cells.1,2 The tumor-intrinsic environment, known as the tumor microenvironment (TME), plays an important role in tumorigenesis and tumor growth, including local drug resistance, immune evasion, and cancer metastasis.3,4 There are non-cancer cell components and non-cellular components in the TME. Non-cancer cell components contain immune cells, fibroblasts, endothelial cells (ECs), adipocytes, and other similar entities. The non-cellular elements include soluble factors and extracellular matrix, such as cytokines, chemokines, extracellular vesicles, and growth factors.5 Multiple immune cells include T and B lymphocytes, natural killer (NK) cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). The progression of tumors is heavily influenced by the intricate interactions among the non-cancer cell components. Therefore, TME is a crucial focus in tumor therapy, attracting significant scientific and clinical interests.6–9 However, the current immunotherapeutic strategies have shown limited effectiveness in a minority of patients with specific tumors, and the field of targeting the tumor microenvironment continues to face several obstacles.10–13 The modulation of the immune system emerges as a central challenge in the widespread adoption of immunotherapies for cancer, owing to their pronounced adverse effects such as non-specific inflammatory responses and autoimmunity.13 Consequently, these limitations expedite the advancement of in vitro tumor models.

The continuous development of microfluidic chips based on MPS (multi-parameter single-cell) technology provides an opportunity to overcome several significant challenges in the realm of tumor immunity.14 The microfluidic chip, commonly referred to as the lab-on-chip, emerged in the 1990s as a platform for conducting various experiments. These chips consist of channels typically ranging in size from tens to hundreds of micrometers, which can manipulate and control fluids in the microfluidic system.15,16 Moreover, the microfluidic chip is more suitable for rapid detection of immune cell motility.17 The TME exhibits distinctive attributes such as anomalous vascular architecture, reduced pH levels, heightened enzyme expression, and oxygen deprivation.18 By precisely controlling fluid dynamics, cell quantities, culture media, and substrates in microfluidic devices, it becomes feasible to faithfully replicate crucial aspects of the TME. Furthermore, microfluidic technology presents several merits, including economic viability, expeditious analysis, capacity for high-throughput experimentation, seamless integration, and a compact device.19 These models possess significant utility in assessing treatment methods and facilitating the observation and measurement of the interactions between tumor cells and immune cells. In addition, it can augment comprehension of the interactions between tumor cells and tumor microenvironment, ultimately propelling the advancement of anticancer strategies.20

II. ADVANTAGES BASED ON MICROFLUIDIC TUMOR MODELS

A. Microfluidic models for the tumor cell culture

Microfluidic technology has been widely utilized in diverse fields of cancer biology and cancer immunotherapy, including tumor growth, cancer cell extravasation, angiogenesis, immunotherapy responses of different cellular constituents, and drug screening. The integration of microfluidic technology with 3D culture systems enables researchers to meticulously regulate variables such as matrix structure, matrix stiffness, cellular composition and ratios, flow rates, and other pertinent attributes. Furthermore, these advanced devices can be combined with high-resolution real-time imaging technology to facilitate preclinical research on specific diseases.21–23 Microfluidics enable the creation of well-regulated flow models that facilitate the development of stable concentration gradients. By manipulating various parameters, such as channel design, channel size, and inlet pressure, precise control of the concentration gradients can be achieved. Additionally, these gradient generators have been utilized to investigate the chemotactic properties of various compounds [such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF)] in different cells (such as tumor cells and endothelial cells). The primary advantage of microfluidic models lies in their ability to predict hydrodynamic behavior at the microscale.19 Furthermore, microfluidic technology offers the capability to exert mechanical force for regulation. The microfluidic devices can be seamlessly integrated with microfluidic platforms for data processing and analysis, such as biochemical sensors and mini-flow cytometers, enabling direct observation under an optical microscope and compatibility with an image analysis system.24–26

The microfluidic 3D culture systems can replicate the extracellular environment of organs and tissues, which facilitates cell clustering and long-term culture, including the pH value, hypoxia, glucose level, cytokines gradients, and so on (Fig. 1).27–29 This process also regulates the expression of relevant genes and proteins, as well as the proliferation and differentiation of tumor cells.30–32 For example, a gel-free and single-cell culture array in the microfluidic chip was exploited to expand tumor stem cells (TSCs). It owns an array of 16 000 hydrophilic microchamber, which is able to capture 2000 single cells one time. This technique is expected to be used to develop targeted therapeutic strategies for TSCs.27 In addition, the integration of miniaturized sensors with microfluidic systems, such as glucose and oxygen sensors, enables the real-time monitoring of relevant indicators. Moreover, a microfluidic system combined with optical glucose sensors allowed precise and reliable glucose measurements under cell culture.28 It is reported that microfluidic devices were effectively used to create oxygen gradients for cell culture, which minimized the need for chemical compounds and eliminated the reliance on pressurized gas cylinders. This approach is applied to successfully demonstrate the occurrence of hyperoxia-induced cell death and hypoxia-induced cytotoxicity under the action of the anti-cancer drug Tirapazamine (TPZ).29 Additionally, some studies demonstrate a method for electrochemical pH modulation of the microdroplets from a microfluidic platform and conducted a study where they achieved pH-controlled release in a simulated gastrointestinal fluid.33,34

FIG. 1.

FIG. 1.

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(a) Microfluidic device equipped with oxygen and glucose sensors. (b) Oxygen gradients were integrated into a microfluidic device.

B. Microfluidic models for tumor cell migration and invasion

Epithelial–mesenchymal transition (EMT) is a crucial process in tumor metastasis, frequently associated with the invasion and migration of tumor cells. The phenomenon of EMT plays a pivotal role in facilitating tumor cells to acquire mesenchymal-like properties, enabling their invasion and subsequent metastatic spread.35 The invasion capacity of cells in vitro is assessed using transwell assay, but this method poses challenges in maintaining a concentration gradient and lacks the ability to continuously monitor the process of cell invasion. Furthermore, it fails to achieve optimal gradient levels in terms of temporal or spatial controllability. In contrast, microfluidic devices offer convenience in cell culture and real-time observation, and they also enable the possibility of modifying the process of tumor cell invasion and migration by controlling concentrations (Fig. 2).36–38

FIG. 2.

FIG. 2.

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(a) The glioblastoma (GBM) tumor vascular microenvironment. The vascular region [human umbilical vein endothelial cells (HUVECs)] is shown in red. The GBM cells (GB3) are represented in blue, while the stromal cells are illustrated in green. (b) A three-channel microfluidic chip was utilized, where the central channel was seeded with HUVECs, while the outer channels were seeded with normal human lung fibroblast cells (NHLFs).

In one study, a 3D microfluidic device was used to investigate the influence of endothelial cells (ECs) on glioma stem cells (GSCs) behavior. The device successfully simulated the microvascular network, which promoted GSC migration, invasion, and maintenance of GSC characteristics.36 Similarly, Truong et al. established the microvascular network for 3 days and subsequently introduced GSCs into the chip. Both the GSCs-on-a-chip model and their animal model demonstrated tumor cell migration. In the presence of vasculature, phosphorylated CXCR4 staining in GSCs exhibited a punctate pattern, indicating its response to CXCL12 secretion by ECs. The migration distance of GSCs treated with AMD3100 (a CXCR4 inhibitor) is shorter.37 Moreover, Song et al. investigated the effects of various oxygen conditions on the migration of human breast cancer cells (MCF10A, MCF-7, and MDA-MB-231) using the microfluidic devices with microvascular channels and successfully achieved a precise replication of the perivascular niche (PVN) through the development of the controllable models in vitro.38

C. Analysis of circulating tumor cells

The metastasis of tumor cells is associated with the fatality rate significantly. The circulating tumor cells (CTCs) serve as the cornerstone for the spread of metastatic cancers. The utilization of CTCs and molecular biology analysis is expected to enhance the accuracy of cancer diagnosis and treatment.39 Among the various techniques used to isolate CTCs, the majority of data related to the clinical utility of CTCs are obtained using the CellSearch system (Veridex).40 Following the advancement of technology, a microfluidic chip known as the “CTC-Chip” has been developed for capturing CTCs. This system involves attaching antibodies to the surface of micropillars in the microfluidic device. The CTC-Chip, which is conjugated with anti-epithelial cell adhesion molecule (EpCAM) antibodies, has demonstrated a high sensitivity in detecting CTCs.41 Moreover, a universal CTC-chip with EpCAM-coated micropillars has been created to capture diverse CTCs.42 The combination of antibodies and EpCAM can achieve high reproducibility of capture efficiency. 123 patients with confirmed pretreatment CTC burden and pathology exhibited significantly poorer progression-free survival (P = 0.037) and cancer-specific survival (P = 0.0041). The patients were divided into two treatment groups: the surgery group and the chemotherapy group. Notably, CTC-positive patients in both treatment groups demonstrated lower rates of progression-free survival (surgery group: P = 0.115, chemotherapy group: P = 0.012). These findings suggest that baseline CTCs are a risk factor for the recurrence and progression of lung cancer. Additionally, the study also focused on the mutational analysis of the captured CTCs. Moreover, it has been confirmed that the universal CTC-chip coated with anti-podoplanin antibodies can be utilized to effectively capture malignant peritoneal mesothelioma (MPM) cell lines. Notably, this study revealed a significant correlation between higher CTC counts (≥2 cells/ml) and unfavorable prognosis (P = 0.030).43 All the above studies indicate that the newly developed CTC-chips exhibit a high sensitivity in detecting CTCs and provide significant diagnostic and prognostic insights.

III. MICROFLUIDIC DEVICES FOR DETECTION OF IMMUNE CELLS IN TME

The immune system is the first line to combat cell malignant, and the chemotaxis and migration of immune cells have important implications for the processes of various diseases. Compared with conventional cell migration detection techniques, microfluidic devices can precisely control the microenvironment and observe the dynamic process of cell migration in real-time at the microscale. Microfluidics has revolutionized the research method of cell migration, which needs lesser costs and has different experimental parameters of cell migration manipulated precisely (Fig. 3).44 Simulation of immune cell migration is critical for understanding tumor-immune dynamic interactions and evaluating immunotherapy efficacy.

FIG. 3.

FIG. 3.

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Tumor-on-a-chip platforms are utilized to simulate the tumor microenvironment (TME) for conducting cancer immunotherapy research.

A. Innate immune cells

1. Tumor-associated macrophages

TAMs are common immune cells in TME, which are derived from circulating monocytes, exhibit notable plasticity, and exert different influences on tumor cell survival, immune responses, and angiogenesis, ultimately yielding pro-tumor or anti-tumor outcomes. They can exhibit distinct phenotypes, including both M1-like and M2-like characteristics. Specifically, M2-TAMs release immunosuppressive cytokines such as TGF-β and IL-10, which effectively inhibit the activity of effector T cells and impede the anti-tumor-immune response.45 Additionally, TAMs influence leukocyte recruitment and function, thereby enhancing their infiltration and contributing to an immunosuppressive microenvironment within the tumor. This phenomenon is closely associated with the failure of tumor therapy and unfavorable clinical prognosis, highlighting the potential of targeting TAMs as a promising immunotherapy approach.46

Recently, a novel microfluidic multi-faceted model of bladder tumors has been used to examine the effects of bacterial distribution on TME immunomodulation in vivo. These results demonstrate that inflammation induced by a biofilm promotes the phenotypic transition of macrophages from a pro-inflammatory state to an anti-inflammatory/pro-tumor state in tumors.47 Dietsche et al. used a similar microfluidic platform to quantitatively measure the secretion of proteins or exosomes at the single-cell level, successfully inducing the polarization of macrophages.48

2. Natural killer cells

NK cells are recognized as the initial defense against the formation of tumor cells, which possess a unique ability to eliminate cancerous cells through various pathways without prior sensitization. Recently, the combination of tumor immunotherapy in situ and microfluidic technology generated the microspheres with NK cells using the amplification of microfluidic electrospray, and NK-92MI encapsulated microspheres for tumor injection in vivo have good prospects for clinical application without side effects caused by natural host immunity.49 As innate lymphoid cells, NK cells secrete cytotoxic perforins and granzymes, which induce apoptosis in target cells and stimulate the immune system to exert anti-tumor activity. Additionally, NK cells possess the capability to recruit classical type 1 DCs with anti-tumor properties, thereby enhancing their cell-killing efficacy. In TME, NK cells can migrate quickly to the tumor site to exert cytotoxic effects on tumor cells after sensing the chemokine gradients such as CXCL12 and activin A. Accordingly, microfluidic devices have been utilized to evaluate the migration ability caused by chemokines in the latest research.50 Moreover, microfluidic devices can be utilized to investigate the responses of NK cells to the inhibitory environment induced by tumors and evaluate the efficacy of checkpoint inhibitors and immune modulators simultaneously.51

3. Dendritic cells

DCs play a significant role in the detection of invading pathogens and the initiation of the adaptive immune response. In TME, DCs receive and integrate environmental signals through sensing receptors, such as cytokine receptors and damage-associated molecular patterns (DAMPs). DCs present antigens via major histocompatibility complex (MHC), inducing activation and differentiation of T cells, and promote innate and adaptive immunity.52 A study integrated microfluidic technology with microscopy and cell tracking analysis is used to detect the response behavior of IFN-DC cells to tumor cells that received drug treatment, facilitating the comprehension of the interactions between IFN-DC cells and cancer cells.53 A recent study aimed to generate tumor cell vaccine models at the single-cell level using microfluidic technology. In a study, the integrated one-to-one electrofusion technology was used to fuse DC cells with Jurkat cells and successfully generated tumor nuclei-free antigen-recipient DC-like (tarDC-like) cells, as well as provided an insight into the development of safer tumor cell vaccines in the field of cancer immunotherapy.54

4. Tumor-associated neutrophils

Neutrophils are recognized as the primary defense against invading pathogens. Recent studies have provided increasing evidence that neutrophils exhibit a diversity of immunophenotypes and possess dynamic functional plasticity. In addition to being closely associated with injury, neutrophils have also been observed in various types of cancers, referred to as tumor-associated neutrophils (TANs).55 Interestingly, TGF-β in the tumor microenvironment triggers the development of a population of TANs displaying a pro-tumor phenotype by secreting immunosuppressive factor Arg-1. Conversely, inhibition of TGF-β leads to the recruitment and activation of TANs exhibiting an anti-tumor phenotype.56 Because neutrophils are significantly associated with various advanced cancers, researchers consider them to be potential clinical biomarkers and therapeutic targets. In order to clearly understand the involvement of neutrophils in tumor progression, a tumor-immune microenvironment with a 3D microfluidic chip was utilized to investigate the impact of neutrophils on the migration of ovarian cancer cells. The study revealed that neutrophils exhibited chemotactic properties toward tumor spheroids and formed neutrophil extracellular traps (NETs).57

B. Adaptive immune cells

1. T lymphocytes

T lymphocytes are found to be the predominant immune cell population, and CD4+ T cells infiltrating TME exert significant influences on the status and activities of other immune cells, serving as pivotal regulators. The infiltration and cytotoxicity of CD8+ T cells are crucial factors in determining anti-tumor-immune effects.58 Pavesi et al. used a microfluidic system to investigate the interaction between cancer cells and T cells in the 3D space, and the results showed that the 3D microfluidic tumor model can quantify the time-dependent cytotoxicity and migration characteristics of TCR-engineered T cells.59 Chimeric Antigen Receptor (CAR) T-cell therapy is an emerging immunotherapy that faces several challenges, such as the difficulty in visually observing the accumulation of CAR-T cells in solid tumors. To address this issue, researchers have developed a microfluidic device capable of mechanically labeling T cells and employed multiple methods to validate the success of this labeling approach.60

2. B lymphocytes

Humoral immunity is primarily mediated by B cells. The identification of tumor-infiltrating B cells (TIL-Bs) in TME often relies on the expression of CD19 or CD20. TIL-Bs have been observed in most solid tumors, which can inhibit tumor progression through the synthesis and secretion of immunoglobulins, as well as promoting T-cell activation to directly kill cancer cells. B cells also play a crucial role in anti-tumor responses by propelling antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and complement activation.61 There are some challenges in the field of antibody-mediated immunodynamics, particularly, the lack of a high-throughput quantitative system for analyzing individual antibody-secreting cells. Therefore, the microfluidic system DropMap was developed, in which single cells, magnetic nanoparticles coated with capture molecules, fluorescent labeled detection antibodies, and fluorescent labeled antigens are encapsulated in droplets, followed by quantitatively analyzing them in a two-dimensional droplet array using immunoassay based on fluorescence relocation.62 However, this method also has limitations as it cannot determine the phenotype of secreted IgG or identify the genotypes of antibodies produced. In response to this, a droplet-based microfluidic technology called CelliGO has been developed, which can perform high-throughput single-cell screening of millions of non-immortal cells based on the phenotype characteristics of secreted IgG.63

C. Assay of the interaction between tumor cells and immune cells

To investigate the interactions between adjacent cells based on their spatial positioning, it is crucial to identify the temporal sequences of factors secreted by different cells. The utilization of microfluidic chips enables the precise manipulation of fluid flow at micro- or nanoscales, facilitating the co-culturing of distinct cells in a chip-based system, such as tumor cells and stromal cells. Microfluidics is also a valuable detection method for investigating the sequential patterns of cytokines.64 In a study, Xie et al. utilized a microfluidic device equipped with three gradient generators and cell docking modules to generate drug concentration gradients, and detected the induction effects of cancer cells supernatant on peripheral blood neutrophils.65 Cancer-associated fibroblasts (CAFs) play a role in tumor progression and drug resistance. Jeong et al. used a microfluidic chip to tightly integrate 3D tumor spheroids and CAFs into hydrogel scaffolds and achieved the co-culture of tumor spheres and CAFs, providing a platform for studying the interaction between tumor cells and CAFs. It was suggested that the co-culturing of 3D tumor cells and CAFs in microfluidic chips with collagen matrix may be helpful for studying TME, drug screening, and evaluating.66

D. Determination of immune cell activities in TME for predicting tumor prognosis

Microfluidic chips can be used to evaluate the effectiveness of immunotherapy. The infiltration and cytotoxicity of immune cells are crucial in immunotherapy. In various cancers, including breast cancer, skin cancer, ovarian cancer, colorectal cancer, and pancreatic cancer, the extent of lymphocyte infiltration has been proven to be related to the prognosis.67 Integrated microscopy technology combined with microfluidic platforms is used to investigate the migration of immune cells in cancer progression, ascertain the influential factors of cell migration, and evaluate the impact of migration on immunotherapy. Recently, Ao et al. proposed a microfluidic-based micro-tumor chip method to predict tumor responses to cancer immunotherapy in preclinical models.68 In the micro-tumor chip, the separated tumor cells were evenly injected into independent microfluidic hole arrays, which generated 960 micro-tumors uniformly on the chip. Each hole represented an in vitro tumor microecosystem, which fully retained the original tumor cell composition, dynamic intercellular interactions, and autocrine/paracrine cytokines. By recording cell activity within 36 h with delayed live-cell imaging, dynamic analysis of the interaction between tumor cells and immune cells, as well as the response of cancer cells to immunotherapy (such as anti-PD1 therapy), was performed. The results showed a good clinical effect in rapidly detecting the response of primary tumors to anti-PD1 therapy (Fig. 4).68,69 Correspondingly, automated high-throughput microfluidic technology is used to track dynamic T-cell infiltration and cytotoxicity in 3D tumor models. This approach can be used to assess the interaction between immune cells and solid tumors and to validate the effectiveness of immunotherapy and combination therapy.69

FIG. 4.

FIG. 4.

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(a) The overall structure of the mini-tumor chip. (b) The concept of the automated screening platform.

IV. ANTI-TUMOR DRUG SCREENING

A bi-directional concentration gradient between anti-tumor drugs and serum can be formed to quantitatively evaluate the dual changes of tumor cell invasion and proliferation under the action of drugs in a microfluidic device. In microfluidics, different functional changes of cells under the action of multi-factors and complex concentration gradients can be observed and analyzed in real time. While traditional drug screening methods typically rely on large and expensive equipment, microfluidic devices have the advantage of micrometer-scale channels that facilitate cell growth. Recently, various microfluidic devices have been employed, such as droplet-based microfluidic devices and concentration gradient-based microfluidic devices. The microfluidic chip with a “Christmas tree” structure was initially used to investigate tumor cell apoptosis, screen anticancer drugs, and analyze drug resistance in tumor cells.70,71 This technology exhibits refined and stable spatial concentration gradients, which can be dynamically adjusted over time to cater to diverse requirements. In contrast to animal experimentation, microfluidic devices have the advantage of minimizing animal mortality and ethical issues.44

V. PERSPECTIVE OF MICROFLUIDIC DEVICE

Microfluidic technology has become a robust tool for research in the fields of biology, pharmacology, and medicine. This review focuses on the recent advances in utilizing microfluidic devices to model the TME and its application progress in tumor immunodynamics and anti-tumor drug screening. In the future, the combination of microfluidics and organoids has broad prospects and potential. Through the amalgamation of diverse technologies such as 3D printing, nanofabrication, and electronics, microfluidic devices enable the replication of in vivo environments more effectively, resulting in the development of multifunctional and fully integrated analysis systems within a single chip. Moreover, artificial intelligence (AI) with powerful computing power and data processing ability could be applied to microfluidic devices, which have the potential to decode and analyze images, as well as screen drugs intelligently. In the field of immunology, AI has been applied to the analysis of inflammatory markers and antibiotics,72 which can be extended to the analysis of complex cellular components and cytokines in tumor immunity in the future to achieve fast and accurate results.

ACKNOWLEDGMENTS

This work was supported by the Foundation of Education Department of Jilin Province (No. JJKH20210312SK) and the Science and Technology Department of Jilin Province (Nos. 20230505042ZP, 20220402079GH, and YDZJ202201ZYTS079), China.

AUTHOR DECLARATIONS

Conflict of Interest

The authors have no conflicts to disclose.

Author Contributions

Linjing Zhu: Data curation (lead); Formal analysis (lead); Investigation (lead); Software (lead); Writing – original draft (lead). Xueling Cui: Conceptualization (equal); Data curation (equal); Funding acquisition (equal); Investigation (equal); Methodology (equal); Writing – original draft (equal). Lingling Jiang: Formal analysis (equal); Methodology (equal); Resources (equal); Writing – review & editing (equal). Fang Fang: Data curation (equal); Investigation (equal). Boyang Liu: Conceptualization (lead); Data curation (lead); Funding acquisition (lead); Investigation (equal); Supervision (lead); Writing – review & editing (lead).

DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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