A doublet mechanics model for the ultrasound characterization of malignant tissues

Non invasive ultrasound-based imaging systems are being more commonly used in clinical bio-microscopy applications for both ex vivo and in vivo analysis of tissue pathological and physiological states. These modalities usually employ high-frequency ultrasound systems to overcome spatial resolution limits of conventional clinical diagnostic approaches. Biological tissues are non continuous, non homogeneous and exhibit a multiscale organization from the sub-cellular level (￡1 mm) to the organ level (31 cm). When the ultrasonic wavelength used to probe the tissues becomes comparable with the tissue's microstructure scale, the propagation and reflection of ultrasound waves cannot be fully interpreted employing classical models developed within the continuum assumption. In this study, we present a multiscale model for analyzing the mechanical response of a non-continuum double-layer system exposed to an ultrasound source. The model is developed within the framework of the Doublet Mechanics theory and can be applied to the non-invasive analysis of complex biological tissues.

Time dependent dispersion of nanoparticles in blood vessels

The dispersion of intravasculary injected nanoparticles can be efficiently described by introducing an effective diffusion coefficient Deff which quantifies the longitudinal mass transport in blood vessels. Here, the original work of Gill and Sankarasubramanian was modified and extended to include 1) the variati- on over time of Deff;2) the permeability of the blood vessels and 3) non-Newtonian rheology of blood. A general solution was provided for Deff depending on space (?), time (?), plug radius (?c) and a subset of permeability parameters. It was shown that increasing the vessel plug radius (thus hematocrit) or permeability leads to a reduction in Deff, limiting the transport of nanoparticles across those vessels. It was also shown that the asymptotic time beyond which the solution attains the steady state behaviour is always independent of the plug radius and wall permeability. The analysis presented can more accurately predict the transport of nanoparticles in blood vessels, compared to previously developed models.

Tribological behavior of shape-specific microplate-enriched synovial fluids on a linear two-axis tribometer

Nano-and micro-particles are being increasingly used to tune interfacial frictional properties in diverse applications,from friction modifiers in industrial lubrication to enhanced biological fluids in human osteoarthritic joints.Here,we assessed the tribological properties of a simulated synovial fluid enriched with non-spherical,poly lactic-co-glycolic acid(PLGA)microparticles(μPL)that have been previously demonstrated for the pharmacological management of osteoarthritis(OA).Three different μPL configurations were fabricated presenting a 20μm×20μm square base and a thickness of 5μm(thin,5H μPL),10μm(10H μPL),and 20μm(cubical,20H μPL).After extensive morphological and physicochemical characterizations,the apparent Young’s modulus of the μPL was quantified under compressive loading returning an average value of~6 kPa,independently of the particle morphology.Then,using a linear two-axis tribometer,the static(μ_(s))and dynamic(μ_(d))friction coefficients of the μPL-enriched simulated synovial fluid were determined in terms of particle configuration and concentration,varying from 0(fluid only)to 6×10^(5) μPL/mL.The particle morphology had a modest influence on friction,possibly because the μPL were fully squeezed between two mating surfaces by a 5.8 N normal load realizing boundary-like lubrication conditions.Differently,friction was observed to depend on the dimensionless parameterW,defined as the ratio between the total volume of the μPL enriching the simulated synovial fluid and the volume of the fluid itself.Both coefficients of friction were documented to grow withWreaching a plateau of μ_(s)~0.4 and μ_(d)~0.15,already at Ω~2×10^(-3).Future investigations will have to systematically analyze the effect of sliding velocity,normal load,and rigidity of the mating surfaces to elucidate in full the tribological behavior of μPL in the context of osteoarthritis.

Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth

Taxane efficacy in triple negative breast cancer(TNBC)is limited by insufficient tumor accumulation and severe off-target effects.Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug.Here,1,000 nm×400 nm discoidal polymeric nanoconstructs(DPN)encapsulating docetaxel(DTXL)and the near infrared compound Iipid-Cy5 were engineered.DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol)template with a polymer mixture comprising poly(lactic-co-glycolic acid)(PLGA)and poly(ethylene glycol)diacrylate(PEG-DA)chains together with therapeutic and imaging agents.The resulting“multi-passage”DPN exhibited higher DTXL loading,Iipid-Cy5 stability,and stiffness as compared to the conventional"single-passage"approach.Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof.Empty DPN had no toxicity on TNBC cells,whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL(IC_(50)=2.6 nM±1.0 nM vs.7.0 nM±1.09 nM at 72 h).In orthotopic murine models,DPN accumulated in TNBC more efficiently than free-DTXL.With only 2 mg/kg DTXL,intravenously administered every 2 days for a total of 13 treatments,DTXL-DPN induced tumor regression and were associated to an overall 80%survival rate as opposed to a 30%survival rate for free-DTXL,at 120 days.All untreated mice succumbed before 90 days.Collectively,this data demonstrates that vascular confined multi-passage DPN,biomimicking the behavior of circulating platelets,can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.