Parameters set-up during casting process.
\r\n\tIn this book, the different factors of liquefaction, the field methods and laboratory tests to identify a potentially liquefiable soil aim to be reviewed; in addition with history cases (ground behavior during the occurrence of an earthquake, state of stress, deformation, shear strength, flow, etc.).
\r\n\tA very important aspect of this topic is the presentation of the different constructive techniques used to ground improvement (vibrocompaction, dynamic compaction, jet grouting, chemical injection, replacement, etc.), placing special emphasis on those constructive methods used to solve problems on structures already located in areas of low relative density with liquefaction potential, where the installation of monitoring and control equipment is also required (tiltmeters, piezometers, topographic points, seismographs, pressure cells, etc.).
As a typical kind of copolymers, an ionomer is an ion containing polymer, which consists of nonionic repeat units and a small amount of ion containing repeat units [1]. In an ionomer, the nonpolar chains are grouped together and the polar ionic groups are attracted to each other. The attractions of ionic units result strongly influence the polymer properties. Due to the presence of non-ionic groups and ionic groups, the membranes made with ionomers are used to achieve special ion-exchange ability, such as letting water molecules pass through and not the metal ions. One specific ion-selective membrane is a perfluorosulfonate ionomer which is called Nafion by DuPont, and the chemical formula is shown in Figure 1. The microstructure of Nafion varies in the length of back bones (I) and branches (II) and in the nature of the ionic side group, usually sulfonate anions (III). Usually, Nafion resins can be made into films or tubes and used in the process of production of chlorine, regeneration of spent acids, separations in chemical processing, lithium-sulfur batteries, as well as used in fuel cells and electrodialysis. [2, 3, 4, 5]
\nA typical chemical formula of Nafion series [6].
In past two decades, significant attention has been directed to the field of ionic electroactive polymers (iEAPs), which generates quick and large strain due to the mass transfer effects in itself. [7] As one typical kind of iEAPs, ionic polymer-metal composites (IPMC) are very suitable for actuators and sensors with many unique advantages of large deformation, low actuating voltage, high compliance, lightness, softness, etc [8–10]. A typical IPMC has a sandwich structure (Figure 2(a)), which consists of a matrix membrane, usually Nafion membrane, and two thin metallic electrode layers on both sides of the membrane. So far, Nafion remains as the benchmark for a majority of research and development in IPMC technology [11].
\nSchematic diagram of the configuration (b) and actuation mechanism of IPMC.
The actuation mechanism of IPMC involves a variety of physical and chemical processes. When an external voltage is applied at the both sides of IPMC, it will induce an electric field gradient across the thickness direction. The ions carrying some solvent molecules will be dragged from one side to another side and results in difference in ion concentrations across the thickness direction. Then the expansion and contraction on both sides of IPMC occur, which consequently results in bending deformation of IPMC (Figure 2(b)) [12].
\nOne of the most important factors seriously affecting the performance of IPMC is the properties of Nafion, which mainly provides the backbone and ion transport medium of IPMC during the actuating process. Commercial Nafion series have a relatively poor thickness range from 50 to 250 μm, which will finally result in low output force. From the perspective of increasing the output force of IPMC, the easiest and most efficient way is to increase the thickness of the matrix membrane. So far, there are two ways to form thick Nafion: hot pressing [13] and solution casting [14], developed by Lee and Kim, respectively. The former uses hot-press technology to integrate multi-layers of commercial Nafion membranes, which easily result to delamination after actuating IPMC repeatedly [15]. The latter overcome this defect, which can obtain the ionomer with arbitrary shape and thickness. However, the work from [14] did not report more information about the micro-properties of casting ionomer. Other researchers [16, 17, 18] researched the formation of casting ionomer a lot for fuel cell and chlor-alkali application. They revealed that temperature, curving time, and the choice of additive affected microstructure of ionomer [19, 20], in which the effects of curving time and temperature on the micro-properties of casting ionomer have been clearly clarified. From the perspective of the additives, Moore et al. [21] has confirmed that casting ionomer would display worse mechanical intensity and higher solubility without the addition of the high boiling additives. Then researchers [22, 23, 24, 25] began to pay attention to the effect of additives and tried to find out that why and how additives seriously affect the morphology formation of casting ionomer. And they experimentally confirmed that the addition of the high boiling additive changed the water content, conductivity and modulus, of casting ionomer. These factors also will exert significant influences on the electromechanical responses of IPMCs based on the casting ionomer.
\nAnother method to improve the performance of IPMC is to blend conductive or nonconductive compounds into Nafion matrix. The emerging nano-scale carbonaceous materials, such as carbon nanotubes (CNTs), graphene, fullerenes, carbon nano-fibers (CNF) and carbon-filled materials and so on, have prompted the research into a new class of actuators consisted of “smart nano-materials”-carbonaceous materials [26, 27, 28, 29]. The mentioned materials just now typically have the advantages of remarkably large specific surface area together with nano-porous structure to guarantee a lot of insertion sites for electrolyte ions [30]. Due to the high strength, stiffness and excellent electrical conductivity of CNTs, CNTs-based composites are widely applied in various research fields [31, 32, 33]. CNTs are also applied to improve the performances of Nafion-based IPMCs. Sulfonated multi-walled carbon nanotube (sMWCNT), with sulfonic acid groups (-SO3H) covalently bonding to the surface of MWCNT and very weak Van der Waals’ force among the bundles, is water-soluble and possess numerous insertion sites while the mechanical properties are hardly weakened compared to the original MWCNT [34, 35, 36]. Therefore, it has been widely used in super capacitors [37, 38] and lithium ion batteries [39, 40]. Considering the working mechanism and characteristics of the Nafion-based IPMCs, sMWCNT is expected to improve the mass transfer performance and elastic modulus, and then result in improvements on the electromechanical and electrochemical performances of the IPMC actuators.
\nThe 5 wt. % Nafion® dispersions (D520) were purchased from DuPont TM. Commercially available Nafion® 117 membrane (N117), purchased from DupontTM, was used as a reference. Concentrated nitric acid (69.5 wt. %), sodium hydroxide Sodium p-aminobenzenesulfonate, NaNO2, Pd(NH3)4Cl2, NaBH4, and N2H4·H2O were purchased from Aldrich. Four additives for casting membranes were purchased from TianLi Chemical Co., including EG, DMSO, DMF and NMF. MWCNT was purchased from the Chinese Academy of Sciences Chengdu Organic Chemical Co. Ltd. All of the materials were analytically pure and used without further purification.
\nWe performed a typical solution casting process of Nafion ionomer as follows: Firstly, we separately pipetted 50 mL of 5 wt. % Nafion® dispersions into four glass vessels. Subsequently, we in sequence added EG, DMSO, DMF and NMF into four glass vessels with the fixed quantity of 5 mL respectively. And then treated the solutions by ultrasonic for 0.5 h for the purpose of uniformity. The solutions were put into oven under vacuum condition with a constant temperature of 80°C for 0.5 h. After the volatilization of solvents with low boiling point, the temperature of the oven was turned up to 120°C for further curing process. The curing time was set up for 6 h. After the oven cooled down, the glass vessels were took out and then immersed into cool water. The casting ionomer peeled off naturally 5 min later. To get the acid form of the ionomers, they were immersed in boiling 5% H2O2, 0.5 M H2SO4 solution and DI water for 1 h, respectively, and finally saved in DI water. As shown in Figure 3, the casting process mainly consists of four steps.
\nSolution casting procedure.
For the convenience, we mark the casting membranes with the additive of EG, DMSO, DMF and NMF as EG, DMSO, DMF and NMF, respectively. During the casting procedure, we only control additive as a variable. Other parameters, such as the precursors, mixed ratio and heat treatment, were employed from the literature [41], as illustrated in Table 1.
\nSamples | \nNafion® precursor | \nAdditives | \nMixed ratio | \nHeat treatment (°C, h) | \n
---|---|---|---|---|
EG | \nD 520 | \nEG | \n10:1 | \n120, 6 | \n
DMSO | \nD 520 | \nDMSO | \n10:1 | \n120, 6 | \n
DMF | \nD 520 | \nDMF | \n10:1 | \n120, 6 | \n
NMF | \nD 520 | \nNMF | \n10:1 | \n120, 6 | \n
Nafion 117a | \n— | \n— | \n— | \n— | \n
Parameters set-up during casting process.
data from Nafion 117 are tested as a contrast.
A certain amount of sMWCNT was added to 3 mL ethylene glycol (EG) and sonicated for 30 min, then the suspensions was mixed with the Nafion solution and stirred for 1 hr. in a poly(dimethylsiloxane) (PDMS, Sylgad184) container (40 × 60 × 40 mm). The mixture was evaporated at 90 and 100°C for 12 h successively to cast sMWCNT/Nafion hybrid membrane. After that, the membrane was annealed at 120°C for 1 h. The hybrid membranes were obtained with sMWCNT weight fraction of 0, 0.25 and 0.5 wt%, respectively. Another hybrid membrane with MWCNT content of 0.5 wt% was also prepared for comparison. The sizes of Nafion membranes are 60 × 40 mm × (210 ± 10) μm (length × width × thickness) under dry state. The composition of the casting solutions and membranes are summarized in Table 2.
\nMembrane type | \nCasting solution composition | \nMembrane composition | \n|||
---|---|---|---|---|---|
\n | CNT (mg) | \nNafion (aq) (g) | \nEG (g) | \nCNT (mg) | \nNafion (s) (g) | \n
Pure Nafion | \n0 | \n19.00 | \n4.5 | \n0 | \n0.9500 | \n
0.25 wt% sMWCNT | \n2.375 | \n18.95 | \n4.5 | \n2.4 | \n0.9475 | \n
0.5 wt% sMWCNT | \n4.750 | \n18.90 | \n4.5 | \n4.8 | \n0.9450 | \n
0.5 wt% MWCNT | \n4.750 | \n18.90 | \n4.5 | \n4.8 | \n0.9450 | \n
Composition of the casting solutions and membranes.
The Pd-IPMCs were fabricated via assembling a hybrid Nafion layer and two palladium electrode layers by the impregnation-reduction method, which has been described in detail in our previous report [42]. The major steps were as follows: 1) Surface roughening treatment. The membranes were roughened with a sandblasting machine, then washed with 20% ethanol solution in an ultrasonic cleaning machine and boiled in 1 M HCl and water for 30 min, successively. 2) Ion adsorption. This step was to soak the membranes in Pd(NH3)4Cl2 solution to adsorb [Pd(NH3)4]2+ via an ion-exchange process. 3) Reduction. In this step, the adsorbed [Pd(NH3)4]2+ was reduced to metallic state by strong reducing agent NaBH4 to form infiltrate electrode. 4) Further plating. In order to increase the thickness of the surface electrode and reduce the surface resistivity effectively, Pd(NH3)4Cl2 and H2NNH2 were put into the same solution simultaneously to grow Pd nano-particles above the infiltrate Pd electrode layer. 5) Ion exchange. This step was to exchange H+ into Li+ (the working ions) by soaking the IPMC strips in 2 M LiCl solution at room temperature for 24 h. The size of IPMC specimens for final characterization was 30 × 5 mm × (220 ± 10) μm (length × width × thickness) under hydrated condition.
\nWe examined the microstructure properties of the casting ionomers using AFM equipment from BRUER, USA with resonance frequency of 380 kHz and selection of tapping mode, which was performed at room temperature and humidity. Due to the fact that surface nano-morphology of the casting ionomers was affected easily by the change of room humidity, we mounted the samples on a silicon substrate. The surface and cross-section morphology of so based IPMCs were observed by SEM (VG3210677 and Hitachi SU-8010). Scanning electron microscopy (SEM) was performed at an accelerating voltage of 20.0 kV. All sample cross-sections were obtained by low-temperature cracking, being placed in liquid nitrogen for 5 min and then broken into pieces.
\nWe employed a Thermal Analysis Model DSC1 from Mettler Toledo, Switzerland to perform DSC analysis of the ionomers and so based IPMCs. The weights of test samples were at the range of 4–8 mg. Before DSC observations, the surface of each sample needed to be treated in an oven with the temperature of 80°C for 2 h. The heating rate 10°C/min and N2 flow rate 80 ml/min of DSC was selected. Thermogravimetric (TG) measurements of sMWCNT and MWCNT were carried out by using a TG analyzer (STA 449C, NETZSCH, Germany) at a heating rate of 20°C min−1 from 20 to 800°C and nitrogen flow rate of 30 mL min−1.
\nIn order to measure the WUR, the membranes with different sMWCNT weight fraction were soaked in DI water for 24 h to be fully saturated; then the membranes were weighed immediately after wiping the water on the surface with filter paper, and the mass was recorded as Mwet (g). After that, the hydrated membranes were dried at 100°C for at least 24 h until a constant mass was obtained, which was recorded as Mdry (g). The WUR (w) of each membrane can be calculated according to Eq. (1).
\nThe IEC was measured using the acid–base titration method with KOH (aq) and HCl (aq) described in detail in ref. [36] and calculated according to Eq. (2).
\nwhere VKOH is the quantity (ml) of KOH (aq), NKOH is the normality (mol) of KOH (aq) and membrane is the mass of the membrane. A minimum of three sets of experiments were performed until the percentage error was well within the experimental limits.
\nThe equivalent elastic modulus of IPMCs was measured using the free oscillation attenuation method, and the geometry of the IPMC specimens for the stiffness and electromechanical tests in this work is illustrated in Figure 4(a). During the test, the specimens were prescribed a small initial deformation firstly, and then the natural frequency f of the specimens was obtained by a fast Fourier transform of the free vibration response curve. Every specimen was tested in wet state in two minutes. The equivalent elastic modulus can be calculated via Eq. (4), which is derived from Euler-Bernoulli beam theory.
\nSchematic illustration for dimensions of IPMC strip (a) and experimental apparatus(b).
Electro-active performance was characterized by measuring the displacement and blocking force of IPMC specimens using the same test apparatus described in detail in ref. [42]. The specimen was clamped by a gold-plated copper clamp on one end firstly, while the other end is freestanding with a free length of 30 mm. Then the specimen was applied a constant potential by a Labview software and an arbitrary power supply (HM8143). The displacement and blocking force were measured with a laser displacement sensor (Keyence LK-G80) and a micro force transducer (Transducer Techniques, GSO-10) at the measuring distance of 15 mm, respectively. All the measurements were carried out in air. The current, potential, displacement and blocking force were recorded by the Lab view software simultaneously for 300 s. The experimental apparatus is shown in Figure 4(b).
\nAs shown in Figure 5, we obtain AFM topography micrographs of polymer chain conformations of the sample EG (a), DMSO (b), DMF (c), NMF (d), with Nafion 117 (e) as a reference. In each subfigure of Figure 5, we defined that bright region is high both in topography and in phase, in which high phase represents the backbone consisted of long polymer chains under tapping mode. Likewise, the gray regions in height reveal the ionic or nano-porous domains with a diameter range of 5–50 nm. We can see some significantly differences by these subfigures of Figure 5. It is interesting that backbones conformations of casting ionomers are more amorphous and loose in Figures 5(a) and 5(b). On the other side, the polymer chains together with ionic domains are more uniform and compact in Figure 5 (c), (d) and (e), which is responsible for the differences of the compatibilities between Nafion chain molecules and additives. When evaporated from casting solutions, additives assist Nafion side chain sulfonic acid groups to move along with perfluorocarbon backbones so as to form solid membranes. Meanwhile, backbone aggregations in ionomers result in the formation of more sulfonic acid group aggregations, i.e. larger size of ionic clusters, which had been revealed by Ma et al. [22].
\nAFM topography images (200 × 200 nm). Images (a), (b), (c), (d), and (e) correspond to the topography of EG, DMSO, DMF, NMF and Nafion 117, respectively.
Figure 6 shows the inner morphology of P-membrane (a), M-membrane (b, d) and S2-membrane (c, e) at different magnification levels. The two hybrid membranes presented quite rough surfaces, while the P-membrane presented a typically smooth polymer surface with several wrinkles. For the S2-membrane, sMWCNT was homogeneously dispersed in Nafion matrix without any entangled structure or obvious agglomeration, which is advantageous to improve the electrochemical and electromechanical performances of the reinforced membranes and corresponding IPMCs. It is also obvious that the dispersion of sMWCNT was much more uniform than that of MWCNT in Nafion matrix, in that the hydrophilic nature of sMWCNT facilitated their dispersion in the Nafion matrix via the hydrophilic interaction between -SO3H groups of Nafion and sMWCNT [43]. The electrode morphology of the S2-IPMC is also shown in Figure 8f. The thickness of the Pt layer on the membrane surface of each IPMC was around 11–16 μm, and the range of the surface resistance of each IPMC was around 2–5 Ω/□. As a result, the surface electrodes, without remarkable difference, had no direct correlation with the increasing content of the sMWCNT. Systematic and quantitative correlations of the surface electrode with other fundamental parameters are complex, which is beyond this work and will be discussed in our forthcoming works.
\nThe inner morphology of P-membrane (a), M-membrane (b, d) and S2-membrane (c, e) at different magnification levels, and the electrode morphology of the S2-IPMC (f).
In order to evaluate the influence of the additives on thermal behavior of the casting membranes and IPMCs, DSC was performed from 0 to 300°C. We divided the overall morphology change of the sample into two temperature points based on the temperature range. 110°C is the first temperature point (Tg), which appears an intense endothermic valley. We thought the reason was due to the glass transition of the polymeric matrix, and the other temperature point ™ is about 230°C [44]. The enthalpy change displayed crystalline region is very little inside the casting ionomers. By testing, we got the Tgs of the samples, which were 104.90, 131.37, 114.81, 109.39 and 117.58°C in sequence. Their Tg values were similar, during which the Tg of DMSO was highest. The difference of Tgs may be attributed to the morphology change of the polymer chain structure and ion clusters [45]. From the DSC results, the Tms of the samples are almost the same, which only exhibit a small difference. We considered that the curing temperature would result to form the same percentage of crystalline region inside the ionomer. DSC results of casting ionomers are shown in Figure 7 and relative parameters are summarized in Table 3.
\nThe DSC results of sample EG(a), DMSO(b), DMF(c), NMF(d) and Nafion 117(e).
Materials | \nTg/°C | \n∆H/mJ | \nTm/°C | \n∆H/mJ | \n
---|---|---|---|---|
EG | \n104.90 ± 2.1 | \n−25.14 | \n224.88 ± 2.4 | \n−7.27 | \n
DMSO | \n131.37 ± 1.6 | \n−29.06 | \n228.85 ± 3.2 | \n−1.69 | \n
DMF | \n114.81 ± 2.8 | \n−29.71 | \n233.25 ± 4.2 | \n−8.00 | \n
NMF | \n109.39 ± 2.2 | \n−30.27 | \n237.37 ± 3.2 | \n−5.59 | \n
Nafion 117 | \n117.58 ± 3.1 | \n−192.92 | \n234.00 ± 2.6 | \n−3.51 | \n
Thermal analysis (Tg,Tm) of Nafion, modified Nafion and so-based IPMCs.
From Figure 8a, it can be found that the weight of SCNT nearly decreased by 10%, while the weight of MWCNT only decreased by 5%. In the curve of MWCNT, the small weight loss around 100°C was caused by the evaporation of absorbed water molecules, while the weight loss between 220 and 400°C was most likely due to the elimination of amorphous carbon [46]. In comparison with MWCNT, the sMWCNT showed a slightly prominent weight loss, which was mainly caused by the decomposition of the grafted azobenzene-4-sulfonic acid and the elimination of amorphous carbon. The slow weight loss between 30 and 130°C was also due to the evaporation of absorbed water molecules. The weight decreased dramatically in the range from 220 to 800°C, which was caused by the decomposition of the side chains of sMWCNT and the elimination of amorphous carbon [40]. The results can also indicate that the sMWCNT would be thermally stable in the membrane casting process.
\nThe TG analysis of MWCNT and sMWCNT(a), the P-membrane, S2-membrane and M-membrane(b).
The TG curves of the S2-membrane and M-membrane shown in Figure 8b, with the same trend, indicate that the hybrid membranes are thermally stable up to ca. 300°C, which is the same as that of the P-membrane. The similar curves were also obtained by Lage [47] and Almeida [48], respectively. The gradual weight loss in the range between 30 and 300°C was mainly due to the evaporation of water molecules. The thermal degradation of the membranes occurred in three stages: the initial stage between 300 and 400°C was due to the desulfonation process of -SO3H groups, while the second stage between 400 and 480°C was caused by the decomposition of the branch chain from the polymer backbone, and the final stage between 480 and 550°C was related to the decomposition of PTFE (polytetrafluoroethylene) chain. It can be concluded that the hybrid membranes had the same thermal stability as that of the P-membrane.
\nAccording to vehicle mechanisms and Grotthus ‘hopping’ theory, water-uptake ratio (WUR) and ionic exchange capacity (IEC) are important factors that strongly affect the hydrated cation migration in Nafion membranes and in terms of mechanical strength and actuation performance of the resulting IPMCs [49, 50]. The water contents of the casting membranes are summarized in Figure 9. Evidently, EG and DMSO have higher water contents than that of the Nafion 117 in fully hydrated states. The water contents follow the sequence: EG > DMSO > Nafion 117 > DMF > NMF.
\nWater content of the samples.
These results show that the additives exert an important effect on the conformational formation. When the ionomer was absorbed enough water molecules, the conformation of ionic clusters will present different morphologies. The conformation formation of ionomer is very complex due to the interaction between polymer backbone and ionic clusters. When solvents were heated and evaporated out of casting solutions, the side chains of ionomer will curve and shrink to form solid ionomers. During this process, the ionic aggregation occurs as well. Generally, the water content of ionomer is proportional to the size of ionic aggregations [45]. From Figure 8, the results confirmed that the additive exerted its impact on the water content of the casting ionomer, which was similar to the results reported by the reference [22].
\nThe IEC of ionomer decides by the quantity of ionic groups in fixed volume of ionomer, which is consistent to the number of H+ in the ionomer. Usually, the increase of the number of sulfonate will result to the increase of IPMCs performance. Figure 4 shows IECs of samples. As shown in Table 4, the used additives lead to the differences of the IECs, of which the IEC of Nafion 117 is highest.
\nSamples | \nIon-exchange capacity (meq/g) | \n
---|---|
EG | \n953 ± 14 | \n
DMSO | \n978 ± 22 | \n
DMF | \n996 ± 10 | \n
NMF | \n941 ± 11 | \n
Nafion 117 | \n1104 ± 16 | \n
Ion-exchange capacity of ionomer samples.
CNT content | \nWUR (%) | \nIEC(meq/g) | \n
---|---|---|
0% | \n22.74 | \n0.79 | \n
0.25% sMWCNT | \n23.54 | \n0.82 | \n
0.5% sMWCNT | \n27.06 | \n0.93 | \n
0.5% MWCNT | \n19.44 | \n0.84 | \n
Properties of the membranes.
The WUR and IEC of the membranes with different CNT content are summarized in Table 5. The WUR increased as the content of sMWCNT in the polymer matrix increased. The WUR of the S2-membrane was nearly increased by 20% with comparison to that of the P-membrane. On the contrary, there was a sharp decrease in WUR of the M-membrane (decreased by 15%), which is consistent with other Nafion-nano-filler systems like MWNT-Nafion [51] and graphene-Nafion [33]. It has been proposed that MWCNT is a hydrophobic particle [51], the substitution of Nafion by MWCNT would lead to a dramatical decrease in water absorption ability of the membrane. Even so, great changes in its hydrophobicity would occur [30] when MWCNT is subjected to chemical modification of MWCNT, like grafting and coating. In this research, the hydrophilic -SO3H groups were grafted onto the surface of MWCNT, which provided sMWCNT with the sites of hydrogen bonding with water. Therefore, there was a significant increase in the water absorption capacity of all the sMWCNT/Nafion membranes than that of the M-membrane. It can also be seen that the IEC increased slightly with the content of sMWCNT increasing in the polymer matrix, which is attributed to the great proton exchange ability of -SO3H groups. In addition, the increase in WUR and IEC of the sMWCNT/Nafion membranes maybe due to the sMWCNT increasing the size of the ion clusters and the number of exchange sites for each cluster [52].
\nFigure 10 represents the deformations of the EG, DMSO, DMF, NMF, and Nafion 117-based IPMC actuators as a function of time at 2.0 V DC voltages, the tip displacements of which show 4.02, 3.22, 3.17, 1.1 and 6.9 mm, respectively. Nafion-based IPMC exhibits a highest tip displacement. And EG-based IPMC has a larger tip displacement than other samples. This reason is attributed to the higher water content of EG-based IPMC than other samples.
\nThe deformations of the EG, DMSO, DMF, NMF, and Nafion 117-based IPMC actuators.
In order to study the dynamic response, the change histories of the deformation of the IPMCs under sinusoidal stimulation under the voltage amplitude of 1 and 2 V at an excitation frequency of 0.1 Hz were recorded and shown in Figure 11a and b, respectively. These results indicate that the deformation of the IPMCs can be controlled well using low sinusoidal voltages. Notably, the peak-to-peak (P–P) displacement increased significantly with respect to the increasing content of sMWCNT. For the S2-IPMC, the maximum P–P displacements were measured to be about 2.06 and 5.28 mm at the driving voltages of 1 and 2.0 V, respectively. In contrast, the maximum P–P displacements of the P-IPMC were 0.40 and 1.96 mm, and the maximum P–P displacements of the M-IPMC were 1.19 and 3.83 mm at the same driving voltages, respectively. The DC excitation measurements have also been carried out under DC 1 and 2 V at 0.02 Hz, respectively. The results, with the same trend to that of the dynamic response, are shown in Figure 12. The maximum displacement of the IPMCs also increased with respect to the content of sMWCNT in the Nafion matrix.
\nThe peak-to-peak (P–P) displacement of harmonic response of the IPMCs under AC 1 V (a) and AC 2 V (b) with the excitation frequency of 0.1 Hz (P: P-IPMC, S1: S1-IPMC, S2: S2-IPMC, M: M-IPMC).
The maximum displacement of step response of the IPMCs under DC 1 V (a) and DC 2 V (b) with the excitation frequency of 0.02 Hz.
It can be demonstrated that the sMWCNT reinforced IPMCs have much more excellent bending performance than P-IPMC and M-IPMC. Due to the favorable hydrophility, ion-exchange capacity and proton conductivity, sMWCNT showed a higher degree of solvated cation diffusion with comparison to MWCNT. With the incorporation of sMWCNT into Nafion matrix, the improvement in potential difference between the interface electrodes could promote the flux of cations. As a result, the incorporation of sMWCNT induced significant improvement in the deformation of the resulting IPMCs.
\nFigure 13 shows the maximum peak-to-peak displacement versus the excitation frequency of the harmonic responses under AC 2 V. Obviously, the maximum P–P displacements decreased remarkably as the excitation frequency increased, indicating an inverse relationship between the deformation and the excitation frequency. The decrease in deformation is caused by shortening the driving time of the potential as the frequency increased. Even so, the harmonic response of the S2-IPMC is much better than those of the P-IPMC and M-IPMC, and that of the SWCNT-Nafion IPMCs with the content of 14 wt% [53]. These results can also demonstrate that a trace amount of the sMWCNT can significantly improve the harmonic response and bending deformation of IPMCs. This may be due to that the reinforcing filler-sMWCNT can effectively shorten the hopping distance and reduce the negative impact of water diffusion [54].
\nThe maximum peak-to-peak displacement versus the excitation frequency of the harmonic responses under AC 2 V.
The effects of casting and blending on the performances of ionomers were analyzed, using a series of experimental tests, as well as the so based IPMCs. The ionomers were successfully obtained based on commercial Nafion® dispersion by solution casting process. The sMWCNT/Nafion membranes and crossponding IPMCs were prepared and characterized as well. The morphologies of the membranes were characterized by AFM topography. Among the casting membrane-based IPMC actuators, EG based IPMC actuator has larger deformation at 2 V DC voltage, whose electromechanical property is most close to that based on Nafion 117. And it is clearly that EG is a more preferable additive during the casting process for the enhancement of IPMC performance. Due to the improvement of water-uptake ratio, proton conductivity and elastic modulus of sMWCNT/Nafion blending membrane, a superior bending deformation and carrying capacity were observed in the sMWCNT/Nafion IPMCs.
\nOur work has confirmed that additives have great influences on the mechanical properties of the casting membranes and consequently electromechanical coupling of IPMCs. And the sMWCNT/Nafion blending membrane would be promising candidates for use in IPMC actuators. Further research works will focus on exploring more methods to improve the performance of the so based IPMCs for different application background.
\nThis work is supported by the National Natural Science Foundation of China (NO.51505369 and 51375140), the key development program of Jiangsu Province in China (NO.BE2017071), the Foundation (NO.M20133004) of Changzhou Key Laboratory of Special Robot and Intelligent Technology, the Project of International Cooperation and Exchange of Changzhou (NO.BE2017071) and the Fundamental Research Funds for the Central Universities, P.R. China. The authors gratefully acknowledge the supports.
\nCell culture is an integral tool in biomedical research. It refers to the removal of cells from tissues or organs, into an artificial in vitro environment. The cells may be directly removed from the tissue before culturing, or they may be derived from a previously established cell line [1, 2]. Among their many applications, in vitro cell culture models allow for the evaluation of the physiology and biochemistry of cells; the study of mutagenesis and carcinogenesis; and drug research and development [1, 2, 3]. Furthermore, in vitro models provide a faster and more cost-effective alternative to in vivo animal models, while also allowing researchers to control and alter the cellular microenvironment.
Breast tumors are complex systems, composed of different cell subpopulations with distinct tumorigenic capabilities within the tumor. In vitro cell culture models have been one of the basic techniques utilized in BC research. Despite the many advances in the field, there is still a need for suitable tumor models that can accurately mimic the disease. Two-dimensional (2D) culture models have been commonly used in BC studies over the years. These have provided valuable insight about the molecular mechanisms involved in the pathology of the disease, yet 2D models are not able to properly model BC complexities [4]. Similarly, animal models require specialized animal facilities, are expensive, laborious, along with the consideration of pharmaco-and toxicokinetic differences between animal and humans which can make results unreliable [5]. Hence, the development of tumor models that can mimic to some extent the complexity present in the tumor microenvironment (TME) is imperative.
The TME is heterogeneous and plays a significant role in tumor development, progression and metastasis [6]. It is composed of multiple cell types such as fibroblasts, myoepithelial and endothelial cells, infiltrated immune cells (e.g., T cells, macrophages), adipocytes and mesenchymal stem cells (MSC), along with the extracellular matrix (ECM) and soluble factors [7, 8]. These cell types are important for modeling the disease as it has been shown that tumor prognosis is not solely based on the tumorigenic cells, but also on how those cells communicate with their environment [9]. For example, cancer associated fibroblasts (CAFs) have been demonstrated to promote cancer cell aggressiveness and survival by the secretion of growth factors and cytokines and the creation of a “protective niche” against drugs [8, 10, 11]. Similarly, immune cells promote angiogenesis [12], immunosuppression, invasion and metastasis [13, 14]. Furthermore, adipocytes and MSCs have been shown to be involved in the secretion of factors related to matrix remodeling, invasion and survival of the tumor [15, 16]. Thereby, models that include multiple cell types are likely to be more mimetic of the pathology and predictive of responses in tissues. As such, custom microscale platforms have been developed to accommodate multiple cell types in spatially defined patterns and locations to enable examination of multi-cell type interactions. Such models include those related to angiogenesis and metastatic processes [17, 18, 19], and due to the lack of spatial control it would have been difficult to recreate such interactions in traditional culture platforms highlighting the applicability of custom platforms for multi-cell type interactions.
The identification of relevant parameters from the tumor microenvironment is imperative for proper assessment and predictability of efficacy of experimental therapies. For this reason, 3D cell culture systems have become more popular due to its potential to better mimic the complexity of the TME and thereby increase the physiological relevance of the study [20, 21]. This modality incorporates scaffolds and 3D cell constructs that have been shown to impact cell proliferation, morphology, signaling and drug resistance in a more physiologically relevant manner [22, 23, 24, 25].
Mimicking BC complexity is challenging, however, progress in microfabrication techniques, tissue engineering and cancer biology have paved the way to more sophisticated models with enhanced biomimetic capabilities that will help to elucidate the intricate nature of BC. In this chapter, we discuss the wide range of culture platforms employed for the generation of breast tumor models and summarize their biomimetic capabilities, advantages, disadvantages and specific applications.
The traditional cell culture methods for studying breast cancer employ two-dimensional monolayer cultures, where cells grow flat on a surface. Two-dimensional culture is still widely used, but with advances in microfabrication now surfaces can be modified with nanostructure topographies and different levels of stiffness to mimic to some extent the physical properties of the matrix surface. These topographies (e.g., roughness, surface geometry) have the capability of providing biomimetic surfaces that have been shown to modify the morphology, proliferation and signaling, among others, of cells [26]. Similarly, changes in the mechanical properties of the ECM (e.g., stiffness) are related to increasing malignant phenotype [27], cancer progression, signaling [28, 29, 30] and drug sensitivity [31]. Despite these technological advances in 2D cultures, multiple studies have shown that cell cultures in 2D felt short to mimic cell phenotypes associated with disease progress such as cell invasion, cell function and expression of pathological markers [4, 23, 32]. In some cases, utilizing 2D culture systems has resulted in the loss of essential cell signaling pathways, hence limiting the ability to fully evaluate cell–cell and cell-ECM interactions [33]. Evidence has also shown that there are inconsistencies when comparing cell morphology, receptor expression, and polarity between cells grown in 2D and the in vivo setting [34].
In order to bridge this gap in biological complexity, multiple methods employing 3D cell culture systems have emerged and continue to be steadily improving, aiming to produce the most in vivo-like structures. Essentially, 3D models can be divided into two groups: cell aggregates (spheroids) and biomaterial constructs [35]. The most basic 3D culture models use scaffolds of synthetic (e.g., polydimethylsiloxane-PDMS, polylactic acid-PLA) and natural (e.g., collagen, Matrigel®, hydrogels) biomaterials to investigate the effect of ECM properties on cancer behavior. Spheroids have been used mostly for drug screening applications since it has been demonstrated they more closely resemble the in vivo environment [36]. Growing BC cells in 3D has also revealed a more realistic drug response [21, 37], cell proliferation and morphology [38], and better representation of tumor heterotypic phenotype and TME [39, 40]. For example, single-cell RNA sequencing of breast cancer spheroids have uncovered cell clusters with specific functions (e.g., proliferation, invasion) that provide evidence of the heterotypic nature and complexity of breast tumors [41]. Figure 1 below depicts the main in vitro 2D and 3D culture modalities along with the most predominant co-culture models (discussed in the next subsection) to study cell crosstalk.
In vitro culture modalities. A) Cells can be cultured in vitro as 2D monolayers, over a 3D scaffold (synthetic or natural material), embedded into a scaffold material or as spheroid constructs. B) Yet, co-culture and multi-culture models are implemented in order to better understand tumor-stroma interactions and cross-talk. The three main co-culture modalities used are compartmentalized, conditioned media and mixed, which incorporate cells cultured in 2D monolayers, 3D scaffolds or spheroids. Created with BioRender.com.
Cancer is a heterogeneous disease and even though there have been various advances in cell culture modalities, thorough comprehension of the crosstalk between cancer and non-cancer cells is still not fully understood [42]. Co-culture and multi-culture models have been long established as appropriate tools for evaluating breast cancer heterotypic interactions in vitro [6]. Co-culture refers to the culturing of two different cell lines, while multi-culture models involve three or more different cells. Historically, co-culture models have been the predominant approach in research. However, despite their ability to identify factors mediating cancer and stromal interactions, co-culture models are deficient in incorporating microenvironment structure, dimensionality, and functional response [42]. With the hopes of bridging the gap between in vitro and in vivo studies, new research has been moving away from the study of only two cell types, to studying multi-cell type systems. This type of model permits researchers to control and evaluate the influence of each cell culture component. It also allows the study of important cell–cell heterotypic signals, which would be impossible to study with a 2-cell type model [43].
There have been an increasing number of studies looking to compare tri-culture models with the more traditional mono-culture or co-culture methods. With the intention of better understanding the bone microenvironment, Pagani et al. compared a tri-culture model of osteoblasts, osteoclasts, and endothelial cells; to single and co-cultures. The results demonstrated that the behavior of the three cell types cultured together was very different from the single or the co-culture model, in terms of proliferation, activity, and viability. These results correlate with previously established data regarding their behavior in vivo [44]. Regier et al. evaluated how increased model complexity would affect gene expression. The results demonstrated that gene expression changes based on the type of model utilized; suggesting how tumor and stromal cells would respond to microenvironments of increased complexity in vivo [42]. Loy et al. investigated the effect a tri-culture model would have on angiogenesis and compared it to simpler models. The results showed that the tri-culture model promoted cell-matrix remodeling and early expression of elastic fiber-related proteins. It also reiterated the significance of multi-culture methods since culturing with fibroblasts, endothelial cells, and smooth muscle cells was required to obtain tissues with appropriate physiological-like properties [45]. All three of these studies highlight the increasing need and importance of more complex heterotypic cultures.
Co-culture models involve a cell growing arrangement, where two or more different cells are cultured with some amount of contact between them [46]. The communication between the cells may be bi-directional or multi-dimensional, and it can happen at the macro-scale or at the micro-scale [47]. The method of choice should be dependent on what is the focus of each individual study and can be grouped in: compartmentalized, conditioned media and mixed culture.
The segregated or compartmentalized model consists of two or more physically separated cells, cultured in a shared environment [6]. This type of culture is preferred when studying paracrine interactions of cells that are not located in close proximity in tissues. Also, this method is useful to identify target cells based on soluble factor signaling since the cells individual response can be examined, facilitating the identification of factors that may play a role in tumor growth and advancement. In compartmentalized co-cultures, one cell population is seeded in the bottom of the standard well, and the other is seeded on a top insert or in an adjacent compartment. By doing this, the cell types remain separated, while still being able to exchange soluble signals in their shared environment [48]. Indirect cell culture eliminates heterotypic interactions mediated by contact between the cell types, which can be seen in direct cell culture. It also allows for cell type specific readouts, which are unachievable in direct cell culture [6]. Such method has provided evidence on genes involved behind stromal invasiveness and metastasis, and the crucial role of fibroblasts in proliferation of estrogen-dependent human breast carcinomas [6, 49, 50]. Gonzalez et al. utilized a 2D indirect co-culture method with human BC cells and human umbilical vein endothelial cells to evaluate the process behind angiogenesis; concluding that melatonin may be an alternative for preventing tumor angiogenesis [51]. While Chiovaro et al. analyzed the role of ECM proteins in bone metastasis, showing that tenascin-W promotes cancer cell migration and proliferation [52].
If multiple cells need to be examined, co-culture platforms, such as transwells, are not useful since they are limited to only two compartments. Hence, the use of customizable culture systems such as microscale devices, is warranted [6]. Our group developed compartmentalized microwell culture platforms, in which we show the contribution of multiple cell types to the sensitivity to heat therapy in tumor cells [43]. The data shown indicates that the presence of macrophages and fibroblasts had a significant protective effect against heat stress in BC cells, thus, perturbing the effectiveness of heat therapy. Others have employed multi-cell type cultures to deconvolute cell communication of metastatic breast tumors. Regier et al. developed a compartmentalized multi-culture method, utilizing BC epithelial cells, bone marrow cells, and human monocytes. The platform allowed the creation of a substantial dataset made up of cell specific gene expression patterns. This was possible by collecting data from an individual cell type, while communicating through paracrine interactions in a heterotypic culture. The study also compared tri-culture to mono-culture and co-culture, which led to the demonstration of how stromal and tumor cells respond differently based on the complexity of the microenvironment [42]. This reiterates the importance of utilizing multi-cultures versus the more traditional co-cultures. A drawback with this method is that physical contact between cells cannot be completely prevented in the long term [47]. In addition, because cell-seeding sometimes requires more than one step, the process may be considered somewhat complicated and time-consuming [6].
Conditioned media transfer utilizes two separately cultured cell populations, where one culture medium is utilized to nourish the other [48]. This type of method is simple and allows one-way signaling from effector to responder [6]. The advantage of utilizing this method is that conditioned media can be profiled for the identification of secreted soluble factor-related effects is possible [47]. Consequently, the role of signaling molecules could be tested in a specific response [6]. Also, this method is useful when the cells of interest cannot be cultured together such as studies involving tumor cells and microbes [53]. However, when employing multiple cell types, the method becomes a bit more complex since identification of the secretor and recipient cells can be complicated. Additionally, when this type of method is utilized, there is no cross-communication within the cells and it is not possible to study bi-directional signals [48]. For this reason, this type of method would not be ideal if the goal is to study multi-cell type interactions that naturally occur in the in vivo tumor environment.
In mixed cell culture, different types of cells are cultured together. Just as with conditioned media transfer, this type of method is accessible and simple. It can be done in 2D or 3D using traditional well plates [6]. If the cells are cultured together in a standard plate, the method is referred to as direct or mixed cell culture. However, if a transwell insert or adjacent compartments are utilized, the method is denoted as indirect or compartmentalized cell culture. Unlike the conditioned media method, mixed co-culture does allow for bi-directional paracrine and juxtacrine signaling, which is of great importance when studying multi-cell type interactions in breast cancer [6]. Because of the cellular arrangement, this method is also ideal for studying how cell–cell contact affects cell behavior [54]. When performing multi-cell type studies, the direct method simply requires the inclusion of the additional cell lines mixed.
Mixed co-culture experiments shed light on distinct microenvironment features based on cancer subtype; and potential mechanisms behind invasive phenotypes [55, 56]. Camp et al. compared the interaction of fibroblasts with the basal-like subtype versus the luminal subtype. The results were increased migration and expression of interleukins in the basal-like BC cell lines, which reiterates the important role of the TME in cancer progression [10]. Buess et al. also looked into evaluating the role of aspects of the TME by studying tumor-endothelial interactions and determining gene expression changes [56]. Multiple other studies have been done utilizing these culture modalities and have provided insight into further understanding the disease [6]. Yet, a disadvantage of this method is the lack of control of the spatial location of cells which can be important when examining and quantifying changes in some tumor cell behaviors such as cell migration and invasion. Also, single cell studies will require multiple cell separation steps that will make this method more time consuming and increase the number of cells needed for analysis due to cell loss during sample handling.
Despite the development and application of the aforementioned cell culture methods, thorough understanding of cancer development and progression continues to be a challenge. As shown in Figure 2, in vitro cell models are mainly categorized in 2D and 3D (as discussed before) and thus, these models become more complex as research continues to be centered on creating experimental models that can mimic cell evolution on the bench with the goal of understanding the biology of the disease and identifying key therapeutic targets. Despite the advances that came with the implementation of 3D multi-culture systems, there still remains a scarcity of models that can recreate the biological complexity of the tumor microenvironment. Biomimetics can be defined as technology that utilizes or emulates tissue function with the intention of improving human lives [57]. Effective biomimetic models need to contribute a 3D environment permissive of cell phenotypic stages while enabling multi-cell type interactions [58]. As cell culture methods continue to evolve, innovative approaches are being created with the hopes of overcoming the limitations of the more traditional methods. Table 1 summarizes the advantages, disadvantages and applications of advanced biomimetic in vitro 3D culture technologies.
Culture platforms employed in breast cancer models. A) Simple 2D platforms consist of cells cultured in flat, nano- or micro- structured substrates (left) that mimic to some extent tissue topography; or they can combine co-culture and microfluidic devices (right) to increase the complexity of the model and better resemble tumor-stroma interactions. B) In three-dimensional models, cells are culture in scaffolds and constructs that further imitate the architecture of the tumor (left). Co-culture and advanced 3D models such as microfluidics, bioprinting and organoids are capable of duplicating the TME and provide physiologically relevant insights about the disease (right). Created with BioRender.com.
Model | Advantages | Disadvantages | Application | Ref. |
---|---|---|---|---|
3D Microfluidics | Small size samples, spatial and temporal control, reduced reagent volumes, controlled gradients, high-throughput | Mechanical stress, complicated set-ups, material fabrication | Invasion, metastasis, vasculature, modeling TME | [20, 37, 59, 60] |
Bioreactors | Long term culture, effective nutrient distribution, large scale | Contamination risk, expensive, specialized equipment, low throughput, limited spatial resolution, high cell numbers needed | Metastasis, drug discovery | [61, 62, 63] |
3D bioprinting | Controlled spatial arrangement of cells and matrix, biomolecular gradients, high-throughput | Lower cell viability, material challenges, lack of standardized methods, high cell numbers needed | Migration, angiogenesis, drug discovery, modeling TME | [64, 65, 66] |
Organoids | Small size samples, retain parental tumor phenotype, can be preserved as biobanks, mimetic of tissue function | Lack of standardized methods, heterogeneous cell samples, high variability across replicates | Drug discovery, invasion, metastasis | [67, 68, 69] |
Comparison of in vitro 3D BC models.
Microfluidic platforms can be utilized to scale down the traditional culture modalities, yet they enable to customize the culture environments to examine more complex interactions [64]. This technology employs microsystems that allow the manipulation of small fluid volumes and control over the spatial location of cell clusters [70]. Its application to improve 3D cell culture models has been increasing since 2012, particularly in BC research [71]. In comparison to macroscopic culture, microfluidic cell culture models have several significant advantages that, when employed, lead towards better biomimetic models. Firstly, cells may be cultured in a spatially controlled environment by controlling fluid patterns and proximity across culture compartments [72, 73, 74, 75, 76, 77]. This technology permits the combination of multiple cell types and to control cell patterning, to recapitulate to some extent tissue observations. For example, microfluidic devices permit the study of angiogenesis while also allowing the study of endothelial migration and evaluation of cell response in co-culture [71, 78]. Also, microfluidics can implement continuous perfusion conditions, and controlled gradients, which are both characteristics that also resemble the cancerous in vivo environment more closely. Gradients are found in angiogenesis, invasion, and migration whereas perfusion is crucial in vasculature and cell extravasation as well for nutrient replenishment. Finally, microfluidic systems enable high-throughput arrays and pose lower contamination risk and reagent consumption which make them very appealing for studies with limited cell samples such as those that employ patient-derived tissues [70, 71].
Recent studies in microfluidic systems have highlighted their capability to recreate and profile some of the biological complexity of the tumor microenvironment. Such studies have revealed important information regarding the processes involved in metastasis and how the tumor microenvironment contributes. For example, single cell RNA sequencing using microfluidic devices have revealed the diversity of the breast epithelium, which sheds light about early tumorigenesis and tumor progression [79, 80]. In addition, microfluidic devices pose as an advantage to personalized medicine by aiding in the selection of appropriate pharmacologic agents. In this regard, Lanz et al. developed a 3D microfluidic device, OrganoPlate®, to be utilized for therapy selection. They showed that MDA-MB-231 (cell line isolated at MD Anderson from a pleural effusion of a 51-year old Caucasian woman) cells embedded in Matrigel® became more sensitive to the drug, thus confirming along with previous studies that drug response is tuned by the ECM. The results were promising and even though further validation is warranted, it appears to be a fine tool for pharmacologic selection and response prediction [37]. Similarly, Yildiz-Ozturk et al. studied the cytotoxicity of carnosic acid and doxorubicin on MCF-7 and MDA-MB-231 BC cell lines and demonstrated the importance of biomimicry in in vitro platforms [20]. A breast metastatic microfluidic model was developed by Kong et al. to mimic the metastasis of circulating breast cancer cells (CBCCs) to the lung and other organs. Their microfluidic device allowed the flow of CBCCs over primary cell culture chambers, which would have been impossible with static conditions. They demonstrated that the metastatic potential of these cell lines was in concordance with animal models, providing a cost-effective and time-saving alternative [81]. Bersini et al. also developed a microfluidic co-culture model made up of metastatic BC cells, and collagen gel-embedded bone marrow-derived stem cells (hBM-MSC) lined with endothelial cells to create an osteo-conditioned microenvironment and access extravasation and micrometastases to bone tissue [59]. They found that BC receptors CXCR2 and bone-secreted chemokine CXCL5 play major roles in the extravasation process. However, due to the complexity of the design, their platform is not high throughput compatible, which adds many challenges, particularly to obtain multiple replicates in a short time. Also, in general it is important to notice that most of the organ on chip microfluidic platforms focus on the metastatic stage of the disease, leaving an evident need for research focusing on the early stages of breast cancer. Yet, some efforts are being done to overcome this gap. As an example, Choi et al. developed a compartmentalized microfluidic device that enabled co-culture of tumor spheroids and normal mammary epithelial cells in close proximity to fibroblasts, with the goal of providing a model that allows researchers to closely examine the mechanistic progression of early-stage breast ductal carcinoma in situ (DCIS) [82].
Even though microfluidic devices have given the opportunity to better replicate the tumor environment, there are still some caveats to its use. Silicone-based devices have been shown to sequester small hydrophobic molecules, which can compromise the results of some studies [70], yet researchers have been addressing this by modifying the material to make it more hydrophilic and reduce molecule sequestration [60]. Also, microfluidic devices in some cases can induce mechanical stress to the cells [83], which can modulate cell responses in an unpredictable manner, and are often limited by complicated set-ups [70], which limits their broad adoption by the scientific and clinical community. As such, simpler fabrication methods and commercial availability of customizable microscale platforms is desirable to overcome such limitations.
Despite the numerous advantages of the aforementioned 3D culture methods, the duration of culture and nutrient availability can be a limitation in static cultures particularly to enable observations that occur in cells over periods of several weeks. In this case, perfusive systems, such as bioreactors, are more appropriate. A bioreactor is a canister that allows the 3D culture of cell clusters for extended periods of time. It is coupled to sensors and actuator components allowing for the controlled delivery of oxygen, nutrients and other parameters [84]. Goliwas et al. developed a perfused 3D BC surrogate model utilizing a bioreactor system that incorporated breast carcinoma epithelial cells and stromal fibroblasts into an extracellular matrix. The study demonstrated that using a bioreactor allowed for analysis of longer growth periods and a greater degree of growth when compared to solid models [85]. Bioreactors have also been utilized to study metastatic progression of breast cancer, and as potential drug development platforms for cancer treatment. Krishnan et al. utilized a compartmentalized bioreactor model, with osteoblasts and metastatic BC cells, to study the colonization of osteoblastic tissue. In their design, cultured osteoblasts were monitored over longer periods and exhibited more in vivo-like characteristics, compared to 2D cell cultures [86]. Marshall et al. developed a physiologically relevant bioreactor system that could be potentially used for pharmacologic development. Their construct was capable of supporting and perfusing larger volume, which poses as an advantage to lab-on-a-chip systems [62]. Other studies have also used bioreactors to assess drug response of BC tissue [63, 87]. Despite bioreactors being an ideal option for cultures that require long-term analysis, there are some factors that might damper their use. Membrane bioreactors may become contaminated and multilayer cell growth may cause transfer limitations [88]. Also, its complex composition and dimensionality limits their implementation in convectional labs and limits the number of experimental replicates [89].
Another technology that has emerged in recent years and that is being applied to 3D culture technology is 3D bioprinting. Its development has been possible thanks to advances in 3D printing technology, biomaterials and tissue engineering methods. Three-dimensional (3D) bioprinting consists of printing cells together with ECM components, biomaterials and bioactive factors [90]. It has been shown that bioprinting techniques can be used to generate 3D tumor models that can better resemble the TME [90, 91]. This has been achieved as bioprinting provides the ability of controlling the spatial arrangement of cells, creating biomolecular gradients and well-organized vessel-like structures (vasculature) within a micron scale resolution [92, 93]. Therefore, bioprinted tumor models are used for angiogenesis, migration and drug development and screening studies as well as TME models [65, 94]. Although 3D bioprinting is widely used in tumor research, very few studies use bioprinted models for BC. Yet, most of these studies are focused on BC metastasis and drug resistance. A study performed by Zhou et al. evaluated the interaction between triple negative breast cancer cells (TNBC) and osteoblasts to assess metastatic progression in bone. They found that osteoblasts increased VEGF secretion and therefore, enhanced the proliferation of BC cells, while osteoblast proliferation was inhibited [58]. Bioprinted BC models have also been used for drug resistance studies. Swaminathan et al. bioprinted pre-formed MDA-MB-231 spheroids along with breast epithelial cells and vascular endothelial cells and evaluated plaxitacel chemoresistance in mono and co-culture. They demonstrated that bioprinted spheroids are more resistant to plaxitacel as it has been shown before in other studies. Yet, this resistance was decreased in co-culture with vascular endothelial cells highlighting the importance of replicating the TME complexities in vitro [95]. Another study by Duan et al. examined drug resistance using 3D bioprinted constructs of BC cells and adipose-derived mesenchymal stem cells (ADMSC). They found increased chemoresistance in BC cells cultured with ADMSC in comparison to monoculture and, thus provided a model to better understand the role of ADMSC in BC progression [66]. Likewise, Campbell et al. bioprinted MCF-7 cancer cells and showed higher resistance to Tamoxifen compared to monolayer culture, providing a more biological-like behavior [66, 96]. Despite the flexibility of 3D bioprinting systems, there are some challenges that need to be overcome to ease its application. Maintaining high viability and original phenotype is an issue in some bioprinting techniques due to exposure of cells to shear stress. Therefore, close control of bioink viscosities, extrusion rates, among other parameters, is imperative [97]. Also, lack of process standardization and guidelines pose another challenge for study comparison and reproducibility.
The most recent 3D cell culture modality are organoids. These are 3D heterotypic in vitro tissue constructs, derived either from primary tissue or stem cells, that have the ability to mimic the in vivo organ [98, 99]. Historically, established cancer cell lines have been widely utilized as single cell models of the cancer disease. However, their use has several drawbacks in terms of their capability to mimic the pathology of the patient. Cell lines can undergo genetic changes, losing the genetic heterogeneity of the original tumor [100]. Organoids also possess substantial similarities to cancer cell lines 3D models (spheroids) such as cell–cell and cell-matrix interactions, gradients of nutrients, oxygen and metabolites, and can be replaced from frozen supplies with ease. They are also relatively easy to handle and can be grown in infinite quantities [101]. Yet, the main characteristic of organoids is their capability to closely resemble and retain the pathology of the parental tumor over several rounds of expansion in vitro [102, 103]. They also have shown therapeutic predictability for some drugs and can be preserved as biobanks and expanded, which allows extended incubation [98, 99]. Given the number of mutational processes involved in cancer development and progression, being able to study tumorigenesis in depth is crucial. Organoids allow for organ-specific mutations to be analyzed and their whole genomes to be sequenced. Intratumor heterogeneity can also be analyzed by growing organoids from separate sections of the same tumor [100]. Another area where organoids can play a major role is drug development. Organoids appear to be much better models for identifying and testing anticancer drugs yet in a patient specific manner. For instance, studies on single cell transcriptomics of organoids have detected differences in drug sensitivity, proving that organoids maintain tumor heterogeneity, which is considered a critical aspect of tumor models [104].
Studies with BC organoids are limited, since this modality has just started to be explored. However, they have gained more popularity in the last few years. Cheung et al. used breast carcinoma organoids to understand tumor invasiveness and metastasis. They found that the heterotypic interactions between epithelial subgroups are key to collective invasion [105]. Broutier et al. was able to demonstrate that liver cancer derived organoids could be utilized for drug screening testing and identification of potential pharmacologic targets [68]. Sachs et al. demonstrated the biomimetic nature of organoids by demonstrating the reflecting histopathology of in vivo tumors, as well as HER2 and hormone receptor status. Moreover, drug screening tests were consistent with patient response [69]. These promising findings suggest that organoids will be an ideal alternative model for cancer research. Nonetheless, successfully cultivating patient organoids from biopsy specimens is still a challenge mainly due to low cell recovery and heterogeneity of collected samples, and limited availability of standardized methods [103, 105].
Breast cancer is an evolutionary disease and cell culture modalities should continue to evolve concomitantly. Even though traditional 2D co-culture methods have provided valuable insights on disease development and progression, there is a need for more heterotypic biomimetic models that can replicate the tumor environment more closely. Some of the consequences of limited biomimetic models has been the large number of investigational drugs that never make it past clinical trials and the lack of clear understanding on the foundations of breast cancer malignant transformation. Aside from the need for more biomimetic models, most of the current research has been focused on the metastatic stage of the disease. Even though understanding tumor progression and the role of its microenvironment is of utmost importance, understanding the early and localized stages of breast cancer is also imperative. Not having an explicit grasp on the biological processes behind progression from early stage to invasive to metastasis has hindered the ability to make a predictive diagnosis in patients with early disease that have a greater probability of invasive cancer progression. Hence, designing new targeted pharmacologic agents becomes a challenge. Despite the continuous development of innovative cell culture modalities, there are still many unanswered questions. However, the hope is that with the emergence of the new methods (bioreactors, organoids, etc.), many of these questions can be interrogated in a controlled and user friendly cell culture environment.
This publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number SC1 GM131967 and partial support from the Puerto Rico Idea Network for Biomedical Research Excellence (PR-INBRE) under Grant No. P20-GM103475.
The authors declare no conflict of interest.
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