Greater Pressure Change Research Articles

Assessing the aneurysm occlusion efficacy of a shear-thinning biomaterial in a 3D-printed model

Metallic coil embolization is a common method for the endovascular treatment of visceral artery aneurysms (VAA) and visceral artery pseudoaneurysms (VAPA); however, this treatment is suboptimal due to the high cost of coils, incomplete volume occlusion, poor reendothelialization, aneurysm puncture, and coil migration. Several alternative treatment strategies are available, including stent flow diverters, glue embolics, gelfoam slurries, and vascular mesh plugs—each of which have their own disadvantages. Here, we investigated the in vitro capability of a shear-thinning biomaterial (STB), a nanocomposite hydrogel composed of gelatin and silicate nanoplatelets, for the minimally-invasive occlusion of simple necked aneurysm models. We demonstrated the injectability of STB through various clinical catheters, engineered an in vitro testing apparatus to independently manipulate aneurysm neck diameter, fluid flow rate, and flow waveform, and tested the stability of STB within the models under various conditions. Our experiments show that STB is able to withstand at least 1.89 Pa of wall shear stress, as estimated by computational fluid dynamics. STB is also able to withstand up to 10 mL s−1 pulsatile flow with a waveform mimicking blood flow in the human femoral artery and tolerate greater pressure changes than those in the human aorta. We ultimately found that our in vitro system was limited by supraphysiologic pressure changes caused by aneurysm models with low compliance.

Role of molecular architecture on the relative efficacy of aurein 2.5 and modelin 5

In order to gain an insight into the mechanism of antimicrobial peptide action, aurein 2.5 and modelin-5 were studied. When tested against Staphylococcus aureus, aurein 2.5 showed approximately 5-fold greater efficacy even though the higher net positive charge and higher helix stability shown by modelin-5 would have predicated modelin-5 to be the more effective antimicrobial. However, in the presence of S. aureus membrane mimics, aurein 2.5 showed greater helical content (75% helical) relative to modelin-5 (51% helical) indicative of increase in membrane association. This was supported by monolayer data showing that aurein 2.5 (6.6mNm−1) generated greater pressure changes than modelin-5 (5.3mNm−1). Peptide monolayers indicted that modelin-5 formed a helix horizontal to the plane of an asymmetric interface which would be supported by the even distribution of charge and hydrophobicity along the helical long axis and facilitate lysis by non-specific membrane binding. In contrast, a groove structure observed on the surface of aurein 2.5 was predicted to be the cause of enhanced lipid binding (Kd=75μM) relative to modelin-5 (Kd=118μM) and the balance of hydrophobicity along the aurein 2.5 long axis supported deep penetration into the membrane in a tilt formation. This oblique orientation generates greater lytic efficacy in high anionic lipid (71%) compared to modelin-5 (32%).

Influence of C-Terminal Amidation on the Efficacy of Modelin-5

To gain insight into the effects of amidation on the mechanism of membrane interaction, we studied two peptides modelin-5-COOH and modelin-5-CONH(2) and found they exhibit high surface activities (23.2 and 27.1 mN/m, respectively). When they were tested against Escherichia coli, amidation was seen to increase efficacy approximately 10-fold. Our results demonstrated that both peptides adopted low levels of α-helix in solution (<20%); however, in the presence of E. coli lipid extract, modelin-5-CONH(2) had a greater propensity (69%) than modelin-5-COOH (32%) to generate α-helical structure. The binding coefficient for both peptides was ∼10 μM, and the Hill coefficient approximated 1, suggesting that for both peptides the interactions with E. coli membranes were monomeric and comparable in strength. The peptides showed a clear preference for anionic lipid, with monolayer data showing that enhanced levels of helicity were associated with a greater pressure change (∼6 mN/m). Use of fluorescein-phosphatidylethanolamine showed the amidated version was able to generate greater levels of membrane disruption, which was confirmed by thermodynamic analysis. The data would imply that both peptides are able to initially bind to bilayer structures, but upon binding, the amidation stabilizes helix formation. This would be expected to help overcome a key rate-limiting step and generate higher local concentrations of peptide at the bilayer interface, which in turn would be predicted to increase efficacy.

Effects of middle-ear pressure on the auditory periphery

A series of 52 young adult guinea pigs were used to study the effects of middle-ear pressure on the electrophysiological response of the cochlea. A round window electrode was used to record the cochlear microphonic (CM) and N1 action potential. Pure tones from 80 to 30 000 Hz were used to elicit the CM response; 0.1-msec clicks presented at ten clicks per second were used for N1 response studies. Middle-ear pressures ranging from −300 to +300 mm H20 were examined. Both pressure and frequency were examined in a pseudorandom order. CM response sensitivity (1 μV isopotential contour) and dynamic range of the CM were measured. Greater changes in the cochlear potentials were noted for negative pressures than for positive pressures. Also, it was found that there was a greater falloff of sensitivity of the CM as a function of pressure for small pressure variations than for greater pressure changes. The effects of middle-ear pressure were frequency dependent. Changes in the dynamic range of the CM were found to be consistent with predicted middle-ear transmission changes. [This research was supported by the Office of Naval Research N00014-67-A-0103-0031.]