We performed coarse-grained molecular dynamics simulations in order to understand the mechanism of membrane poration by shock wave induced nanobubble collapse. Pressure profiles obtained from the simulations show that the shock wave initially hits the membrane and is followed by a nanojet produced by the nanobubble collapse. While in the absence of the nanobubble, the shock wave with an impulse of up to 18 mPa s does not create a pore in the membrane, in the presence of a nanobubble even a smaller impulse leads to the poration of the membrane. Two-dimensional pressure maps depicting the pressure distributed over the lateral area of the membrane reveal the differences between these two cases. In the absence of a nanobubble, shock pressure is evenly distributed along the lateral area of the membrane, while in the presence of a nanobubble an unequal distribution of pressure on the membrane is created, leading to the membrane poration. The size of the pore formed depends on both shock wave velocity and shock wave duration. The results obtained here show that these two properties can be tuned to make pores of various sizes.

To study the properties of poloxamer molecules P85 and P188 and micelles containing these poloxamers in bulk water and also next to lipid bilayers, we performed coarse-grained molecular dynamics computer simulations. We used MARTINI force-field and adjusted Lennard-Jones nonbonded interaction strength parameters for poloxamer beads to take into account the presence of polarizable water. Simulations of systems containing poloxamer molecules or micelles solvated in bulk water showed that structural properties, such as radii of gyration of the molecules and micelles, agree with the ones inferred from experiments. We observed that P85 micelle is almost spherical in shape, whereas the P188 micelle is distorted from being spherical. Simulations containing systems with the water-lipid bilayer interface showed that hydrophilic blocks of poloxamers interact with lipid headgroups of the bilayer and remain at the interface, whereas hydrophobic blocks prefer to insert into the central hydrophobic region of the bilayer. Simulations containing poloxamer micelles next to lipid bilayer showed no permeation of these micelles into the bilayer. To study the "healing" properties of P188 poloxamer, we performed simulations on a system containing a P188 micelle next to "damaged" lipid bilayer containing a pore. We observed that hydrophobic chains of poloxamers got inserted into the bilayer through the pore region, ultimately closing the pore.

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Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CART cell therapies, and mathematical modeling of CART cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CART cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity. Keywords cellular kinetic-pharmacodynamic model, chimeric antigen receptor-T cell (CAR-T cell) therapy, model-informed drug development (MIDD), quantitative systems pharmacology (QSP)

Passage of a shock wave across living organisms may produce bubbles in the blood vessels and capillaries. It was suggested that collapse of these bubbles imposed by an impinging shock wave can be responsible for the damage or even destruction of the blood-brain barrier. To check this possibility, we performed molecular dynamics computer simulations on systems that contained a model of tight junction from the blood-brain barrier. In our model, we represent the tight junction by two pairs of interacting proteins, claudin-15. Some of the simulations were done in the absence of a nanobubble, some in its presence. Our simulations show that when no bubble is present in the system, no damage to tight junction is observed when the shock wave propagates across it. In the presence of a nanobubble, even when the impulse of the shock wave is relatively low, the implosion of the bubble causes serious damage to our model tight junction.

Collapse of bubbles, microscopic or nanoscopic, due to their interaction with the impinging pressure wave produces a jet of particles moving in the direction of the wave. If there is a surface nearby, the high-speed jet particles hit it, and as a result damage to the surface is produced. This cavitation effect is well known and intensely studied in case of microscopic sized bubbles. It can be quite damaging to materials, including biological tissues, but it can also be beneficial when controlled, like in case of sonoporation of biological membranes for the purpose of drug delivery. Here we consider recent simulation work performed to study collapse of nanobubbles exposed to shock waves, in order to understand the detailed mechanism of the cavitation induced damage to soft materials, such as biological membranes. We also discuss the connection of the cavitation effect with the traumatic brain injury caused by blasts. Specifically, we consider possible damage to model membranes containing lipid bilayers, bilayers with embedded ion channel proteins like the ones found in neural cells and also protein assemblies found in the tight junction of the blood brain barrier.

To study the interaction between poloxamer molecules and lipid bilayers using molecular dynamics simulation technique with the united-atom resolution, we augmented the GROMOS force-field to include poloxamers. We validated the force-field by calculating the radii of gyration of two poloxamers, P85 and P188, solvated in water and by considering the poloxamer density distributions at the air/water interface. The emphasis of our simulations was on the study of the interaction between poloxamers and lipid bilayer. At the water/lipid bilayer interface, we observed that both poloxamers studied, P85 and P188, behaved like surfactants: the hydrophilic blocks of poloxamers became adsorbed at the polar interface, while their hydrophobic block penetrated the interface into the aliphatic tail region of the lipid bilayer. We also observed that when P85 and P188 poloxamers interacted with damaged membranes that contained pores, the hydrophobic blocks of copolymers penetrated into the membrane in the vicinity of the pore and compressed the membrane. Due to this compression, water molecules were evacuated from the pore.

We performed a series of coarse-grained computer simulations in order to study how the placement of melittin and magainin-h2 antimicrobial peptides on the surface of the bilayer changes the local pressure profiles in the bilayer. The simulations were done using the NPT ensemble when the total stress on the bilayer was zero and also using the NP(z)AT ensemble, with a nonzero total stress. In the NPT ensemble, although the total stress was zero, each leaflet of the bilayer experienced a nonzero stress, and the stresses are equal by magnitude, but opposite in their direction. The observed stresses acting on the monolayers may cause the rupture of the monolayers to release the stress. Our simulations were done at different peptide to lipid ratio (P/L). When the P/L ratio was 1/50 there was no large difference in the local pressure profile for bilayers with melittin versus bilayers with magainin-h2. When simulations were performed in the NP(z)AT ensemble at P/L = 3/100 we observed a large difference in the pressure profiles in the bilayers with melittin peptides compared to the bilayer with magainin-h2. The observed in this case difference in stress may explain the difference in actions of melittin and magainin at high P/L.