Mechanical complexity of living cells can be mapped onto simple homogeneous equivalents.

Biological cells are built up from different constituents of varying size and stiffness which all contribute to the cell's mechanical properties. Despite this heterogeneity, in the analysis of experimental measurements one often assumes a strongly simplified homogeneous cell and thus a single elastic modulus is assigned to the entire cell. This ad-hoc simplification has so far mostly been used without proper justification. Here, we use computer simulations to show that indeed a mechanically heterogeneous cell can effectively be replaced by a homogeneous equivalent cell with a volume averaged elastic modulus. To demonstrate the validity of this approach, we investigate a hyperelastic cell with a heterogeneous interior under compression and in shear/channel flow mimicking atomic force and microfluidic measurements, respectively. We find that the homogeneous equivalent cell reproduces quantitatively the behavior of its heterogeneous counterpart, and that this equality is largely independent of the stiffness or spatial distribution of the heterogeneity.

Nominally identical microplastic models differ greatly in their particle-cell interactions.

Due to the abundance of microplastics in the environment, research about its possible adverse effects is increasing exponentially. Most studies investigating the effect of microplastics on cells still rely on commercially available polystyrene microspheres. However, the choice of these model microplastic particles can affect the outcome of the studies, as even nominally identical model microplastics may interact differently with cells due to different surface properties such as the surface charge. Here, we show that nominally identical polystyrene microspheres from eight different manufacturers significantly differ in their ζ-potential, which is the electrical potential of a particle in a medium at its slipping plane. The ζ-potential of the polystyrene particles is additionally altered after environmental exposure. We developed a microfluidic microscopy platform to demonstrate that the ζ-potential determines particle-cell adhesion strength. Furthermore, we find that due to this effect, the ζ-potential also strongly determines the internalization of the microplastic particles into cells. Therefore, the ζ-potential can act as a proxy of microplastic-cell interactions and may govern adverse effects reported in various organisms exposed to microplastics.

Viscoelastic properties of suspended cells measured with shear flow deformation cytometry.

Numerous cell functions are accompanied by phenotypic changes in viscoelastic properties, and measuring them can help elucidate higher level cellular functions in health and disease. We present a high-throughput, simple and low-cost microfluidic method for quantitatively measuring the elastic (storage) and viscous (loss) modulus of individual cells. Cells are suspended in a high-viscosity fluid and are pumped with high pressure through a 5.8 cm long and 200 µm wide microfluidic channel. The fluid shear stress induces large, ear ellipsoidal cell deformations. In addition, the flow profile in the channel causes the cells to rotate in a tank-treading manner. From the cell deformation and tank treading frequency, we extract the frequency-dependent viscoelastic cell properties based on a theoretical framework developed by R. Roscoe [1] that describes the deformation of a viscoelastic sphere in a viscous fluid under steady laminar flow. We confirm the accuracy of the method using atomic force microscopy-calibrated polyacrylamide beads and cells. Our measurements demonstrate that suspended cells exhibit power-law, soft glassy rheological behavior that is cell-cycle-dependent and mediated by the physical interplay between the actin filament and intermediate filament networks.

Cells in the human body are viscoelastic: they have some of the properties of an elastic solid, like rubber, as well as properties of a viscous fluid, like oil. To carry out mechanical tasks ­ such as, migrating through tissues to heal a wound or to fight inflammation ­ cells need the right balance of viscosity and elasticity. Measuring these two properties can therefore help researchers to understand important cell tasks and how they are impacted by disease. However, quantifying these viscous and elastic properties is tricky, as both depend on the time-scale they are measured: when pressed slowly, cells appear soft and liquid, but they turn hard and thick when rapidly pressed. Here, Gerum et al. have developed a new system for measuring the viscosity and elasticity of individual cells that is fast, simple, and inexpensive. In this new method, cells are suspended in a specialized solution with a consistency similar to machine oil which is then pushed with high pressure through channels less than half a millimeter wide. The resulting flow of fluid shears the cells, causing them to elongate and rotate, which is captured using a fast camera that takes 500 images per second. Gerum et al. then used artificial intelligence to extract each cell's shape and rotation speed from these images, and calculated their viscosity and elasticity based on existing theories of how viscoelastic objects behave in fluids. Gerum et al. also investigated how the elasticity and viscosity of cells changed with higher rotation frequencies, which corresponds to shorter time-scales. This revealed that while higher frequencies made the cells appear more viscous and elastic, the ratio between these two properties remained the same. This means that researchers can compare results obtained from different experimental techniques, even if the measurements were carried out at completely different frequencies or time-scales. The method developed by Gerum et al. provides a fast an inexpensive way for analyzing the viscosity and elasticity of cells. It could also be a useful tool for screening the effects of drugs, or as a diagnostic tool to detect diseases that affect the mechanical properties of cells.

Accuracy and performance of the lattice Boltzmann method with 64-bit, 32-bit, and customized 16-bit number formats.

Fluid dynamics simulations with the lattice Boltzmann method (LBM) are very memory intensive. Alongside reduction in memory footprint, significant performance benefits can be achieved by using FP32 (single) precision compared to FP64 (double) precision, especially on GPUs. Here we evaluate the possibility to use even FP16 and posit16 (half) precision for storing fluid populations, while still carrying arithmetic operations in FP32. For this, we first show that the commonly occurring number range in the LBM is a lot smaller than the FP16 number range. Based on this observation, we develop customized 16-bit formats-based on a modified IEEE-754 and on a modified posit standard-that are specifically tailored to the needs of the LBM. We then carry out an in-depth characterization of LBM accuracy for six different test systems with increasing complexity: Poiseuille flow, Taylor-Green vortices, Karman vortex streets, lid-driven cavity, a microcapsule in shear flow (utilizing the immersed-boundary method), and, finally, the impact of a raindrop (based on a volume-of-fluid approach). We find that the difference in accuracy between FP64 and FP32 is negligible in almost all cases, and that for a large number of cases even 16-bit is sufficient. Finally, we provide a detailed performance analysis of all precision levels on a large number of hardware microarchitectures and show that significant speedup is achieved with mixed FP32/16-bit.

Temperature-Dependent Conformation Behavior of Isolated Poly(3-hexylthiopene) Chains.

We use atomistic as well as coarse-grained molecular dynamics simulations to study the conformation of a single poly(3-hexylthiopene) chain as a function of temperature. We find that mainly bundle and toroid structures appear with bundles becoming more abundant for decreasing temperatures. We compare an atomistic and a Martini-based coarse-grained model which we find in very good agreement. We further illustrate how the temperature dependence of P3HT can be connected to that of simple Lennard-Jones model polymers in a vacuum. Upon adding solvent (THF) we observe the occurrence of a prominent swelling of the molecular size at a temperature of about 220 K. This swelling is in close agreement with the interpretation of recent spectroscopic experiments which allows us to explain the experimental observations by an increased frequency of bundle structures.

Red blood cell shape transitions and dynamics in time-dependent capillary flows.

The dynamics of single red blood cells (RBCs) determine microvascular blood flow by adapting their shape to the flow conditions in the narrow vessels. In this study, we explore the dynamics and shape transitions of RBCs on the cellular scale under confined and unsteady flow conditions using a combination of microfluidic experiments and numerical simulations. Tracking RBCs in a comoving frame in time-dependent flows reveals that the mean transition time from the symmetric croissant to the off-centered, nonsymmetric slipper shape is significantly faster than the opposite shape transition, which exhibits pronounced cell rotations. Complementary simulations indicate that these dynamics depend on the orientation of the RBC membrane in the channel during the time-dependent flow. Moreover, we show how the tank-treading movement of slipper-shaped RBCs in combination with the narrow channel leads to oscillations of the cell's center of mass. The frequency of these oscillations depends on the cell velocity, the viscosity of the surrounding fluid, and the cytosol viscosity. These results provide a potential framework to identify and study pathological changes in RBC properties.

In Vitro Examinations of Cell Death Induction and the Immune Phenotype of Cancer Cells Following Radiative-Based Hyperthermia with 915 MHz in Combination with Radiotherapy.

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA-MB-231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5-15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.

Vortical flow structures induced by red blood cells in capillaries.

OBJECTIVE: Knowledge about the flow field of the plasma around the red blood cells in capillary flow is important for a physical understanding of blood flow and the transport of micro- and nanoparticles and molecules in the flowing plasma. We conducted an experimental study on the flow field around red blood cells in capillary flow that is complemented by simulations of vortical flow between red blood cells. METHODS: Red blood cells were injected in a 10 × 12 µm rectangular microchannel at a low hematocrit, and the flow field around one or two cells was captured by a high-speed camera that tracked 250 nm nanoparticles in the flow field, acting as tracers. RESULTS: While the flow field around a steady "croissant" shape is found to be similar to that of a rigid sphere, the flow field around a "slipper" shape exhibits a small vortex at the rear of the red blood cell. Even more pronounced are vortex-like structures observed in the central region between two neighboring croissants. CONCLUSIONS: The rotation frequency of the vortices is to a good approximation, inversely proportional to the distance between the cells. Our experimental data are complemented by numerical simulations.

A hyperelastic model for simulating cells in flow.

In the emerging field of 3D bioprinting, cell damage due to large deformations is considered a main cause for cell death and loss of functionality inside the printed construct. Those deformations, in turn, strongly depend on the mechano-elastic response of the cell to the hydrodynamic stresses experienced during printing. In this work, we present a numerical model to simulate the deformation of biological cells in arbitrary three-dimensional flows. We consider cells as an elastic continuum according to the hyperelastic Mooney-Rivlin model. We then employ force calculations on a tetrahedralized volume mesh. To calibrate our model, we perform a series of FluidFM[Formula: see text] compression experiments with REF52 cells demonstrating that all three parameters of the Mooney-Rivlin model are required for a good description of the experimental data at very large deformations up to 80%. In addition, we validate the model by comparing to previous AFM experiments on bovine endothelial cells and artificial hydrogel particles. To investigate cell deformation in flow, we incorporate our model into Lattice Boltzmann simulations via an Immersed-Boundary algorithm. In linear shear flows, our model shows excellent agreement with analytical calculations and previous simulation data.

Flow and hydrodynamic shear stress inside a printing needle during biofabrication.

We present a simple but accurate algorithm to calculate the flow and shear rate profile of shear thinning fluids, as typically used in biofabrication applications, with an arbitrary viscosity-shear rate relationship in a cylindrical nozzle. By interpolating the viscosity with a set of power-law functions, we obtain a mathematically exact piecewise solution to the incompressible Navier-Stokes equation. The algorithm is validated with known solutions for a simplified Carreau-Yasuda fluid, full numerical simulations for a realistic chitosan hydrogel as well as experimental velocity profiles of alginate and chitosan solutions in a microfluidic channel. We implement the algorithm in an easy-to-use Python tool, included as Supplementary Material, to calculate the velocity and shear rate profile during the printing process, depending on the shear thinning behavior of the bioink and printing parameters such as pressure and nozzle size. We confirm that the shear stress varies in an exactly linear fashion, starting from zero at the nozzle center to the maximum shear stress at the wall, independent of the shear thinning properties of the bioink. Finally, we demonstrate how our method can be inverted to obtain rheological bioink parameters in-situ directly before or even during printing from experimentally measured flow rate versus pressure data.

Flow-accelerated platelet biogenesis is due to an elasto-hydrodynamic instability.

Blood platelets are formed by fragmentation of long membrane extensions from bone marrow megakaryocytes in the blood flow. Using lattice-Boltzmann/immersed boundary simulations we propose a biological Rayleigh-Plateau instability as the biophysical mechanism behind this fragmentation process. This instability is akin to the surface tension-induced breakup of a liquid jet but is driven by active cortical processes including actomyosin contractility and microtubule sliding. Our fully three-dimensional simulations highlight the crucial role of actomyosin contractility, which is required to trigger the instability, and illustrate how the wavelength of the instability determines the size of the final platelets. The elasto-hydrodynamic origin of the fragmentation explains the strong acceleration of platelet biogenesis in the presence of an external flow, which we observe in agreement with experiments. Our simulations then allow us to disentangle the influence of specific flow conditions: While a homogeneous flow with uniform velocity leads to the strongest acceleration, a shear flow with a linear velocity gradient can cause fusion events of two developing platelet-sized swellings during fragmentation. A fusion event may lead to the release of larger structures which are observable as preplatelets in experiments. Together, our findings strongly indicate a mainly physical origin of fragmentation and regulation of platelet size in flow-accelerated platelet biogenesis.

Differences of the Immune Phenotype of Breast Cancer Cells after Ex Vivo Hyperthermia by Warm-Water or Microwave Radiation in a Closed-Loop System Alone or in Combination with Radiotherapy.

The treatment of breast cancer by radiotherapy can be complemented by hyperthermia. Little is known about how the immune phenotype of tumor cells is changed thereby, also in terms of a dependence on the heating method. We developed a sterile closed-loop system, using either a warm-water bath or a microwave at 2.45 GHz to examine the impact of ex vivo hyperthermia on cell death, the release of HSP70, and the expression of immune checkpoint molecules (ICMs) on MCF-7 and MDA-MB-231 breast cancer cells by multicolor flow cytometry and ELISA. Heating was performed between 39 and 44 °C. Numerical process simulations identified temperature distributions. Additionally, irradiation with 2 × 5 Gy or 5 × 2 Gy was applied. We observed a release of HSP70 after hyperthermia at all examined temperatures and independently of the heating method, but microwave heating was more effective in cell killing, and microwave heating with and without radiotherapy increased subsequent HSP70 concentrations. Adding hyperthermia to radiotherapy, dynamically or individually, affected the expression of the ICM PD-L1, PD-L2, HVEM, ICOS-L, CD137-L, OX40-L, CD27-L, and EGFR on breast cancer cells. Well-characterized pre-clinical heating systems are mandatory to screen the immune phenotype of tumor cells in clinically relevant settings to define immune matrices for therapy adaption.

Influence of patch size and chemistry on the catalytic activity of patchy hybrid nonwovens.

In this work, we provide a detailed study on the influence of patch size and chemistry on the catalytic activity of patchy hybrid nonwovens in the gold nanoparticle (Au NP) catalysed alcoholysis of dimethylphenylsilane in n-butanol. The nonwovens were produced by coaxial electrospinning, employing a polystyrene solution as the core and a dispersion of spherical or worm-like patchy micelles with functional, amino group-bearing patches (dimethyl and diisopropyl amino groups as anchor groups for Au NP) as the shell. Subsequent loading by dipping into a dispersion of preformed Au NPs yields the patchy hybrid nonwovens. In terms of NP stabilization, i.e., preventing agglomeration, worm-like micelles with poly(N,N-dimethylaminoethyl methacrylamide) (PDMA) patches are most efficient. Kinetic studies employing an extended 1st order kinetics model, which includes the observed induction periods, revealed a strong dependence on the accessibility of the Au NPs' surface to the reactants. The accessibility is controlled by the swellability of the functional patches in n-butanol, which depends on both patch chemistry and size. As a result, significantly longer induction (t ind) and reaction (t R) times were observed for the 1st catalysis cycles in comparison to the 10th cycles and nonwovens with more polar PDMA patches show a significantly lower t R in the 1st catalysis cycle. Thus, the unique patchy surface structure allows tailoring the properties of this "tea-bag"-like catalyst system in terms of NP stabilization and catalytic performance, which resulted in a significant reduction of t R to about 4 h for an optimized system.

Frequency-dependent higher-order Stokes singularities near a planar elastic boundary: Implications for the hydrodynamics of an active microswimmer near an elastic interface.

The emerging field of self-driven active particles in fluid environments has recently created significant interest in the biophysics and bioengineering communities owing to their promising future for biomedical and technological applications. These microswimmers move autonomously through aqueous media, where under realistic situations they encounter a plethora of external stimuli and confining surfaces with peculiar elastic properties. Based on a far-field hydrodynamic model, we present an analytical theory to describe the physical interaction and hydrodynamic couplings between a self-propelled active microswimmer and an elastic interface that features resistance toward shear and bending. We model the active agent as a superposition of higher-order Stokes singularities and elucidate the associated translational and rotational velocities induced by the nearby elastic boundary. Our results show that the velocities can be decomposed in shear and bending related contributions which approach the velocities of active agents close to a no-slip rigid wall in the steady limit. The transient dynamics predict that contributions to the velocities of the microswimmer due to bending resistance are generally more pronounced than those due to shear resistance. Bending can enhance (suppress) the velocities resulting from higher-order singularities whereas the shear related contribution decreases (increases) the velocities. Most prominently, we find that near an elastic interface of only energetic resistance toward shear deformation, such as that of an elastic capsule designed for drug delivery, a swimming bacterium undergoes rotation of the same sense as observed near a no-slip wall. In contrast to that, near an interface of only energetic resistance toward bending, such as that of a fluid vesicle or liposome, we find a reversed sense of rotation. Our results provide insight into the control and guidance of artificial and synthetic self-propelling active microswimmers near elastic confinements.

Precise 2D-Patterned Incompatible Catalysts for Reactions in One-Pot.

Precise and direct two-dimensional (2D) printing of the incompatible polymer acid-base catalysts and their utility in one-pot two-step reactions were shown. Multistep catalytic reactions using incompatible catalysts in a one-pot reaction cascade requires special methods and materials to isolate the catalysts from each other. In general, this is a tedious process requiring special polymer architectures as the carrier for the catalysts to preserve the activity of otherwise incompatible catalysts. We propose the immobilization of incompatible polymer catalysts, such as polymer acid and base catalysts, on a substrate in variable sizes and amounts by precise 2D printing. The terpolymers with basic (4-vinylpyridine) and acidic (styrene sulfonic acid) functionalities and methacryloyl benzophenone as a UV cross-linking unit were used for 2D printing on poly(ethylene terephthalate) (PET). The printed meshes were immersed together in a reaction solution containing (dimethoxymethyl)benzene and ethyl cyanoformate, resulting in a two-step acid-base catalyzed cascade reaction; that is, deacetalization followed by carbon-building reaction. The time-dependent consumption of (dimethoxymethyl)benzene to the intermediate benzaldehyde and the product was monitored, and a kinetic model was developed to investigate the underlying reaction dynamics. The complexity of multistep Wolf-Lamb-type reactions was generally significantly decreased by using our approach because of the easy polymerization and immobilization procedure.

Computational modeling of active deformable membranes embedded in three-dimensional flows.

Active gel theory has recently been very successful in describing biologically active materials such as actin filaments or moving bacteria in temporally fixed and simple geometries such as cubes or spheres. Here we develop a computational algorithm to compute the dynamic evolution of an arbitrarily shaped, deformable thin membrane of active material embedded in a three-dimensional flowing liquid. For this, our algorithm combines active gel theory with the classical theory of thin elastic shells. To compute the actual forces resulting from active stresses, we apply a parabolic fitting procedure to the triangulated membrane surface. Active forces are then dynamically coupled via an immersed-boundary method to the surrounding fluid whose dynamics can be solved by any standard, e.g., Lattice-Boltzmann, flow solver. We validate our algorithm using the Green's functions of Berthoumieux et al. [New J. Phys. 16, 065005 (2014)10.1088/1367-2630/16/6/065005] for an active cylindrical membrane subjected (i) to a locally increased active stress and (ii) to a homogeneous active stress. For the latter scenario, we predict in addition a nonaxisymmetric instability. We highlight the versatility of our method by analyzing the flow field inside an actively deforming cell embedded in external shear flow. Further applications may be cytoplasmic streaming or active membranes in blood flows.

Wolf-Lamb-type Catalysis in One Pot Using Electrospun Polymeric Catalyst Membranes.

Multistep catalytic transformations using incompatible catalysts (Wolf-Lamb-type) in a one-pot reaction cascade require site isolation of different catalysts by compartmentalization. In this work, the use of different electrospun catalytic membranes in a modular way as individual compartments is shown for one-pot Wolf-Lamb-type reaction cascades. The data are presented for one-pot cascade reaction sequences catalyzed by acidic and basic membranes made by electrospinning polymeric acid (poly(styrene-co-styrene sulfonic acid-co-4-methacryloyl-oxybenzophen)) and basic (poly(styrene-co-4-vinylpyridine-co-4-methacryloyl-oxybenzophen)) catalysts, respectively. The two-step, one-pot system used is the acidic catalyzed deacetylation of dimethoxybenzylacetale to benzaldehyde, which reacts with ethyl cyanoformate to result in a high yield of product (over 90%) under base-catalyzed conditions. The reaction kinetics are further monitored and evaluated by using differential equations, showing the necessity of a parameter Δt to represent a retarded start for the second reaction step. The concept provides an easy and upscalable approach for use in Wolf-Lamb-type systems.

Thermodynamic insights into the entropically driven self-assembly of amphiphilic dyes in water.

Self-assembly of amphiphilic dyes and π-systems are more difficult to understand and to control in water compared to organic solvents due to the hydrophobic effect. Herein, we elucidate in detail the self-assembly of a series of archetype bolaamphiphiles bearing a naphthalene bisimide (NBI) π-core with appended oligoethylene glycol (OEG) dendrons of different size. By utilizing temperature-dependent UV-vis spectroscopy and isothermal titration calorimetry (ITC), we have dissected the enthalpic and entropic parameters pertaining to the molecules' self-assembly. All investigated compounds show an enthalpically disfavored aggregation process leading to aggregate growth and eventually precipitation at elevated temperature, which is attributed to the dehydration of oligoethylene glycol units and their concomitant conformational changes. Back-folded conformation of the side chains plays a major role, as revealed by molecular dynamics (MD) and two dimensional NMR (2D NMR) studies, in directing the association. The sterical effect imparted by the jacketing of monomers and dimers also changes the aggregation mechanism from isodesmic to weakly anti-cooperative.

Creeping motion of a solid particle inside a spherical elastic cavity⋆.

On the basis of the linear hydrodynamic equations, we present an analytical theory for the low-Reynolds-number motion of a solid particle moving inside a larger spherical elastic cavity which can be seen as a model system for a fluid vesicle. In the particular situation where the particle is concentric with the cavity, we use the stream function technique to find exact analytical solutions of the fluid motion equations on both sides of the elastic cavity. In this particular situation, we find that the solution of the hydrodynamic equations is solely determined by membrane shear properties and that bending does not play a role. For an arbitrary position of the solid particle within the spherical cavity, we employ the image solution technique to compute the axisymmetric flow field induced by a point force (Stokeslet). We then obtain analytical expressions of the leading-order mobility function describing the fluid-mediated hydrodynamic interactions between the particle and the confining elastic cavity. In the quasi-steady limit of vanishing frequency, we find that the particle self-mobility function is higher than that predicted inside a rigid no-slip cavity. Considering the cavity motion, we find that the pair-mobility function is determined only by membrane shear properties. Our analytical predictions are supplemented and validated by fully resolved boundary integral simulations where a very good agreement is obtained over the whole range of applied forcing frequencies.

Elucidating Aggregation Pathways in the Donor-Acceptor Type Molecules p-DTS(FBTTh2)2 and p-SIDT(FBTTh2)2.

We investigated the aggregation behavior of the donor-acceptor molecules p-DTS(FBTTh2)2 (T1) and p-SIDT(FBTTh2)2 (H1) in MTHF solutions. Using optical spectroscopy, we found that T1 forms aggregates in solution while H1 aggregates only when processed as a thin film, but not in solution. Free energy molecular dynamics (MD) simulations based on force fields derived from quantum-mechanical density functional theory fully reproduce this difference. Our simulations reveal that this difference is not due to the lengthy carbon side chains. Rather, the molecular symmetry of T1 allows for an aggregated state in which the central donor units are spatially well-separated while a similar configuration is sterically impossible for H1. As a consequence, any aggregation of H1 necessarily involves aggregation of the central donors which requires, as a first step, stripping the central donor of its protective MTHF solvation shell. This unfavorable process leads to a significant kinetic hindrance for aggregation and explains the strongly differing aggregation behavior of T1/H1 in MTHF despite their otherwise similar structures.