Buffo, Antonio

Frungieri, Graziano

Vanni, Marco

Vasquez Giuliano, Lorenzo

English

PORTO@iris (Publications Open Repository TOrino - Politecnico di Torino)

29 November 2022POLITECNICO DI TORINORepository ISTITUZIONALEBreakup of shear activated nano-therapeutics in a microfluidic device by a CFD - Stokesian Dynamics approach /Vasquez Giuliano, Lorenzo; Frungieri, Graziano; Buffo, Antonio; Vanni, Marco. - ELETTRONICO. - (2021), pp. 1138-1139. ((Intervento presentato al convegno 25th International Congress of Theoretical and Applied Mechanics tenutosi aMilano (Italia) nel 22-27 agosto 2021.OriginalBreakup of shear activated nano-therapeutics in a microfluidic device by a CFD - Stokesian DynamicsapproachPublisher:PublishedDOI:Terms of use:openAccessPublisher copyright(Article begins on next page)This article is made available under terms and conditions as specified in the  corresponding bibliographic description inthe repositoryAvailability:This version is available at: 11583/2973069 since: 2022-11-14T16:22:29ZIUTAM - International Union of Theoretical and Applied MechanicsICTAMMilano 2020+1Virtual25th International Congress of Theoretical and Applied MechanicsAugust 22-27, 20211138Thematic Session FMBREAKUP OF SHEAR ACTIVATED NANO-THERAPEUTICS IN A MICROFLUIDIC DEVICE BY A CFD-STOKESIAN DYNAMICS APPROACHLorenzo Vasquez Giuliano1, Graziano Frungieri *1, Antonio Buffo1, and Marco Vanni11Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, Torino, ItalyXXV ICTAM, 23-28 August 2020, Milano, ItalyBREAKUP OF SHEAR ACTIVATED NANO-THERAPEUTICS IN A MICROFLUIDICDEVICE BY A CFD-STOKESIAN DYNAMICS APPROACHLorenzo Vasquez Giuliano1, Graziano Frungieri ∗1, Antonio Buffo1, and Marco Vanni11Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, Torino, ItalySummary The treatment of arterial obstructions can be strongly improved by the development of drug carriers with a highly localizedaction. Our research focuses on the investigation of Shear Activated Nano-Therapeutics, a novel class of drug carriers consisting inaggregates of nanoparticles, which are locally activated by the breakup induced by the viscous stress acting on them as they travel inobstructed blood vessels. We adopted a coupled Computational Fluid Dynamics - Stokesian Dynamics technique able to compute thehistory of the viscous shear forces experienced by the aggregates and to study the dynamics of breakup. We investigate the behaviourof different potential morphologies of the aggregates, in order to identify the most suitable for such a delivery strategy and to identifythe critical structural properties to be taken into account when designing such carriers.INTRODUCTIONArterial obstructions represent one of the main causes of disease and death worldwide [1]. When treating this disease,the dose of active agent that can be administered to the patient has to be carefully chosen in order to limit the potentialadverse effects due to the free circulation of the drug in the blood stream. For this reason, targeted drug delivery techniqueshave received considerable attention over the last years. One of the most promising delivery strategy is based on theobservation that in obstructed blood vessel abnormally large shear stress are present. This feature of the hemodynamiccondition has therefore pushed research towards the development of Shear Activated Nano-Therapeutic (SANT) particles[2]. SANTs are micro-metric agglomerates of polymeric primary nanoparticles on which a clot-lysing drug is deposited.As the nanoparticles are held together mainly through relatively weak Van-der-Waals forces, SANTs can be engineeredin such a way that they break up into smaller fragments when they enter a high shear zone; these fragments, because oftheir smaller size, experience lower hydrodynamic drag forces, thus they are more likely to adhere to the obstruction andto perform their clot-lysing action.In this work we use a coupled Computational Fluid Dynamics - Stokesian Dynamics approach able to investigate thebreakup dynamics of aggregates of primary particles [3, 4]. We tested our method on a microfluidic device designed insuch a way as to mimic a pathological vessel obstruction. CFD simulations are performed to compute the flow field in thedevice and to extract a set of particle trajectories including the history of experienced shear stresses. Stokesian Dynamicssimulations are instead carried out to compute the distribution of mechanical stress inside the aggregate structure, fromwhich the occurrence of breakup can be predicted. We investigate different potential SANTs morphologies by comparingthem in terms of conditions for the onset of breakup and size distribution of the generated fragments.METHODSComputational Fluid DynamicsWe used ANSYS Fluent 19.2 to simulate the flow field of a Newtonian fluid with viscosity µ = 1 × 10−3 Pa · sflowing in a rectangular microchannel. The presence of the clot is modelled by introducing a 90% lumen obstruction. Thedomain is divided in 105 hexahedrical cells (left panel in Figure 1). The flow rate is adjusted in order to obtain the typicalvalues of shear stress in a blood vessel (10 Pa in the unrestricted vessel and 100 Pa in the obstructed vessel).The computed flow field is used to extract the trajectories of a set of 1000 aggregates. Being their Stokes and Reynoldsnumbers much lower than the unity, the aggregates can be treated as tracer particles, i.e. massless particles with negligibleinertia; their equation of motion therefore reads as:ẋp(t) = u(xp(t)) (1)where ẋp(t) is the velocity of the particle and u(xp(t)) is the velocity of the flow at the particle position.Stokesian DynamicsIn Stokesian Dynamics (SD) simulation, the morphology of the aggregates is taken into full account. This technique,by using a first order approximation of the flow field, allows one to evaluate the hydrodynamic forces acting on eachprimary particle composing the aggregate and, based on these, to evaluate the normal stress acting at each inter-particlecontact [4]. In order to identify the most suitable morphology for our delivery strategy, three classes of clusters character-ized by different shape and porosity are studied; we analyze the behaviour of aggregates obtained by a diffusion limitedaggregation (DLCA), Random Close Packing aggregates (RCP) and hollow RCP aggregates. In order to get statisticallyrobust results, for every class we studied 100 aggregate realizations. Therefore, a statistical analysis has been conductedin order to count for the variety of aggregate morphologies and aggregate trajectories.∗Graziano Frungieri. E-mail: graziano.frungieri@polito.it.O105828 - FM12 - Micro- and Nano-fluidics - OralICTAMMilano 2020+1Virtual25th International Congress of Theoretical and Applied MechanicsAugust 22-27, 20211139Thematic Session FMXXV ICTAM, 23-28 August 2020, Milano, ItalyFigure 1: Left) Microchannel with inlet (blue surface), outlet (red surface), symmetry plane (green surface) and walls (grey surfaces).The inset shows the trajectories of a subset of tracer particles. Right) Wall shear stress on the bottom wall of the microchannel.Location of the maximum instantaneous tensile stressFigure 2: Left) Distribution of normal force in a DLCA cluster. A ball and stick representation has been used to highlight the inter-particle bonds. Right) Cumulative Distribution Function of the maximum tensile force experienced by RCP clusters (red), DLCA (blue)and hollow RCP (green). On the x-axis, a is the radius of the NPs, 〈U〉 is the average velocity in the constricted section.RESULTSThe flow field in the microdevice and the trajectories of a set of tracer particles were obtained by running CFDsimulations. Figure 1 right) reports the contour plot of the shear stress evaluated at the bottom wall of the microchannel.It can be noticed that the shear stress is relatively mild (≈ 10 Pa) in the unrestricted section, it reaches a peak value (≈ 150Pa) at the entrance of the constricted section and then goes down to a value of 100 Pa in the narrowed region.By Stokesian Dynamics we computed the distribution of the normal forces at the inter-particle contacts of the aggre-gates, as they move along the microchannel. A sample instantaneous distribution for a DLCA cluster is shown on the leftside of Figure 2. For this class of aggregates, the highest tensile forces are observed in the internal region, thus suggestingthat the expected dominant mechanism of breakup should be the fragmentation in two almost equally sized fragments. Onthe contrary, in the case of RCP and hollow RCP clusters, the highest tensile forces are observed in the external region,so that a progressive erosion of the cluster should instead be expected [4]. In the right plot of Figure 2 the mechanicalresponses of three different populations of aggregates are compared through the Cumulative Distribution Functions ofthe maximum experienced tensile stress. Hollow RCP aggregates emerged as the most fragile structure (i.e. the highestinternal tensile force were observed for this class), RCP aggregates as the most resistant, whereas DLCA aggregates hadan intermediate behaviour.Results are encouraging and show the feasibility of such a deliver strategy. The CFD-Stokesian Dynamics approachappears as a promising tool to identify the fundamental properties of the aggregates to take in account when designingshear-activated drug carriers.References[1] C.J.L. Murray, A.D. Lopez. Mortality by cause for eight regions of the world: Global burden of disease study. The Lancet, 349:1269-1276, 1997[2] N. Korin, M. Kanapathipillai, B.D. Matthews, M. Crescente, A. Brill, T. Mammoto, K. Ghosh, S. Jurek, S.A. Bencherif, D. Bhatta, A.U. Coskun,C.L. Feldman, D.D. Wagner, D.E. Ingber, Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 337: 738-742,2012.[3] J. De Bona, A. S. Lanotte, M. Vanni, Internal stresses and breakup of rigid isostatic aggregates in homogeneous and isotropic turbulence. J. FluidMech. 755: 365-396, 2014.[4] M. Vanni. Accurate modelling of flow induced stresses in rigid colloidal aggregates.Computer Physics Communications, 192: 70-90, 2015

Breakup of shear activated nano-therapeutics in a microfluidic device by a CFD - Stokesian Dynamics approach

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Breakup of shear activated nano-therapeutics in a microfluidic device by a CFD - Stokesian Dynamics approach

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