Comparison of in vitro 3D BC models.
\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.).
Control of magnetization with the help of femtosecond laser pulses is a hot topic in fundamental science [1–5]. Understanding ultrafast magnetization dynamics on an ultrashort timescale promises to enable technologies based on the quantum-level interplay of nonlinear optics and magnetism. All-optical control of the magnetism in novel magnetic materials is a particularly important issue for further development of faster magnetic information storage/processing and spintronic nanodevices. The thermal effect limits the application of the technology of heat-assisted magnetic recording due to relatively long cooling time (~1 ns) [6]. One of the solutions to this problem can be all-optical nonthermal control of the magnetization. For fundamental research, hybrid structures give the unique possibility to engineer high-quality two-dimensional interfaces and create phenomena which do not exist in a bulk material. On the contrary, new functionalities may emerge from the coexistence of two materials with complementary properties, such as magnetism and ferroelectricity, metallic and dielectric, antiferromagnetic and ferromagnetic, etc.
\nAn interesting combination is formed by a metallic ferromagnetic ultrathin film on top of a dielectric ferrimagnet, based on yttrium iron garnet (YIG) with different substitutions. The functionality of YIG systems has been shown to be very broad, with examples such as the excitation of surface plasmons [7], the propagation of nonlinear spin-waves [8, 9], Bose-Einstein condensation of a magnon gas [10], high-temperature photomagnetism [11], the observation of the inverse Faraday effect induced by an ultrafast laser pulse [12–14], and many others. A combination of a metal layer on a garnet system may create the possibility to modify different properties. Recently, it was reported that ion beam sputtered Fe films on a 100 nm-thick YIG layer possess a perpendicular magnetic anisotropy [15]. In the thickness range between 5 and 10 nm, the stripe domain structure of YIG was transferred into the Fe films due to the presence of strong interlayer exchange coupling [15]. Static and dynamic properties were also investigated for a 30-nm permalloy film on a 0.5 µm (YBiLu)3(FeAl)5O12 layer that is characterized by a perpendicular anisotropy [16]. A strong direct exchange coupling is revealed via the formation of enlarged closure domains with a preferred orientation at the interface between the permalloy film and the garnet layer. As a result, the domain pattern of such a heterostructure shows an increased zero-field stripe period in comparison to the parent garnet layer [16]. The magnetization reversal process and magnetic domain structure were the focus points of these studies. YIG films with iron partially substituted with Co2+ and Co3+ ions [17] show interesting magnetic properties, such as several spin-reorientation phase transitions in a temperature range of 20–300 K [18], and both quasistatic [19] and ultrafast [20] light-induced changes in magnetic anisotropy. Light pulses excite large-angle magnetization precession in such garnets, the phase and the amplitude of the precession being determined by the polarization of the light. If coupled with a nanostructure ferromagnetic (metallic) overlayer, such photomagnetic effects in the garnet may also be transferred to the overlayer, thus creating new possibilities for ultrafast switching.
\nFor instance, it is known for a metal/dielectric heterostructure that spin-orbital interaction may initiate a transfer of angular momentum between the layers and thus cause correlations in the magnetization dynamics [21]. Understanding optical control of the magnetism in magnetic heterostructures is a particularly important issue for further development of faster magnetic information storage/processing and spintronic nanodevices. Optical control of spins in Co/SmFeO3 heterostructures by the X-ray pulse with duration 70 ps has been demonstrated using X-ray photoemission electron microscopy, revealing that the dynamics of the spins in the metallic Co and the dielectric SmFeO3 are strongly coupled [22]. In the general case, a novel ultrafast magnetization dynamics in ferromagnetic metal/garnet heterostructures can be expected due to the coupling between the ferromagnetic and garnet films and/or the influence of the effective magnetic field of the ferromagnetic metallic film. Using the YIG:Co film in the ferromagnetic/garnet heterostructures gives unique possibility to investigate light-induced magnetization dynamics at the sub-picosecond timescale.
\nThis chapter describes experimental and theoretical studies of the magnetization behavior from statics to ultrafast light-induced magnetization dynamics in ultrathin 2 nm Co films deposited on Co-substituted yttrium iron garnet thin film. In particular, we demonstrate that ion beam sputtering can be used for the formation of Co/garnet heterostructures. The magnetization reversal process and magnetic anisotropy of the Co/garnet heterostructures are measured by both magneto-optical magnetometry and ferromagnetic resonance (FMR). To investigate the ultrafast magnetization dynamics in both garnet and Co/garnet heterostructure induced by femtosecond laser pulses, we carried out time-resolved measurements at room temperature using a magneto-optical pump-probe method. We demonstrated that the frequency of the spin precession in a Co/garnet bilayer can be modulated by exciting linearly polarized femtosecond pulses. The experimental results presented here were obtained on 2 nm Co/garnet heterostructure, which has a strong magnetostatic interlayer coupling. In this heterostructure, two distinct precession frequencies were observed. One is attributed to the magnetization precession of the 2 nm cobalt and the other to that of the 1.8-μm-thick garnet. The spin oscillation frequencies of the two layers differ by about a factor of two and are strongly dependent on the out-of-plane external magnetic field. We compared magnetization dynamics in the Co and bare garnet films separately via selective probing and showed that magnetization precession in the garnet via the photomagnetic effect can be manipulated by the magnetostatic interlayer coupling. The experimental results are discussed within the phenomenological model.
\nInitial garnet thin films composed of Y2Ca1Fe3.9Co0.1Ge1O12 (YIG:Co) were grown by liquid-phase epitaxy on Gd3Ga5O12 (GGG) (001)-oriented substrate. The initial thickness of garnet films was 6.5 µm. The initial garnet surface was etching, and Co/YIG:Co heterostructures were formed using the dual ion beam sputtering technique [23] on the base of an A 700 Q Leybold vacuum system. The base pressure was below 8 × 10−6 mbar in the vacuum chamber. The damage-free etching of the garnet films and subsequent deposition of the Co layers were carried out in situ at a pressure of 2.5 × 10−4 mbar [24].
\nFigure 1 illustrates the stage of the heterostructure preparation. The initial garnet film was smoothed to 5.8 µm thickness with a 0.6-keV oxygen ion beam with current density of 0.2 mA/cm2, corresponding to the ion flux of 3.2 × 1015 cm−2 × c−1 [24]. The oxygen ions improve garnet transmittance in the energy range between 0.5 and 1 keV. The garnet films are sputtered at a near-normal incidence angle. At this angle, optimal smoothing of the optical materials (quartz, glass, ceramic) is achieved for up to sub-nanometer roughness [25]. The garnet sputtering rate is about 0.22 µm/h. A final smoothing of the garnet surfaces was completed using a 0.3-keV oxygen ion beam for over 10 minutes. Au and Co targets were sputtered with a 1.5-keV argon ion beam at 0.25 mA/cm2 current density [24]. The incident angle of argon ions is 60° with respect to the target normal, so that the sputtered flux is deposited onto substrate at near-normal incidence angle. The deposition rates of Au and Co are 8.4 and 5.4 nm/min, respectively. A 4-nm Au film was used to protect the 2-nm Co layer before oxidation. For this thickness, the Au film is continuous and exhibits surface roughness close to the substrate of about 0.2 nm [26]. The Co/YIG:Co heterostructures and reference YIG:Co films are prepared onto the same substrate and in the same experimental conditions.
\nSchematic configuration of the heterostructure during preparation: (a) the YIG:Co film after smoothing from 6.5 µm to 5.8 µm thickness, (b) after ion beam etching to 1.8 µm on the garnet part, (c) after deposition of 4-nm Au/2 nm Co bilayer on the garnet part, and (d) the 20 × 20 µm pattern area on the Co/garnet part.
A 20 × 20 μm Au/Co pattern, for comparison of coupling between Co and garnet films and domain structures modifications on garnets, was fabricated by a lift-off photolithography. The photolithographic process can be represented as follows. In the first step, the garnet film was coated with the light-sensitive chemical photoresist to form a homogeneous layer of about 1 μm thickness. In the second step, the photoresist on garnet surface was exposed through a lithographic mask with high-intensity ultraviolet (UV) radiation. This mask contains the copy of pattern. The 20 × 20 μm windows are opened to the exposing UV light passes through the mask. The dose of UV exposure and the development process were precisely controlled to result in a sharp edge profile of resist patterns. In the third step, the irradiated photoresist area was washed away, leaving the photoresist in the unexposed area. In the fourth step, after deposition of the Au/Co bilayers, a chemical etching was used to remove the previously unexposed photoresist. In such way, the pattern from mask was transferred to the garnet film. As a result, the Co(homogeneous) and Co(pattern)/garnet heterostructures as well as reference garnet films with discrete thicknesses were prepared onto the same GGG (001) substrate by combining the ion beam processing with photolithographic technique (see Figure 1).
\n(a) SEM images of the initial 6.5 µm YIG:Co film, (b) 5.8 µm YIG:Co film after etching, of YIG:Co films, and (c) the cross-sectional image of the Co(50nm)/YIG:Co interface .
The surface morphology of both the bare YIG:Co film and Co/YIG:Co heterostructure was measured by high-resolution scanning electron microscopy (SEM) using a FEI’s Helios NanoLab DualBeam system. The root mean square (rms) surface roughness was examined by atomic force microscope in tapping mode. The initial garnet surface is rough with protrusions, while YIG:Co contains troughs of about 100–200 nm in diameter (see Figure 2(a)). The ion beam smoothing the garnet surface area showed significantly reduced rms parameters from 3.5 to 0.3 nm after etching the garnet film from 6.5 µm to 5.8 µm (see Figure 2(b)). The surface roughness remains approximately the same after ion beam etching down to 1 µm. Ion beam thinning of the garnet film also decreases the rms parameter to 0.25 nm. This is comparable to surfaces of roughness similar to high-quality Si substrate (0.18 nm).
\nThe surfaces of the Co/garnet heterostructures are continuous and exhibit a slightly increased rms parameter from 0.3 to 0.37 nm after the deposition of Au(4nm)/Co(2 nm) bilayer structures on the ion beam-smoothed garnet surfaces. A cross section of the Co/garnet interface was observed using a 30-keV gallium-focused ion beam. The low contrast of the Co(≤5 nm)/garnet interfaces results from charge accumulation in the dielectric garnet film. Therefore, only for the SEM image observation, the thickness of the Co layer was increased up to 50 nm for the enhancement of the contrast at the Co/garnet interface. The Co/garnet interface is sharp, and the thickness of the transition layer is thinner than 1–2 nm (see inset of Figure 2(c)).
\nThe optical transmittance, magneto-optical both Kerr (θk) and Faraday (θF) rotations were performed on Co/YIG:Co heterostructures and reference YIG:Co film using light from a mode-locked Ti-sapphire laser (MaiTai HP, Spectra-Physics) operating within the 400–1040 nm range and a repetition rate of 80 MHz. For the detection of the angle of magneto-optical rotation, a lock-in amplifier was used in combination with a standard modulation technique with a photoelastic modulator.
\nThe investigation of the optical absorption and the Faraday rotation spectra in YIG:Co garnet demonstrated that the contribution of Co ions in octahedral sites is substantially smaller than that of tetrahedral Co ions [27]. Furthermore, the latter can be observed in near-infrared range, where pure YIG is fully transparent. Both an optical transmittance and magneto-optical Faraday rotation spectra for YIG:Co film are shown in Figure 3. At wavelengths longer than about 800 nm, the absorption is small and is equal to about 102 cm−1 (see Figure 3(b)). Essentially in the wavelength range of 450–1300 nm, the absorption is caused by crystal field transitions of Fe3+, Co2+, and Co3+ ions in both tetrahedral and octahedral sites. The crystal field transitions in octahedral sites have weaker oscillator strength than that the tetrahedral ones. However, at wavelengths shorter than 450 nm, the strong optical absorption of the garnet film is related to charge transfer transitions from oxygen ligands O2− to octahedral Fe3+ and Co3+ ions. The scheme of crystal field and charge transfer transitions for Co ions (Figure 3(a)) was obtained from experimental and theoretical investigations [27, 28]. In a band model, the charge transfer transition is connected with electron excitation from a valence band to conduction ones, which are created by O 2p and Fe (Co) 3d orbitals, respectively. Although a determination of band gap Eg is difficult owing to the garnets not exhibiting sharp absorption edge, the lowest charge transfer transitions of octahedral Co3+ (1A1→1T2) ions give Eg ≈ 2.85 eV. This value agrees well with the band gap of pure YIG (Eg = 2.9 eV). In the general case, the optical absorption is correlated with the magneto-optical Faraday rotation (defined by rotation angle θF) (see Figure 3(c)). The energy levels of the Co ions do not coincide with the 3d levels of the Fe ions. Therefore, the optical excitation of YIG:Co film leads to additional transitions of Co ions as well as affect the Fe3+ ion transitions and consequently results in magneto-optical effects with spectral sensitivity.
\n(a) Scheme of crystal field and charge transfer transitions according to Refs. [27, 28], (b) optical transmittance, and (c) magneto-optical Faraday rotation spectra of 1.8 μm YIG:Co film.
The contribution of Co ion transitions to magneto-optical Faraday rotation spectrum is clearly seen by comparison of previously reported spectra for both YIG [29] and YIG:Co films [27]. In our case, for the garnet film, we observed the reduction of θF close to the optical transitions of tetrahedral Co2+ and Co3+ ions as well as octahedral Co3+ ones. It is important to note that for different garnet thicknesses and both YIG and YIG:Co films reported, θF is practically the same in the wavelength range of 800–900 nm, where no optical transitions of Co ions are expected (see Figure 3(b)). This indicates that magnetic anisotropy (induced by the temperature, light, etc.) of the garnet can be modified due to inhomogeneous distribution of Co dopant in the garnet lattice. The contribution of low spin octahedral Co3+ ions to magnetic anisotropy is zero in single-ion approximation. Since tetrahedral Co2+ and Co3+ ions are responsible for growth-induced magnetic anisotropy [30], one can assume that the reduction in garnet thickness leads to a change in the uniaxial anisotropy and thus to a change in the magnetization reversal process. To confirm this, in the next sections we performed investigations of both the magnetic anisotropy and magnetization reversal processes in ultrathin Co layer and garnet thin films.
\nThe process of magnetization reversal has been studied at room temperature in reflection with the linear magneto-optic Kerr effect (MOKE) and in transmission with the Faraday effect. From the data, we separated different magneto-optical contributions from the Co layer and garnet-only films. The perpendicular magnetization component of the ultrathin Co layer was measured using the polar MOKE (P-MOKE) geometry, with the angle of incidence of the laser light close to the sample normal and the external magnetic field HZ perpendicular to the surface of the sample (see Figure 4(a)). The measurements of the in-plane magnetization components of the Co layer were performed in the longitudinal MOKE (L-MOKE) geometry, with a 49o angle of incidence of the light (see Figure 5(a)). The magnetic field HX was applied in the sample plane for various orientations with respect to the garnet [100] direction. The process of magnetization reversal to the determination of Faraday rotation angle θF of the garnet-only films was studied in the magneto-optical Faraday geometry, with perpendicular and in-plane magnetic field orientation (Figure 4).
\nAccording to the optical absorption spectra in Figure 3(b), Au/Co/garnet heterostructures are transparent enough to be investigated in transmission geometry, for example at 690 nm wavelength. From the experimental curves, we separated the different magneto-optical contributions of the Co layer and garnet films using vector magneto-optical magnetometry and measurements for reference garnet film [31]. The P-MOKE hysteresis loops observed for the 2-nm-thick Co film grown on garnet film indicate an in-plane magnetization of Co (see Figure 4(c)). Figure 4(b) and 5(b) show Faraday rotation hysteresis loops measured for garnet film and a perpendicular applied field HZ and an in-plane field HX, respectively. From the hysteresis loop shown in Figure 4(b), one deduces a Faraday rotation from the garnet layer of about θF = 0.08 degrees and a paramagnetic linear contribution from the GGG substrate. For the in-plane applied magnetic field in the garnet [100] direction, the saturating field is about 0.6 kOe (Figure 5(b)).
\n(a) The experimental configuration with Kerr and Faraday effects for perpendicular magnetic field orientation HZ to the sample plane. Hysteresis loops measured for YIG:Co and Co/YIG:Co at 690 nm wavelength in: (b) Faraday and (c) P-MOKE geometries.
The L-MOKE magnetization curve for the Co layer measured with the in-plane external magnetic field HX are shown in Figure 5(c). From L-MOKE hysteresis loops, the remanence parameter is plotted on inset of Figure 5(c) as a function of azimuthal angle ϕH. The shape of these loops is practically independent on the azimuthal sample orientation and confirms the “easy plane” type of the magnetic anisotropy with a saturation in-plane field of about 0.3 kOe. To determine magnetic anisotropy of both garnet films and Co layer, we performed FMR measurements at room temperature.
\n(a) The experimental configuration with Kerr and Faraday effects for sample in-plane magnetic field orientation HX. Hysteresis loops measured for YIG:Co and Co/YIG:Co at 690 nm wavelength in: (b) Faraday and (c) L-MOKE geometries.
The typical FMR line measured in the external magnetic field applied to the sample at polar angle θH = 65° is presented in Figure 6. The Co layer and garnet film contributions to this FMR line can be clearly seen. The linewidth values of Co and garnet films are different. The peak-to-peak FMR linewidth ΔH is related to the relaxation rate of magnetization motion, which is caused by intrinsic Gilbert damping α and magnetic inhomogeneities ΔH(0) in ferromagnet:
FMR lines for Co/YIG:Co heterostructure measured at θH = 65° and ϕH = 0° of the external magnetic field H.
The experimental dependencies of a resonance field HR on the angles θH and ϕH for the garnet film and the Co layer are plotted in Figures 7 and 8, respectively. The existence of easy magnetization axes along the <111> directions for the garnet contributions was deduced by analyzing HR(θH,ϕH) (see Figure 7(a,b)). This result correlates well with the Faraday experiments for garnet film, shown in Figure 4(b). For the 2-nm Co layer, the easy magnetization axis lies in the sample plane (see Figure 8(a)) and is also connected with the ”easy plane” type of the magnetic anisotropy (Figure 8(b)). As observed before, the magnetic anisotropy of the YIG:Co has two contributions [18]: magnetocrystalline cubic and growth-induced uniaxial ones. Hence, a qualitative analysis of the FMR and magnetization curves gives rise to the following description of the magnetic anisotropy energy EA, which contains cubic, growth-induced and uniaxial anisotropies:\n
The polar (for ϕH = 0° and 45°) and azimuthal (for θH = 90°) dependences of the resonance field HR for YIG:Co film. The dots are experimental values, and solid lines were fitted using Eq. (1).
where
The polar (for ϕH = 0° and 45°) and azimuthal (for θH =90°) dependences of the resonance field HR for 2-nm Co layer on YIG:Co film. The dots are experimental values, and the solid line was fitted using Eq. (1).
where fFMR is the FMR frequency. The equilibrium angles θ and ϕ of the magnetization can be found by the minimization of
Thus, let us analyze, step by step, the magnetic anisotropy constants of the Co layer and garnet films from FMR field and magnetization loops. First, for the Co layer deposited on the garnet film, the effective anisotropy constant is
Here, we report on an influence of the 2-nm Co layer on both the domain structure geometry and magnetization reversal processes in the YIG:Co film. The period and shape of domains in Co/YIG:Co heterostructure are explained by competition of different energies. Taking into account the domain period in garnet film of order of 10 μm, the 20 × 20 μm Au/Co pattern is required for the observation of domain structure of garnet films under ultrathin Co layer [40], i.e., the size of pattern square is larger than domain period of garnet films. Figure 9 shows the images of domain structure for patterned Co/garnet area recorded at HZ = 0 and HZ = 40 Oe, respectively.
\nImages of magnetic domain structure in 2-nm Co/YIG:Co pattern area recorded at: (a) HZ = 0 and (b) HZ = 40 Oe. The image size is 140 × 130 μm.
In Figure 9(a), both in garnet and Co/garnet (square areas) structures, stripe domain structures are observed. In this case, the period and the domain size in the Co/garnet structure is less than in the garnet film.
\nThe hysteresis loops recorded for both bare YIG:Co (full points) and Co/YIG:Co (open points) films.
At HZ = 40 Oe, the domain structure was observed only at Co/garnet pattern (see Figure 9(b)). Moreover, the clear difference in the magnetization reversal process with and without the 2-nm cover Co layer on garnet film was observed in the field range near the coercivity (see Figure 10). First, for Co/garnet heterostructure, we observe the reduced θF value compared to the bare garnet film, i.e., the contribution of the hard axis from the Co/garnet interface to hysteresis loop is found. Second, the value of the reversal magnetic collapse field is noticeably increasing from 40 to 55 Oe. In Figure 9(b), the presence of Co/garnet domains on a monodomain background garnet area is well visible. In this case, the extra energy is required to switch the in-plane interfacial magnetic moment in the garnet film. For these reasons, the strong in-plane magnetic anisotropy of the ultrathin Co layer induces significant stray field on the garnet surface. Therefore, for the Co/garnet heterostructure, reduction of the domain period occurs as a consequence of decreasing the magnetostatic energy.
\nWe present the results of a study of ultrafast photoinduced magnetization dynamics in Co/YIG:Co heterostructures via the excitation of photomagnetic anisotropy [19, 20]. This anisotropy is related to an optically induced charge transfer between the anisotropic Co2+ and Co3+ ions on tetrahedral sites in the garnet lattice. The deposition of ultrathin Co layer on garnet film can result in a new type of magnetization dynamics due to the influence of the effective magnetic field of the Co layer and/or the magnetic coupling between the metallic layer and garnet film.
\nTo investigate the ultrafast magnetization dynamics in both bare YIG:Co film and Co/YIG:Co heterostructure induced by femtosecond laser pulses, we carried out time-resolved measurements at room temperature using a conventional magneto-optical pump-probe method. Pump pulses with a duration of 35 fs from an amplifier (Spitfire Ace, Spectra-Physics) at a 500 Hz repetition rate were directed at an angle of incidence about 10° from the sample normal parallel to the [001] crystallographic axis of the sample, while the probe pulses at a 1 kHz repetition rate of the pump were incident along the sample normal, see Figure 11. A pump beam with a wavelength of 800 nm and energy of 2 μJ was focused onto a spot about 100 μm in diameter on the sample. The pump energy was relatively small in order to not heat significantly the metallic layers of Au and Co. The sample was excited by the pump through the Co side of the bilayer. A probe beam with a wavelength of 800 nm was about two times smaller in size and the energy than the pump. The parameter of delay time Δt (see Figure 1) between the pump and the probe pulses could be adjusted up to 1.3 ns. The linear polarization of the pump beam was defined by angle φ to the [100] axis. The amplitude of the magnetization precession was maximal when the polarization plane of the pump was along [100] or [010] axes. On the contrary, the polarization of the probe beam was along the [1–10] axis.
\nSample configuration and the experimental geometry with the external magnetic field H applied with angle θH = 65°.
In this experimental geometry, we measured the Faraday rotation angle θF of the probe as a function of the delay time Δt between the pump and probe pulses. The rotation θF(Δt) is proportional to the out-of-plane component of the magnetization MZ. An external magnetic field H up to 5 kOe was applied along the (1–10)plane at θH = 65° with respect to the sample normal. At the same time, H was above domain collapse field, so that a coherent spin dynamics without domain structure was investigated.
\nThe experimental results presented below were obtained on 2-nm Co/YIG:Co heterostructure, in which strong magnetostatic interlayer coupling has been found. Figure 12 shows the magnetization precession (angle of Faraday rotation) as a function of the delay time Δt for different values of the amplitude of the external magnetic field with angle θH = 65°. We expect that the magnetization dynamics corresponds to a precession of the Co and garnet moments around the effective field. For a relatively small external magnetic field, one can find a slow oscillation with a main single frequency of 4.2 GHz, see Figure 12(a), corresponding to the garnet film [41]. We observe periodic oscillation modulated by a higher-frequency oscillation in Figure 12(b). Fast Fourier transforms (FFTs) were taken for these dependences, and the resulting power spectra confirm the presence of two different oscillation frequencies f1 and f2 (see Figure 12(b)). Both of these frequencies increase with increasing amplitude of the external magnetic field. However, we observed a main single higher oscillation frequency for the external magnetic field above 4 kOe (see Figure 12(c)). The Faraday rotation transients for varying external magnetic field H were fitted (Figure 12) with two damped sine contributions:\n
Time-resolved Faraday rotation as a function of the delay time Δt for (a) H = 1.47 kOe, (b) 2.31 kOe, and (c) 4.22 kOe. The red solid lines were fitted using FFT analysis and Eq. (3). The right panel—the FFT spectra.
where τi is the time decay, Ai the amplitude, and φi the phase. The fitted curves using FFT analysis and Eq. (3) are in good agreement with the experimental data (see Figure 12).
\nDependence of the magnetization component MZ on the amplitude of external field H for the garnet and Co layer.
From the experimental curves, we deduced amplitudes of the oscillations using fitting by Eq. (3). It is clearly seen that upon increasing H, the contribution from the garnet vanishes so that at the field above 4 kOe, the contribution from the Co layer dominates (see Figure 13). The dependence of perpendicular component of the magnetization MZ is proportional to the Faraday rotation θF.
\n(a) Dependence of the frequency of magnetization precession on a function of magnetic field amplitude H for garnet (full points) and Co (open points) films of a heterostructure. The calculated FMR frequency dependences are shown using both Eqs. (1) and (2) with magnetic anisotropy constants (solid lines). The measured FMR data are shown as stars. (b) Calculation of magnetization orientation θM as a function of the amplitude of H for YIG:Co film and 2-nm Co layer.
Figure 14(a) plots the frequencies f1 and f2 obtained from experimental data for different values of the H. The dashed line is determined by the FMR frequency where the resonance field values for Co and garnet films are located (stars). To compare obtained frequencies, we calculated the FMR frequency as a function of the external magnetic field with angle θH = 65° in both the cobalt and garnet films using a typical FMR equation [35], considering constants of the magnetic anisotropy of the 2-nm Co and 1.8 μm garnet film. The frequencies f1 and f2 differing by about a factor of two correspond to the precession of the magnetization excited in garnet and Co films, respectively. We see from Figure 14(a) that the experimental magneto-optical response data (points) agree well with the measured FMR results with single 9.5 GHz frequency (stars) and calculated FMR frequency (solid lines) for both contributions in the bilayer using Eq. (2).
\nSuch a layer selective probing of the magnetization dynamics can be understood by a simple phenomenological model. The equilibrium state of magnetization vector at the Co/YIG:Co heterostructure could be found using the phenomenological model of magnetic anisotropy (Eq. (1)) after minimizing the total energy including energies of the magnetic anisotropies, the Zeeman at external magnetic field, and the demagnetization. Figure 14(b) shows the dependence of magnetization angle θM, on an external magnetic field H for both Co and garnet films. According the Faraday configuration, the polarization rotation of the probe beam was proportional to the perpendicular magnetization component along [001] axis at the garnet (see Figure 11). Thus, θF is proportional to the amplitude of the magnetization precession. During increasing θM, we observed increasing the amplitude of the magnetization precession. A quantitative analysis of dependences of the angle on the external magnetic field shows the possibility of the excitation of magnetization precession at two regimes: first, at low magnetic field below 1 kOe, the amplitude of magnetization precession dominates at the garnet film due to the large angle between magnetic field H and magnetization of garnet Mgarnet and small perpendicular magnetization component of cobalt MCo; second, at high magnetic field above 4 kOe, the amplitude of magnetization precession is dominated at the Co film with the significant perpendicular component MCo when the magnetization vector Mgarnet is close to H.
\nGraphical illustration of the precessional dynamics for: (a) H < 1.5 kOe, (b) 1.5 < H < 4.3 kOe, and (c) H > 4.3 kOe.
We can conclude that we observe three types of magnetization precession in the bilayer: (i) mainly single-frequency precession (1–5 GHz) from the garnet for H < 1.5 kOe, (ii) a double frequency to modulated signal for 1.5 < H < 4.3 kOe, and (iii) mainly single-frequency precession (>20 GHz) from the cobalt film for H > 4.3 kOe (see the graphical illustration of the precessional dynamics in Figure 15).
\nIn this part, we compare magnetization dynamics in the Co and bare garnet films separately via selective probing and show that magnetization precession in the garnet can be manipulated by magnetostatic interlayer coupling.
\nTime-resolved Faraday rotation of the Co/garnet heterostructure as a function of the delay time ∆t for different (a) magnetic field amplitude and (b) pump polarization. Solid line was fitted using the classical oscillation function including damping for a 2-nm Co layer on a garnet film.
A rather unique combination of magnetic properties of the layers allows us to realize different regimes of the laser-induced dynamics. Changing the strength of the out-of-plane H, we were able to obtain conditions when the magnetization dynamics was dominated either by the Co or the garnet layer. As discussed in the previous part, for H < 1 kOe photoinduced dynamics of Co/garnet, the heterostructure is dominated by the magnetization precession of the garnet film, while at H > 4 kOe, the magnetization precession results from the Co layer. Time dependence of the z-component of the magnetization precession was on the function of the external magnetic field H and the angle of polarization plane of the pump beam. Figure 16(a) shows the magnetization precession curves measured at H = 1.5 kOe, 2.3 kOe, and 4.6 kOe for φ = 0o. The laser-excited precessions of the magnetizations at two different frequencies are deduced from Figure 14 as FMR frequencies in both the Co and the garnet films.
\nGraphical illustration of an ultrafast demagnetization dynamics in a 2-nm Co layer for (a) Δt < 0, (b) 0 <Δt <tw (pulse duration), and (c) Δt > tw.
The photoinduced magnetization precession for different pump beam polarizations at an external magnetic field with 4.6 kOe is shown in Figure 16(b). These curves demonstrate no polarization dependence of the magnetization precession [42]. For such metallic ferromagnets, the ultrafast light-induced demagnetization is typical [43, 44]. The thermal demagnetization is seen as a sub-picosecond change of the magneto-optical signal measured at H = 4.6 kOe. The observed light-induced magnetization dynamics is a result of temperature increase of electron system on femtosecond timescale and a subsequent ultrafast reduction of MCo [45], which effectively change the equilibrium orientation of the magnetization in this layer and thus triggers spin oscillations (see the graphical illustration in Figure 17).
\nTo study the influence of the Co film on the ultrafast magnetization dynamics at the garnet film, the time-resolved Faraday measurements at low-field regime below 1 kOe were performed [42]. In this case, the amplitude of magnetization precession at YIG:Co film always dominates that of the Co film (see Figure 13). First, we measured the laser-induced magnetization dynamics in a bare garnet film. Figure 18(a) shows that changing the polarization of the pump induces a shift of the phase of the precession Δψ = 120o in the bare garnet film. In this case, the decay coefficient of photoinduced anisotropy is τg ~ 20 ps. In case of the deposition of the 2-nm Co film on this garnet film, the polarization sensitivity of the magnetization precession disappears. The polarization angles of pump beam with φ = 0 and 90o trigger magnetization precession in YIG:Co with the same phase (Δψ ≈ 0), see Figure 18(b). The time of relaxation of magnetization precession after pump pulse is τc ~ 60 ps. This value is enlarged due to the influence of light-induced demagnetization at Co layer. The magnetization dynamics triggered in YIG:Co film and the Co/YIG:Co heterostructure with the same polarization of the pump light are clearly different. However, the frequencies of these precessions are similar.
\nTime-resolved Faraday rotation of (a) bare garnet and (b) Co/garnet films as a function of the delay time Δt for H(θH = 65°) = 0.75 kOe and different pump polarization φ. Dashed lines were fitted using the exponential function with decay coefficients τL.
The laser excitation of Co/YIG:Co heterostructure leads to both an thermal demagnetization at Co film and a photomagnetic effect at the garnet [20]. These effects induced changing the magnetization orientation given by the effective field Heff in the heterostructure (see Figure 17). In this case, ultrafast change triggers the precession of the magnetization vector around the new orientation H*eff (see Figure 17(c)). In YIG:Co, the polarization-dependent excitation with different initial phase of magnetization precession leads to a photoinduced magnetic anisotropy [19]. However, in our heterostructure, the phase of magnetization precession is defined by both the effective anisotropy (magnetocrystalline, uniaxial, and photoinduced) field and the stray field from 2-nm Co film (the magnetization of cobalt is significant larger than the magnetization of garnet). The magnetostatic coupling between Co and YIG:Co films leads to a change in the phase of magnetization precession in YIG:Co film. Thus in heterostructure, the magnetization is precessed around the effective magnetic field with the isotropic in-plane component due to the ”easy plane” of magnetic anisotropy of Co film.
\nIn this chapter, we have presented the experimental investigation of ultrathin Co/garnet heterostructure by using time-resolved pump-probe magneto-optical spectroscopy in combination with linear magneto-optical Faraday and Kerr effects and ferromagnetic resonance. Ion beam processing procedure for preparation of Au/Co/garnet heterostructure with a sub-nanometer roughness parameter at the interface has been proposed. It was found that Gilbert damping of the ultrathin Co layers on the garnet surfaces is comparable to the damping of high-quality single and polycrystalline Co layers grown on metallic underlayers. We showed that the magnetic and magneto-optical properties of Co/garnet heterostructures can be engineered by covering the ultrathin Co layer. In particular, a strong magnetostatic interlayer coupling between the 2-nm Co layer and YIG:Co film has been found. In addition, the modification of the domain structure due to the magnetostatic coupling has been demonstrated. In principle, depositing ultrathin ferromagnetic layers on a garnet film can also lead to new effects in magnetization dynamics, due to the influence of the effective magnetic field of the ferromagnetic layer and/or the coupling between ferromagnetic layer and garnet.
\nThe growth of a 2-nm Co layer on top of the garnet significantly changes the mechanism of the laser-induced precession in the heterostructure. We observed the modulation of spin precession in a Co/garnet heterostructure with distinct frequencies. The excitation efficiency of these precessions strongly depends on the amplitude and orientation of external magnetic field. In addition, we demonstrate that the laser pulse triggers polarization-independent precession in both the Co and garnet layers via the magnetostatic coupling between these layers.
\nThese results demonstrate that magnetic metal/dielectric heterostructures are interesting and promising objects for further investigations of all-optical ultrafast light-induced phenomena and their potential applications.
\nThis work was supported by the National Science Centre Poland for OPUS project DEC-2013/09/B/ST3/02669. The author would like to acknowledge the contributions of M. Pashkevich for measurements and A. Stognij for heterostructures preparation. The author is grateful to M. Tekielak, R. Gieniusz, A. Maziewski, A. Kirilyuk, A. Kimel, and T. Rasing for fruitful discussions and research support.
\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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