Spatiotemporal dynamics of doxorubicin elution from embolic beads within a microfluidic network

Abstract

Anticancer treatment using embolic drug-eluting beads (DEBs) has shown multifarious advantages compared to systemic chemotherapy. However, there is a growing need for a better understanding of the physical parameters governing drug-elution from embolic devices under physiologically relevant fluidic conditions. In the present study, we investigated the spatiotemporal dynamics of doxorubicin hydrochloride elution from drug-loaded hydrogel embolic beads within a microfluidic device, consisting of a network of interconnected microchannels, which replicates the architectural properties of microvascular systems. Drug-elution has been investigated experimentally at a single-bead level, using in-house developed microscopy-and spectrofluorimetry-based methods. Results demonstrated that the kinetics of drug-elution and the amount of eluted drug strongly depended on the location of the embolic event within the embolised channel (e.g. fractional amount of eluted drug after 3 hours was equal to ~0.2 and ~0.6 for completely-confined and partially-confined bead, respectively). Drug-elution from partiallyconfined bead showed a counterintuitive dependence on the local Reynolds number (and thus on the mean fluid velocity), as a result of dynamic changes in bead compressibility causing the displacement of the bead from the primary embolic site. Conversely, the kinetics of drug-elution from fully-confined bead was less affected by the local Reynolds number and bead displayed faster elution from the surface area exposed to the systemic flow, which was associated with the formation of fluid eddies nearby the bead post embolisation.

In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System

“…5 Interestingly, DOX release rates were more reduced in the 6-mm SR method than in the free-flowing method for all 3 bead sizes. Since the passage of DOX across the nylon mesh was too rapid (<1 min) to have any major impact on DOX release, this could not explain the release rate reduction observed in the 6-mm SR. A possible explanation might be that the packing or the confinement of the beads in the SR affected the DOX release rate, as previously shown by Carugo et al 42 Furthermore, the release rate of DOX from the beads was positively correlated to higher stirring rates in the free-flowing method ( Fig. 3a and Table 3).…”

“…The packing or confinement of the beads might also influence their release of DOX which would account for the more in vivoelike release profile of the SR method than the free-flowing method. 42 The release profiles from the free-flowing method at 3 stirring rates (0, 100, and 400 rpm) were evaluated with the 2 theoretical models, film control and internal depletion layer ( Figs. 2a and 2b).…”

Computational fluid dynamics (CFD) studies of a miniaturized dissolution system

“…It should be noted, however, that the simulations in this study were carried out with empty sample reservoirs and that the presence of drug-releasing beads would probably influence the intra-compartmental hydrodynamics somewhat. In addition, differing packing or confinement patterns of the beads would probably affect the drug release rate (Carugo et al, 2015). It is also worth noting that the balance between the inertia and drag forces on the beads will be size-dependent, which in the Stokes equation would result in a settling velocity that is proportional to the size squared (Harker et al, 2002).…”

Visualization and Evaluation of Chemoembolization on a 3D Decellularized Organ Scaffold

“…Nonetheless, the dialysis analysis greatly simplified the native environment and assumed that the membrane permeation process was fast and neglectable. Carugo et al utilized a microfluidic chip to mimic the in vivo dimensions of the artery in a liver tumor, which enabled the investigation of the distribution of embolic agents in narrow blood vessels . However, these microfluidic chips were hard to recapture the permeability of blood vessels and therefore unable to examine the drug-release kinetics.…”

“…Carugo et al utilized a microfluidic chip to mimic the in vivo dimensions of the artery in a liver tumor, which enabled the investigation of the distribution of embolic agents in narrow blood vessels. 14 However, these microfluidic chips were hard to recapture the permeability of blood vessels and therefore unable to examine the drug-release kinetics. Troendle et al recently applied mathematical models to simulate the drug molecular diffusion through a 3D vasculature of the tumor and forecasted the temporal and spatial distribution of the drug at sub-micrometer resolution.…”