_:b41512378 . _:b41512403 . _:b41512384 "A number of these papers also produced phase-diagrams relating the conformation to other properties of the flow, such as shear rate, confinement and flow velocity>>2223<<. The slipper phase, according to the work of Fedosov and colleagues2223, occurs when both shear rates and confinement are low, however the shear rates and confinement parameters of our simulations favour the parachute conformation23." . _:b41512385 . _:b41512384 . _:b581740363 . _:b41512386 . . _:b581740359 . . "PMC0" . . _:b41512382 . . _:b41512401 "Flexible nanoparticles, such as liposomes and polymersomes, have been demonstrated to translocate across pores considerably smaller than themselves>>3637<<. Therefore, flexible nanoparticles may perform differently than more rigid nanoparticles, such as gold. The addition of active targeting domains, such as iRGD, to nanoparticles can also improve uptake properties of nanoparticles from the" . _:b41512392 . _:b41512381 "results and discussion" . . _:b581740357 . _:b41512400 "Generally sizes between 40-100\u2009nm have previously been demonstrated to persist in the blood due to reduced loss due to blood extravasation and filtration by the reticuloendothelial systems of the liver, spleen and kidneys>>153435<<. Our results for specific delivery to a tumour fall within this range, thus making the data more significant with respect to translation from simulation to experimental data. Nanoparticle mechanical properties will also influence the EPR" . _:b41512399 "Generally sizes between 40-100\u2009nm have previously been demonstrated to persist in the blood due to reduced loss due to blood extravasation and filtration by the reticuloendothelial systems of the liver, spleen and kidneys>>1534<<35. Our results for specific delivery to a tumour fall within this range, thus making the data more significant with respect to translation from simulation to experimental data. Nanoparticle mechanical properties will also influence the" . _:b581740356 . _:b581740359 . . _:b581740358 . _:b41512395 . _:b581740360 . _:b581740362 . . _:b41512397 "This concept forms part of the enhanced permeability and retention (EPR) effect or passive-targeting, that has been proven previously in many studies>>3233<<. The EPR effect is based on the combination of the increased permeability of the vasculature supplying tumours and reduction or absence of lymphatic vessels that form a drainage network from tissues back to the blood. Therefore" . _:b41512393 . . _:b41512400 . _:b41512403 . . _:b41512388 . . _:b41512398 . . _:b41512381 _:b41512382 . _:b41512381 _:b41512383 . . . _:b581740358 . . _:b41512378 _:b41512380 . . _:b581740356 . _:b581740361 . _:b581740357 . _:b41512378 _:b41512379 . _:b581740358 . _:b581740359 . _:b581740360 . _:b41512390 "This generally improves the systemic half-life and reduces immune cell interaction properties, thus increasing the potential therapeutic load at target tissues>>27<<28. Therefore, in our simulations we can assume that such nanoparticles will be inert. In previous studies, it has been demonstrated that certain compositions of nanoparticles can interact with both themselves and red blood cells, with" . . _:b581740363 . _:b41512381 _:b41512400 . _:b41512381 _:b41512401 . _:b581740360 . _:b41512394 "A similar but less defined pattern in flow is also apparent in the work of Tan and co-workers and McWhirter and colleagues>>18<<31." . _:b41512381 _:b41512402 . _:b581740361 . _:b581740362 . _:b41512381 _:b41512403 . _:b581740362 . _:b581740363 . _:b581740357 "2"^^ . _:b581740356 . . _:b581740356 "2"^^ . _:b41512381 _:b41512384 . _:b41512381 _:b41512385 . _:b41512381 _:b41512386 . _:b581740359 "2"^^ . _:b41512385 "The slipper phase, according to the work of Fedosov and colleagues>>2223<<, occurs when both shear rates and confinement are low, however the shear rates and confinement parameters of our simulations favour the parachute conformation23." . _:b41512381 _:b41512387 . _:b41512381 _:b41512388 . _:b41512381 _:b41512389 . _:b41512381 _:b41512390 . _:b41512379 . _:b581740358 "2"^^ . _:b41512381 _:b41512391 . _:b41512381 _:b41512392 . _:b41512381 _:b41512393 . _:b41512381 _:b41512394 . _:b41512395 "A similar but less defined pattern in flow is also apparent in the work of Tan and co-workers and McWhirter and colleagues>>1831<<." . _:b581740361 . . _:b41512381 _:b41512395 . _:b41512381 _:b41512396 . _:b41512381 _:b41512397 . _:b41512381 _:b41512398 . . _:b41512381 _:b41512399 . . . . _:b41512380 . _:b41512393 "Similar conclusions, demonstrating improved nanoparticle distribution with higher haematocrit, were made by Tan and colleagues>>31<<. Whilst their conclusions are similar, they focus on scenarios in the presence or absence of RBCs, using a haematocrit of 38%, which is considerably higher than the 10-12% expected in capillaries." . . . _:b41512381 . _:b41512382 . _:b41512403 "fenestrations have been reported at tumour vasculature, fenestration density, irregular flow and poor cellular junction formation also are characteristic of tumour vasculature, inevitably influencing overall uptake into tumour tissues>>35<<. This experiment also demonstrates the importance of the inclusion of Brownian fluctuations within laminar flow models, as no delivery could be achieved without its consideration." . _:b41512383 . . _:b581740361 "2"^^ . _:b41512390 . _:b581740360 "2"^^ . . _:b41512392 "It can also regulate accessibility of various blood components to the wall based on particle properties such as charge and size>>30<<." . . _:b581740363 "2"^^ . _:b581740357 . _:b41512388 "Several studies have demonstrated that both specific and non-specific interaction with proteins can affect the nanoparticle residency in the blood>>2425<<. Protein interactions are dictated by the surface chemistry and charge. A common solution to this is to use a coating that limits protein adsorption such as polyethylene glycol (PEG) or similar26." . _:b41512378 . _:b41512398 "Generally sizes between 40-100\u2009nm have previously been demonstrated to persist in the blood due to reduced loss due to blood extravasation and filtration by the reticuloendothelial systems of the liver, spleen and kidneys>>15<<3435. Our results for specific delivery to a tumour fall within this range, thus making the data more significant with respect to translation from simulation to experimental data. Nanoparticle mechanical properties will also influence the" . _:b581740362 "2"^^ . . _:b41512379 . _:b41512386 "The slipper phase, according to the work of Fedosov and colleagues2223, occurs when both shear rates and confinement are low, however the shear rates and confinement parameters of our simulations favour the parachute conformation>>23<<." . "10.1038%2Fsrep10649" . _:b41512388 . _:b41512389 . _:b41512390 . _:b41512391 . . _:b41512384 . _:b41512387 . _:b41512394 . _:b41512385 . _:b41512401 . _:b41512378 "methods" . _:b41512386 . . . _:b41512387 . _:b41512383 "Previous studies have utilised several techniques, most notably immersed finite element methods, to incorporate red blood cell deformation and red blood cell interactions within flow models>>212223<<. Although a similar approach could be utilised within the model described, the additional computational burden required would limit the capabilities of the model to include much of the desired additional functionality. In these" . . _:b41512396 . _:b41512383 . . _:b41512396 . _:b41512399 . _:b41512391 "This generally improves the systemic half-life and reduces immune cell interaction properties, thus increasing the potential therapeutic load at target tissues>>2728<<. Therefore, in our simulations we can assume that such nanoparticles will be inert. In previous studies, it has been demonstrated that certain compositions of nanoparticles can interact with both themselves and red blood cells, with" . _:b41512397 . _:b41512398 . _:b41512396 "This concept forms part of the enhanced permeability and retention (EPR) effect or passive-targeting, that has been proven previously in many studies>>32<<33. The EPR effect is based on the combination of the increased permeability of the vasculature supplying tumours and reduction or absence of lymphatic vessels that form a drainage network from tissues back to the blood. Therefore" . _:b41512399 . _:b41512379 "Brownian motion forces can be simulated by the methods presented by Andrews and Bray>>40<<, requiring the calculation of the translational diffusion coefficient (Dc), using the Stokes-Einstein equation:" . _:b41512389 . _:b41512392 . _:b41512402 "The addition of active targeting domains, such as iRGD, to nanoparticles can also improve uptake properties of nanoparticles from the blood>>38<<39. It should be noted that whilst irregular and larger fenestrations have been reported at tumour vasculature, fenestration density, irregular flow and poor cellular junction formation also are characteristic of tumour vasculature," . _:b41512380 "Their density is obtained from the literature>>43<<. Nanoparticle movement within pores is generated through Brownian motion, using a shorter time-step than in the main vessel, due to the narrow geometry." . _:b41512393 . _:b41512394 . _:b41512395 . _:b41512389 "A common solution to this is to use a coating that limits protein adsorption such as polyethylene glycol (PEG) or similar>>26<<. This generally improves the systemic half-life and reduces immune cell interaction properties, thus increasing the potential therapeutic load at target tissues2728. Therefore, in our simulations we can assume that such nanoparticles will" . . _:b41512397 . _:b41512380 . _:b41512387 "Several studies have demonstrated that both specific and non-specific interaction with proteins can affect the nanoparticle residency in the blood>>24<<25. Protein interactions are dictated by the surface chemistry and charge. A common solution to this is to use a coating that limits protein adsorption such as polyethylene glycol (PEG) or similar26." . _:b41512400 . _:b41512391 . _:b41512401 . _:b41512381 . _:b41512402 . _:b41512382 "Previous studies have utilised several techniques, most notably immersed finite element methods, to incorporate red blood cell deformation and red blood cell interactions within flow models>>21<<2223. Although a similar approach could be utilised within the model described, the additional computational burden required would limit the capabilities of the model to include much of the desired additional functionality. In these" . _:b41512402 .