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176 Xuan Mu and Yu Shrike Zhang
The strategy of mechanical deformation has been employed in another microfluidic
device with a redesigned shape of physical constraints (Fig. 7A–C) [161]. In this device,
an array of curved tunnels is used to enhance the magnitude of deformation and to extend
the deformation time, thus improving the efficiency of delivery for primary T cells. The
delivery efficiency of siRNAs and 70-kDa dextran is approximately 90% and 80%,
respectively. This approach has been exploited for knock-in editing of the PD-1 gene
of human primary T cells to insert a HindIII restriction enzyme cleavage site. PD-1 is
a transmembrane receptor of T cells for negatively regulate immune activation; the ablation of PD-1 has been found to significantly improve in vivo antitumor efficacy of T cell
therapies [164,165]. The membrane deformation-based transfection has shown a successful reduction of the percentage of cells with high PD-1 expression, thus promising for
producing therapeutic T cells for cancer immunotherapy.
Bulky electroporation is one of the most widely used approaches for transfecting cells
yet often suffers from low efficiency and a tendency to damage cells [166,167]. These
issues of bulky electroporation can be circumvented by 2D nanochannel-based electroporation (NEP). However, the 2D configuration restricts the throughput, leading to only
about 200 cells that can be transfected per chip [168,169]. A 3D NEP-positive electrophoresis (pDEP) chip has been developed to extend the throughput of transfection to
0.6–1 million cells per chip (Fig. 7D) [170]. The significant improvement is due to
the high density of nanochannels approximately 40,000 cm
2
, as well as the use of pDEP
to precisely position single cells close to the outputs of nanochannels. Thus, this device
demonstrates a marked capability to deliver plasmids to a large number of cells at the
single-cell resolution. Another benefit of 3D nanochannel-based electroporation is the
uniformity of the delivery. The single-cell deviation of propidium iodide (PI) intensity
is only approximately 1%, much smaller than that by bulky electroporation (around 50%).
The 3D nanochannel-based electroporation has also been exploited to transfect a specific
natural killer cell line, NK-92, with CAR plasmids. The efficiency of CAR plasmids
delivery is estimated from the GFP reporter gene. The 3D nanochannel-based electroporation leads to a much higher delivery efficiency of 74% than 28% of the bulky one.
Also, the 3D nanochannel-based electroporation leads to higher cell viability (around
90%) than that (around 70%) of the bulky one. These results imply that the 3D
nanochannel-based electroporation is particularly promising for producing a large number of therapeutic T cells efficiently.
The immune response of T cells can be enhanced via fusing with antigen-presenting
cells (APC) by a time-resolved and high-throughput microfluidic approach [171]. The
microfluidic chip has 4200 individual wells arranged in a hexagonal pattern. Single
murine CD8+ T cells (hybridoma B3Z) are isolated in these wells by sedimentation
and size-exclusion. Up to 90% of wells are occupied by a single T cell. A monolayer
of the mouse fibroblast cell line K89 is then covered on the array of cell-laden wells
for synchronized contact. B3Z has a TCR specific to a peptide segment in the H-2K
b
177Tumor-on-a-chip devices for cancer immunotherapy
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Fig. 7 On-chip production of therapeutic cells. (A) Schematic and scanning electron microscopy (SEM)
images of the microfluidic chip with an array of curved tunnels. (B) Deformation of a cell during passing
the curved tunnel. (C) Three types of cells are codelivered with siRNA (green) and dextran (blue).
(D) Schematic of the multilayer 3D DEP-NEP platform. pDEP precisely positions cells close to the
nanochannel outputs. NEP enables the direct delivery to the positioned cells. (E) Schematic and images
of the parallel microchannels. The cells are ruptured to generate nanovesicles probably due to the elongated shape and the abrupt change of pressure at the end of the channels. (F) (i) Schematic of the integrated microfluidic chip for engineering and producing immunogenic exosomes on-demand.
(ii) Fluorescence image of the flow of immunomagnetic beads and the mixing with cell culture media.
(iii) Isolation of exosomes in serpentine channels. (iv) Leukocytes are cultured on chips. (v) SEM image
(Continued)
178 Xuan Mu and Yu Shrike Zhang
major histocompatibility complex (MHC) class I that is expressed by K89. Thus, the pair
of B3Z and K89 can be used to investigate the stimulation of T cell immunity [172]. The
response of the B3Z T cell to the APC K89 is monitored by Ca
dose-dependent manner. Furthermore, the time-resolved Ca
2+
2+
signals and shows a
signal spikes demonstrate
a considerable range of response profiles of single B3Z T cells, which provides key
insights into the heterogeneity of T cell stimulation [173].
5.2 Exosomes
Exosomes are nanovesicles or nanoscale compartments with a lipid bilayer in the diameter of 30–150 nm, secreted by cells for critical intercellular communications. Exosomes
contain a range of biomolecules, such as cytosolic proteins, signal transduction proteins,
nucleic acids, and metabolic enzymes [174]. In particular, some exosomes are immunogenic, which contains the MHC class I and II and other molecules that can mediate
immune responses [175,176]. For example, dendritic cell-derived exosomes, loaded with
MHC I/II restricted cancer antigens, can promote T cell- and natural killer cell-based
immunotherapy for nonsmall cell lung cancer [177–179]. Thus, exosomes have been recognized as a novel nanodelivery system for cancer immunotherapy [180,181]. In comparison to lipid- or silica-based delivery systems, exosomes are generated from living,
tissue- and patient-specific cells, highly biocompatibility, as well as flexibility in loading
desired content, thus particularly useful for therapeutic applications. However, several
hurdles impede the broad utility of engineered exosomes, including low yield, heterogeneous content, and time-consuming operation [182]. Microfluidic techniques have
been exploited to address these hurdles for engineering exosomes.
Fig. 7, cont’d of the engineered exosomes. (G) Three-step loading and pairing of cells. From left to
right, cells are first loaded into the smaller capture cup at the backside of the weir; and then the
direction of the flow is reversed, and the cells are transferred to the larger trap at the front of the
weir; the second cell type is loaded from top to down and make close contact with the first type
of cells. (A–C: Reproduced with permission from Han X, Liu Z, Ma Y, Zhang K, Qin L. Cas9
ribonucleoprotein delivery via microfluidic cell-deformation chip for human T-cell genome editing and
immunotherapy. Adv Biosyst 2017;1(1–2):1600007. Copyright 2017 John Wiley and Sons. D:
Reproduced with permission from Chang L, Gallego-Perez D, Zhao X, Bertani P, Yang Z, Chiang C-L,
Malkoc V, Shi J, Sen CK, Odonnell L. Dielectrophoresis-assisted 3D nanoelectroporation for non-viral cell
transfection in adoptive immunotherapy. Lab Chip 2015;15(15):3147– 3153. Copyright 2015 Royal
Society of Chemistry. E: Reproduced with permission from Jo W, Jeong D, Kim J, Cho S, Jang SC, Han C,
Kang JY, Gho YS, Park J. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA
carriers. Lab Chip 2014;14(7):1261–1269. Copyright 2014 Royal Society of Chemistry. F: Reproduced
with permission from Zhao Z, McGill J, Gamero-Kubota P, He M. Microfluidic on-demand engineering
of exosomes towards cancer immunotherapy. Lab Chip 2019;19(10):1877–1886. Copyright 2019 Royal
Society of Chemistry. G: Reproduced with permission from Skelley AM, Kirak O, Suh H, Jaenisch R,
Voldman J. Microfluidic control of cell pairing and fusion. Nat Methods 2009;6(2):147–152. Copyright
2009 Springer Nature.)
Microfluidic techniques have been used to fabricate exosome-like nanovesicles from
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living embryonic stem cells (Fig. 7E) [183]. The embryonic cells are perfused through
narrow slits (in a width of 4 μm) at a high speed of 43.3 m s
1
within microfluidic channels; the cells undergo an abrupt pressure change and dramatic elongation through the
slits, thus leading to collapse into nanovesicles. These nanovesicles maintain the same
content, such as RNAs, and the same enclosed lipid-bilayer membrane, as the original
embryonic cell. Of note, membrane proteins are well preserved in the generated nanovesicles, which have an important function for endocytosis [184,185]. In contrast, other
RNA vesicles, prepared from lipid assembly [63,186], often lack these intact membrane
proteins and usually require additional operations to tether specific molecules on the
membrane.
Furthermore, the surface properties and shape of the slits affect the size and distribution
of the exosome-like nanovesicles [183]. The surface roughness is expected to increase friction force and the shear stress imposed on the cells. This argument is proved by modifying
polytetrafluoroethylene (PTFE) on the slits. The PTFE coating is believed to reduce the
friction force, and indeed, reduces the number of generated nanovesicles. Besides the surface property, the length of slits affects the diameter of the generated nanovesicles. As the
length increases from 100 to 400 μm, the diameter decreases from 332 to 90 nm. The
reduced diameter in the longer slits is probably due to the extended time of cells exposed
to the shear stress. The utility of these exosome-like nanovesicles has been proved to transfect other cells with the RNAs of original stem cells, such as Oct 3/4 and Nanog.
To further increase the generation efficiency of nanovesicles, another microfluidic
chip with silicon nitride blades (500-nm-thick) has been developed [187]. The silicon
nitride (SixNy) blade on the edge of grooved channels is made by growing a 100nm-thick silicon oxide layer and SixNy, followed by inductively coupled plasma
reaction-ion-etching (RIE). The cells flowing inside the channels are frequently sliced
by the silicon nitride blade, leading to cell fragments. These cell fragments assemble into
enclosed exosome-like nanovesicles in the diameter from 100 to 300 nm, due to minimization of the free energy of lipid bilayers. Largely due to the novel blade design,
the production of these nanovesicles from one million cells is up to around
1.5 10
10
, almost 100 times higher than that by natural secretion [188]. In addition,
the ratio of intact vesicles to the original cells is also improved. By using fluorescent beads,
around 30% cytoplasm of original cells is retained in the vesicles, higher than previous
methods based on only shear forces [183,189].
The exosomes, rapidly generated by an automated and highly integrated microfluidic
approach, have shown therapeutic effects (Fig. 7F) [190]. The microfluidic chip is made
by 3D printed mold and PDMS casting, containing multiple functional units connected
with channels, including an on-line cell culture chamber, medium collection channels,
exosome isolation serpentine channels, and on-demand engineering chamber. Human
blood leukocytes, cultured in the chamber, spontaneously generate native exosomes that
179Tumor-on-a-chip devices for cancer immunotherapy
180 Xuan Mu and Yu Shrike Zhang
are collected in the downstream channels and mixed with magnetic beads. The beads
were modified with tumor antigenic peptides to isolate MHC I-positive exosomes. Subsequently, a photocleavable linker between the beads and the antigenic peptides enables a
highly efficient release (approximately 95%) of engineered exosomes from the magnetic
beads. The magnetic bead may hinder the update of exosomes and thus should be
removed for therapeutic applications. The utility of glycoprotein 100-modified
exosomes has been demonstrated in the uptake and cytokine secretion of dendritic
monocytes. The uptake of engineered exosomes is about two folds as that of native ones;
the engineered exosomes also increases the expression of interferon-γ (IFN-γ) by two
folds, in comparison to native ones. Furthermore, the engineered exosomes have been
found to stimulate the ex vivo production of CD8 + T cells derived from the spleen of
transgenic mice. This study shows a rapid, integrated, and multifunctional microfluidic
device that promises the engineered exosomes for cancer immunotherapy.
5.3 Fused hybrid cells
The strategy of fusing immune cells, especially dendritic cells (DCs), with cancer cells has
been exploited for making cancer vaccine for cancer immunotherapy [191,192].DC
plays a crucial role in cancer immunotherapy, as it links the innate and the adaptive
immune responses and contains costimulatory and adhesion molecules necessary to
induce T-cell immunity [193]. For stimulating specific antitumor response for clinical
therapeutics [194], DCs can be fused with cancer cells to load specific cancer antigens
by a series of approaches, including the use of polyethylene glycol (PEG) for dehydration
[195–198] and electroporation [199,200]. The efficiency of cell fusion largely lies in the
pairing of cells. The lack of close contact between cells is frequently encountered in conventional methods, lowering the overall efficiency of cell fusion [199].
Microfluidics has microstructures with a size similar to cells, which is useful to precisely pair single cells. A dense array of weirs with the passive hydrodynamic flow is one
particular method for pairing and fusing cells (Fig. 7G) [199]. Two single cells of different
types in a large population have been paired with close contact and fused by three-step
perfusion of cell suspensions. This method demonstrates an overall fusion efficiency of
approximately 50% and has been applied to multiple types of cells, including cancer cells
(myeloma), immune cells (B cells), and mouse embryonic stem cells (mESCs) and embryonic fibroblasts (mEFs). Moreover, the optical transparency of the microfluidic chip
allows the real-time monitoring of the fusion process, providing detailed and dynamic
information for optimization and analysis.
The on-chip integration of fusing and culture functions may facilitate the characterization and monitoring of fusion efficacy and some downstream operations.
A microfluidic chip has a dual-chamber design [201], which allows the convenient transfer of cells from fusing units to culture ones. One chamber at the top of the channel is
small (approximately 40 μm in diameter) and is coated with electrodes for cell fusion. The
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other chamber on the bottom of the channel has no electrodes and is large (approximately
150 μm in diameter) for culturing fused cells. To transfer fused cells from the small chamber to the big one is high-throughput and straightforward, achieved by merely flipping
the microfluidic chip. The fused cells demonstrate the growth and the formation of colonies within 72 h. Based on hydrodynamic trapping and electrofusion, a cancer cell line,
A549, and an immune cell line, THP-1, are fused on the microfluidic chips with the
pairing efficiency of 68% and the fusion rate of approximately 64% [202].
6. Screening immune cells
The screening of immunes cells is often a necessary step in monitoring the efficacy
of cancer immunotherapy. T cells, either native or engineered, are inherently and highly
diverse [203]. The highly complex repertoire of T cells poses a daunting challenge in
identifying a small portion of T cells that are therapeutic. This challenge motivates the
adoption of advanced techniques, such as microfluidics, which holds great promise for
making the screening process accurate, rapid, and high-throughput. Two categories of
microfluidic approaches have been frequently used to screen and sort immune cells,
including two-phase droplets and hydrodynamic phenomena. While these microfluidic
techniques may not be tumor-on-chips by nature, they are closely related and can be
possibly combined as functional units in the future.
181Tumor-on-a-chip devices for cancer immunotherapy
6.1 Droplet-based approaches
The microfluidic droplet-based approach can separate individual cells into tiny volumes
(i.e., picoliter droplets) that can act as a bioreactor for a range of biochemical analyses,
such as single cell-sequencing [204,205]. This capability is desired to dissect T cell heterogeneity at the single-cell level [206,207], and to identify candidate T cells for cancer
immunotherapy [208–210].
One microfluidic droplet-based approach has been used for functional screening and
real-time monitoring of the activation of exemplary single TCR T cells upon the interaction with target tumor cells (Fig. 8A) [208]. The exemplary T cell expresses either
MART-1- or NY-ESO-1-specific TCR. The NY-ESO-1 TCR can recognize the
MHC I complex of the target myelogenous leukemia cells, K562. Thus, only the
T cell with NY-ESO-1-specific TCR can be activated by recognizing K562 cells.
The activation leads to the signal of enhanced green fluorescent protein (eGFP) for imaging. In contrast, the T cell with MART-1 cannot be activated by K562 cells, due to the
lack of the specific TCR, and thus, is a negative control. The droplets are then perfused
into another chip to form an inverted floating array [211]. Due to buoyance in a denser
carrier oil, the aqueous droplets enter the well (140 μm in diameter and 130 μmin
182 Xuan Mu and Yu Shrike Zhang
height) at the ceiling of microchannels [208]. This array enables the observation of the
kinetics of T cell activation in a high-throughput manner. Also, the droplets in the inverted
floating array can be sorted and retrieved on demand [208]. A pulse laser beam is used to
heat the carrier oil to generate air bubbles surrounding a cell-laden droplet; the bubbles
occupy the space of the trapping wells and expels the aqueous droplet away from the
well [212]. Thus, the activated T cell or the one of interest can be removed from the
well. The use of laser gives rise to operational flexibility; the droplets in any position in
the array can be removed and sorted. The downstream molecular analysis of the sorted
droplet via single-cell RT-PCR confirms the TCR of T cells with 100% specificity [211].
Another microfluidic chip was used to isolate and analyze magnetic particle-labeled
CD8+ T cells from patient’s peripheral blood [210]. The nanoparticles are
multifunctional, which are labeled with tetramerized MHC, from a large library
4
(> 10
), for identifying the immune response of T cells; it is also modified with specific
ssDNA primers for identifying the antigen specificity of the MHC. The microfluidic chip
has a unit of deterministic lateral displacement that separates nanoparticle-bound T cells
from unbonded nanoparticles [213,214]. The nanoparticle-bound cells are mixed with
lysis and RT-PCR reagents, followed by encapsulation in the water-in-oil droplets
for gene sequencing. In comparison to a standard fluorescence-activated cell sorting
(FACS) [215], the microfluidics-based approach identifies more TCR genes and uses
only one-tenth of cells (0.1 million). This microfluidic approach is also envisioned to
be deployable in a point-of-care setting by optimizing the capture and isolation of
T cells from the blood.
Cancer antigen-specific antibody has proven useful to treat lymphomas [216–218].
The concentration and affinity of the antibody have been known to correlate to the
immune response and therapeutic efficacy [219]. However, the kinetic secretion of antibodies in a large population of cells, such as B cells, is challenging to be investigated in a
quantitative, sensitive, and time-resolved manner. It is mainly because conventional
techniques suffer from either a small number of sampled cells or only endpoint results
that do not reflect the dynamic expression of the immune response. A microfluidic
droplet-based approach is promising to break these technical barriers and shed light
on the fundamental immunity mechanisms and new strategies for cancer immunotherapy
(Fig. 8B) [209,220]. This microfluidic device, termed DropMap, encapsulates single
antibody-secreted cells in tens of thousands of 40-pL droplets that form a 2D array.
The droplets are immobilized by physical confinement, thus showing fixed coordinates
in the array for long-term observation. The secreted antibody is detected by forming an
immune complexity with antigen-coated nanoparticles and fluorescence-labeled secondary antibody. The nanoparticles, under an external magnetic field, assemble into a line
that shows fluorescence associated with the amount of the secreted antibody. In comparison to a single microbead in a previous study [221], the use of multiple nanoparticles
within the droplet provides higher binding capacity and kinetics, benefiting assay
Fig. 8 On-chip screening of immune cells. (A) Schematic of several steps in the functional screening of
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T cells, including the mix of T cells and tumor cells, encapsulation in a droplet, formation of an invert
floating array, observation of T cell activation, sorting cells of interest, and downstream molecular analysis. (B) Image of the encapsulation of cells and reagents in single droplets in a microfluidic chip. Red
arrows indicate single cells. (C) Under an external magnetic field (B), the magnetic nanoparticles form a
beadline, parallel to the direction of the B. In the absence of target cytokines secreted by the cells, no
binding occurs on the magnetic beadline and the fluorescence remains homogeneous within the
droplet. (D) In the presence of the target cytokine, the immune complex is formed on the magnetic
beadline and the fluorescence becomes focused on the beadline. (E) Schematic and simulation results
of the enrichment of immune cells using siphoning structures. (F) Fluorescence beads are focused and
enriched after passing three siphoning structures that are shown in the SEM images. (A: Reproduced
with permission from Segaliny AI, Li G, Kong L, Ren C, Chen X, Wang JK, Baltimore D, Wu G, Zhao W. Functional TCR T cell screening using single-cell droplet microfluidics. Lab Chip 2018;18(24):3733–3749. Copyright 2018 Royal Society of Chemistry. B–D: Reproduced with permission from Bounab Y, Eyer K, Dixneuf S,
Rybczynska M, Chauvel C, Mistretta M, Tran T, Aymerich N, Chenon G, Llitjos JF. Dynamic single-cell
phenotyping of immune cells using the microfluidic platform DropMap. Nat Protoc 2020;15
(9):2920–2955. Copyright 2020 Springer Nature. E and F: Reproduced with permission from Martel JM,
Smith KC, Dlamini M, Pletcher K, Yang J, Karabacak M, Haber DA, Kapur R, Toner M. Continuous flow microfluidic bioparticle concentrator. Sci Rep 2015;5:11300. Creative Commons license.)
184 Xuan Mu and Yu Shrike Zhang
performance. DropMap determines the secretion rate ranging from around 4 to 10,000
antibodies per second, consistent with previous results [222,223].
6.2 Hydrodynamics-based approaches
Microfluidics also provides a hydrodynamic way for screening immune cells, which relies
on the intrinsic properties of liquid flow and cells, thus more convenient to operate than
others relying on microstructures or labeling [224]. The hydrodynamic approach is often
used to isolate immune cells from patients’ blood, followed by the downstream analysis of
the immune response for cancer immunotherapy. Because immune cells are usually larger
than red blood cells, the two cells may experience different directions and magnitudes of
hydrodynamic forces in spiral microfluidic channels. The unbalanced forces provide a
basis to gradually position cells at distinct locations within the channel, where the forces
become balanced [225]. Larger immune cells migrate toward the inner wall of the spiral
channel, while smaller red blood cells move toward the outer wall. The utility of this
approach is demonstrated in the isolation of immune cells from airway secretion
[226]. Approximately 94% polymorphonuclear leukocytes (PMNs) from 50-μL airway
secretion can be recovered.
Besides isolation, the hydrodynamic force can be used to enrich the immune cells
(Fig. 8C) [227]. The enrichment occurs under mild flow conditions, thus being more
cytocompatible, compared with other enriching methods, such as filtration and centrifugation. The immune cells are positioned near one side of the microfluidic channel,
while the liquid is removed by continuously siphoning structures at the other side. After
flowing the microfluidic enrichment chip at 4 mL min
by approximately 400 folds, and the percentage of recovered cells is more than 95%. The
enrichment of immune cells is associated with the geometric design of the microfluidic
chips, such as the magnitude of siphoning and the number of repeated units, thus providing tunability to various cells by revising the design. The density difference between
immune cells (1.07 g mL
1
of lymphocyte) and red blood cells (1.11 g mL1) underlies
another hydrodynamic principle for isolating immune cells [228]. This microfluidic chip,
combined with a standard density-gradient medium, Ficoll solution, allows approximately 95% recovery of peripheral blood mononuclear cells, as well as in situ fluorescence
analysis with four-color immunostaining.
1
, the immune cells are enriched
7. Conclusion
In this chapter, we introduced the powerful and versatile utility of microfluidics,
especially tumor-on-a-chip models, for multiple aspects of cancer immunotherapy, from
recapitulating the tumor microenvironment and predicting the therapeutic efficacy to
peripheral applications such as screening and producing immune cells. Microfluidics
provides versatile engineering tools to manipulate cells and to mimic the in vivo micro-
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environment, which enhances the efficiency of drug screening and prediction of therapeutic efficacy, especially in the context of personalized cancer immunotherapy. As
discussed in this chapter, some engineering approaches seem imperative in dissecting
and elucidating the sophisticated immune-cancer interactions, which often cannot be
realized by other techniques but microfluidics. The potential of microfluidics-based
approaches is enormous for cancer immunotherapy; however, to further adapt tumoron-a-chip techniques for characterizing, treating, and monitoring cancer remains a
daunting challenge. To address this challenge requires a continuous effort of both immunologists and bioengineers, as well as a tight collaboration between different disciplines.
For example, the importance of including immune cells in the tumor-on-chips cannot be
over-emphasized [35]. The immune cells play important roles not only in tissue homeo-
stasis and regeneration but also in immunotherapy. We envision a rosy future for the
translational research of the bioengineered tumor-on-a-chip models and approaches.
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185Tumor-on-a-chip devices for cancer immunotherapy
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