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Time-Lapsing Perfusion: Proof of Concept of a Novel Method to Study Drug Delivery in Whole Organs.

ABSTRACT: Perfusion is one of the most important processes maintaining organ health. From a computational perspective, however, perfusion is among the least-studied physiological processes of the heart. The recent development of novel nanoparticle-based targeted cardiac therapy calls for novel simulation methods that can provide insights into the distribution patterns of therapeutic agents within the heart tissue. Additionally, resolving the distribution patterns of perfusion is crucial for gaining a full understanding of the long-term impacts of cardiovascular diseases that can lead to adverse remodeling such as myocardial ischemia and heart failure. In this study, we have developed and used a, to our knowledge, novel particle-tracking-based method to simulate the perfusion-mediated distribution of nanoparticles or other solutes. To model blood flow through perfused tissue, we follow the approach of others and treat the tissue as a porous medium in a continuum model. Classically, solutes are modeled using reaction-advection-diffusion kinetics. However, because of the discrepancy of scales between advection and diffusion in blood vessels, this method becomes practically numerically unstable. Instead, we track a bolus of solutes or nanoparticles using particle tracking based purely on advection in arteries. In capillaries, we employ diffusion kinetics, using an effective diffusion coefficient to mimic capillary blood flow. We first demonstrate the numerical validity and computational efficiency of this method on a two-dimensional benchmark problem. Finally, we demonstrate how the method is used to visualize perfusion patterns of a healthy and ischemic human left ventricle geometry. The efficiency of the method allows for nanoparticle tracking over multiple cardiac cycles using a conventional laptop, providing a framework for the simulation of experimentally relevant timeframes to advance preclinical research.

SUBMITTER: Diem AK

PROVIDER: S-EPMC6990391 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Time-Lapsing Perfusion: Proof of Concept of a Novel Method to Study Drug Delivery in Whole Organs.

Diem Alexandra K AK Valen-Sendstad Kristian K

Biophysical journal 20190928 12

Perfusion is one of the most important processes maintaining organ health. From a computational perspective, however, perfusion is among the least-studied physiological processes of the heart. The recent development of novel nanoparticle-based targeted cardiac therapy calls for novel simulation methods that can provide insights into the distribution patterns of therapeutic agents within the heart tissue. Additionally, resolving the distribution patterns of perfusion is crucial for gaining a full ...[more]

PMID: 31648790

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Project description:UNLABELLED:Intraarterial microdosing (IAM) is a novel drug development approach combining intraarterial drug delivery and microdosing. We aimed to demonstrate that IAM leads to target exposure similar to that of systemic full-dose administration but with minimal systemic exposure. IAM could enable the safe, inexpensive, and early study of novel drugs at the first-in-human stage and the study of established drugs in vulnerable populations. METHODS:Insulin was administered intraarterially (ipsilateral femoral artery) or systemically to 8 CD IGS rats just before blood sampling or 60-min (18)F-FDG uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius) and systemic muscles (spinotrapezius). The (18)F-FDG uptake slope analysis was used to compare the interventions. Plasma levels of insulin and glucose were compared using area under the curve calculated by the linear trapezoidal method. A physiologically based computational pharmacokinetics/pharmacodynamics model was constructed to simulate the relationship between the administered dose and response over time. RESULTS:(18)F-FDG slope analysis found no difference between IAM and systemic full-dose slopes (0.0066 and 0.0061, respectively; 95% confidence interval [CI], -0.024 to 0.029; P = 0.7895), but IAM slope was statistically significantly greater than systemic microdose (0.0018; 95% CI, -0.045 to -0.007; P = 0.0147) and sham intervention (-0.0015; 95% CI, 0.023-0.058; P = 0.0052). The pharmacokinetics/pharmacodynamics data were used to identify model parameters that describe membrane insulin binding and glucose-insulin dynamics. CONCLUSION:Target exposure after IAM was similar to systemic full dose administration but with minimal systemic effects. The computational pharmacokinetics/pharmacodynamics model can be generalized to predict whole-body response. Findings should be validated in larger, controlled studies in animals and humans using a range of targets and classes of drugs.

Dataset Information

Time-Lapsing Perfusion: Proof of Concept of a Novel Method to Study Drug Delivery in Whole Organs.

Publications

Time-Lapsing Perfusion: Proof of Concept of a Novel Method to Study Drug Delivery in Whole Organs.

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