Cutting soft matter: scaling relations controlled by toughness, friction, and wear.

Cutting mechanics of soft solids is gaining rapid attention thanks to its promising benefits in material characterization and other applications. However, a full understanding of the physical phenomena is still missing, and several questions remain outstanding. E.g.: How can we directly and reliably measure toughness from cutting experiments? What is the role of blade sharpness? In this paper, we explore the simple problem of wire cutting, where blade sharpness is only defined by the wire radius. Through finite element analysis, we obtain a simple scaling relation between the wire radius and the steady-state cutting force per unit sample thickness. The cutting force is independent of the wire radius if the latter is below a transition length, while larger radii produce a linear force-radius correlation. The minimum cutting force, for small radii, is given by cleavage toughness, i.e., the surface energy required to break covalent bonds in the crack plane. The force-radius slope is instead given by the wear shear strength in the material. Via cutting experiments on polyacrylamide gels, we find that the magnitude of shear strength is close to the work of fracture of the material, i.e., the critical strain energy density required to break a pristine sample in uniaxial tension. The work of fracture characterizes the toughening contribution from the fracture process zone (FPZ), which adds to cleavage toughness. Our study provides two important messages, that answer the above questions: toughness can be estimated from wire-cutting experiments from the intercept of the force-radius linear correlation, as previously explored. However, as we discovered, this only estimates cleavage toughness. Additionally, the force-radius slope is correlated with the work of fracture, giving an estimation of the dissipative contributions from the FPZ.

Force decomposition and toughness estimation from puncture experiments in soft solids.

Several medical applications, like drug delivery and biosensing, are critically preceded by the insertion of needles and microneedles into biological tissue. However, the mechanical process of needle insertions, especially at high velocities, is currently not fully understood. Here, we explore the insertion of hollow needles into transparent silicone samples with an insertion velocity v ranging from 0.1 mm s-1 to 2.3 m s-1 (with needle radius R = 101.5 µm, thus strain rates ∼v/R ranging from 1 s-1 to 2.3 × 104 s-1). We use a double-insertion method, where the needle is inserted and re-inserted at the same location, to estimate the fracture properties of the material. The deflection of the specimen's free surface is found to be different between insertion and re-insertion experiments for identical needle positions, which is associated with different force magnitudes between insertion/reinsertion. This aspect was previously neglected in the original double-insertion method, thus here we develop a method based on imaging, image analyses and force measurements to decompose the measured force into individual force components, including deflection force Fd, frictional and spreading force Ff + Fs, and cutting force Ft. We estimate that the toughness Γ of our silicone samples, calculated using the cutting force Ft and the crack dimensions, increases with needle velocity, and ranges within observed values in previous literature for the same material and for some soft biological materials. In addition to toughness Γ, other parameters, such as critical force Fc and mechanical work Wc, also show strain-rate dependence, suggesting tissue stiffening, due to accumulated strain energy, at high speeds.

Energetics of cytoskeletal gel contraction.

Cytoskeletal gels are prototyped to reproduce the mechanical contraction of the cytoskeleton in vitro. They are composed of a polymer network (backbone), swollen by the presence of a liquid solvent, and active molecules (molecular motors, MMs) that transduce chemical energy into the mechanical work of contraction. These motors attach to the polymer chains to shorten them and/or act as dynamic crosslinks, thereby constraining the thermal fluctuations of the chains. We describe both mechanisms thermodynamically as a microstructural reconfiguration, where the backbone stiffens to motivate solvent (out)flow and accommodate contraction. Via simple steady-state energetic analysis, under the simplest case of isotropic deformation, we quantify the mechanical energy required to achieve contraction as a function of polymer chain density and molecular motor density. We identify two limit regimes, namely, fast MM activation (FM), and slow MM activation (SM). FM assumes that MMs provide all the available mechanical energy 'instantaneously' and leave the polymer in a stiffened state, i.e. the MM activity occurs at a time scale that is much smaller than that of solvent diffusion. SM assumes that the timescale for MM activation is much longer than that of solvent diffusion. To achieve the same final contracted state, FM requires the largest amount of work per unit reference volume, while SM requires the least. For all intermediate cases where the timescale of MM activation is comparable with that of solvent diffusion, the required work ranges between these two limits. We provide all these quantities as a function of chain density and MM density. Finally, we compare our results on contraction energetics with experiments and observe good agreement.

How friction and adhesion affect the mechanics of deep penetration in soft solids.

The mechanics of puncture and soft solid penetration is commonly explored with the assumption of frictionless contact between the needle (penetrator) and the specimen. This leads to the hypothesis of a constant penetration force. Experimental observations, however, report a linear increment of penetration force with needle tip depth. This force increment is due to friction and adhesion, and this paper provides its correlation with the properties of the cut material. Specifically, the force-depth slope depends on the rigidity and toughness of the soft material, the radius of the penetrator and the interfacial properties (friction and adhesion) between the two. We observe that adhesion prevails at relatively low toughness, while friction is dominant at high toughness. Finally, we compare our results with experiments and observe good agreement. Our model provides a valuable tool to predict the evolution of penetration force with depth and to measure the friction and adhesion characteristics at the needle-specimen interface from puncture experiments.

The morphological role of ligand inhibitors in blocking receptor- and clathrin-mediated endocytosis.

Cells often internalize particles through endocytic pathways that involve the binding between cell receptors and particle ligands, which drives the cell membrane to wrap the particle into a delivery vesicle. Previous findings showed that receptor-mediated endocytosis is impossible for spherical particles smaller than a minimum size because of the energy barrier created by membrane bending. In this study, we investigate the morphological role of ligand inhibitors in blocking endocytosis, inspired by antibodies that inhibit virus ligands to prevent infection. While ligand inhibitors have the obvious effect of reducing the driving force due to adhesion, they also have a nontrivial (morphological) impact on the entropic and elastic energy of the system. We determine the necessary conditions for endocytosis by considering the additional energy barrier due to the membrane bending to wrap the inhibiting protrusions. We find that inhibitors increase the minimum radius previously reported, depending on their density and size. In addition, we extend this result to the case of clathrin-mediated endocytosis, which is the most common pathway for virus entry. The assembly of a clathrin coat with a spontaneous curvature increases the energy barrier and sets a maximum particle size (in agreement with experimental observations on spherical particles). Our investigation suggests that morphological considerations can inform the optimal design of neutralizing viral antibodies and new strategies for targeted nanomedicine.

Quasi-Linear Viscoelastic Characterization of Soft Tissue-Mimicking Materials.

We present a novel method based on the quasi-linear viscoelastic (QLV) theory to describe the time-dependent behavior of soft materials. Unlike previous methods for deriving QLV parameters, we characterize the elastic and viscous behavior of materials separately by using two different sets of experiments. To model the nonlinear elastic behavior, we fit the elastic stress response with a one-term Ogden model. Then, we model the relaxation behavior with a Prony series to compare the stress relaxation of the material at different timescales. This new method allows us to characterize materials with narrow confidence intervals (high accuracy), independently from the loading conditions. We validate our model using samples made of phantom materials that mimic normal and cancerous prostate tissues in terms of Young's modulus. Our model is shown to distinguish materials with similar elastic (viscous) properties but different viscous (elastic) properties. Drawing a precise distinction between the phantoms, this method could be useful for prostate cancer (PCa) diagnosis; but significant clinical studies will be needed in the future.

Role of boundary conditions in determining cell alignment in response to stretch.

The ability of cells to orient in response to mechanical stimuli is essential to embryonic development, cell migration, mechanotransduction, and other critical physiologic functions in a range of organs. Endothelial cells, fibroblasts, mesenchymal stem cells, and osteoblasts all orient perpendicular to an applied cyclic stretch when plated on stretchable elastic substrates, suggesting a common underlying mechanism. However, many of these same cells orient parallel to stretch in vivo and in 3D culture, and a compelling explanation for the different orientation responses in 2D and 3D has remained elusive. Here, we conducted a series of experiments designed specifically to test the hypothesis that differences in strains transverse to the primary loading direction give rise to the different alignment patterns observed in 2D and 3D cyclic stretch experiments ("strain avoidance"). We found that, in static or low-frequency stretch conditions, cell alignment in fibroblast-populated collagen gels correlated with the presence or absence of a restraining boundary condition rather than with compaction strains. Cyclic stretch could induce perpendicular alignment in 3D culture but only at frequencies an order of magnitude greater than reported to induce perpendicular alignment in 2D. We modified a published model of stress fiber dynamics and were able to reproduce our experimental findings across all conditions tested as well as published data from 2D cyclic stretch experiments. These experimental and model results suggest an explanation for the apparently contradictory alignment responses of cells subjected to cyclic stretch on 2D membranes and in 3D gels.

Contraction of polymer gels created by the activity of molecular motors.

We propose a theory based on non-equilibrium thermodynamics to describe the mechanical behavior of an active polymer gel created by the inclusion of molecular motors in its solvent. When activated, these motors attach to the chains of the polymer network and shorten them creating a global contraction of the gel, which mimics the active behavior of a cytoskeleton. The power generated by these motors is obtained by an ATP hydrolysis reaction, which transduces chemical energy into mechanical work. The latter is described by an increment of strain energy in the gel due to an increased stiffness. This effect is described with an increment of the cross-link density in the polymer network, which reduces its entropy. The theory then considers polymer network swelling and species diffusion to describe the transient passive behavior of the gel. We finally formulate the problem of uniaxial contraction of a slab of gel and compare the results with experiments, showing good agreement.

Quantifying the Impact of Cancer on the Viscoelastic Properties of the Prostate Gland using a Quasi-Linear Viscoelastic Model.

Pathological disorders can alter the mechanical properties of biological tissues, and studying such changes can help to better understand the disease progression. The prostate gland is no exception, as previous studies have shown that cancer can affect its mechanical properties. However, most of these studies have focused on the elastic properties of the tissue and have overlooked the impact of cancer on its viscous response. To address this gap, we used a quasi-linear viscoelastic model to investigate the impact of cancer on both the elastic and viscous characteristics of the prostate gland. By comparing the viscoelastic properties of segments influenced by cancer and those unaffected by cancer in 49 fresh prostates, removed within two hours after prostatectomy surgery, we were able to determine the influence of cancer grade and tumor volume on the tissue. Our findings suggest that tumor volume significantly affects both the elastic modulus and viscosity of the prostate (p-value less than 2%). Specifically, we showed that cancer increases Young's modulus and shear relaxation modulus by 20%. These results have implications for using mechanical properties of the prostate as a potential biomarker for cancer. However, developing an in vivo apparatus to measure these properties remains a challenge that needs to be addressed in future research. STATEMENT OF SIGNIFICANCE: This study is the first to explore how cancer impacts the mechanical properties of prostate tissues using a quasi-linear viscoelastic model. We examined 49 fresh prostate samples collected immediately after surgery and correlated their properties with cancer presence identified in pathology reports. Our results demonstrate a 20% change in the viscoelastic properties of the prostate due to cancer. We initially validated our approach using tissue-mimicking phantoms and then applied it to differentiate between cancerous and normal prostate tissues. These findings offer potential for early cancer detection by assessing these properties. However, conducting these tests in vivo remains a challenge for future research.

Mechanics of diffusion-mediated budding and implications for virus replication and infection.

Budding allows virus replication and macromolecular secretion in cells through the formation of a membrane protrusion (bud) that evolves into an envelope. The largest energetic barrier to bud formation is membrane deflection and is trespassed primarily thanks to nucleocapsid-membrane adhesion. Transmembrane proteins (TPs), which later form the virus ligands, are the main promotors of adhesion and can accommodate membrane bending thanks to an induced spontaneous curvature. Adhesive TPs must diffuse across the membrane from remote regions to gather on the bud surface, thus, diffusivity controls the kinetics. This paper proposes a simple model to describe diffusion-mediated budding unravelling important size limitations and size-dependent kinetics. The predicted optimal virion radius, giving the fastest budding, is validated against experiments for coronavirus, HIV, flu and hepatitis. Assuming exponential replication of virions and hereditary size, the model can predict the size distribution of a virus population. This is verified against experiments for SARS-CoV-2. All the above comparisons rely on the premise that budding poses the tightest size constraint. This is true in most cases, as demonstrated in this paper, where the proposed model is extended to describe virus infection via receptor- and clathrin-mediated endocytosis, and via membrane fusion.

Engineered nasal dry powder for the encapsulation of bioactive compounds.

In this review, we present the potential of nasal dry powders to deliver stable bioactive compounds and their manufacture using spray-drying (SD) techniques to achieve encapsulation. We also review currently approved and experimental excipients used for powder manufacturing for specific target drugs. Polymers, sugars, and amino acids are recommended for specific actions, such as mucoadhesive interactions, to increase residence time on the nasal mucosa; for example, high-molecular weight polymers, such as hydroxypropyl methylcellulose, or mannitol, which protect the bioactive compounds, increase their stability, and enhance drug absorption in the nasal mucosa; and leucine, which promotes particle formation and improves aerosol performance.