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

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.

A control mechanism for intra-mural peri-arterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain.

The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer's disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.

Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aß Drainage.

Alzheimer's Disease (AD) is the most common form of dementia and to date there is no cure or efficient prophylaxis. The cognitive decline correlates with the accumulation of amyloid-ß (Aß) in the walls of capillaries and arteries. Our group has demonstrated that interstitial fluid and Aß are eliminated from the brain along the basement membranes of capillaries and arteries, the intramural periarterial drainage (IPAD) pathway. With advancing age and arteriosclerosis, the stiffness of arterial walls, this pathway fails in its function and Aß accumulates in the walls of arteries. In this study we tested the hypothesis that arterial pulsations drive IPAD and that a valve mechanism ensures the net drainage in a direction opposite to that of the blood flow. This hypothesis was tested using a mathematical model of the drainage mechanism. We demonstrate firstly that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations. Secondly, we demonstrate that a valve mechanism such as directional permeability of the IPAD pathway is necessary to achieve a net reverse flow. The mathematical simulation results are confirmed by assessing the pattern of IPAD in mice using pulse modulators, showing no significant alteration of IPAD. Our results indicate that forces other than the cardiac pulsations are responsible for efficient IPAD.

Sustainable computational science: the ReScience initiative.

Computer science offers a large set of tools for prototyping, writing, running, testing, validating, sharing and reproducing results; however, computational science lags behind. In the best case, authors may provide their source code as a compressed archive and they may feel confident their research is reproducible. But this is not exactly true. James Buckheit and David Donoho proposed more than two decades ago that an article about computational results is advertising, not scholarship. The actual scholarship is the full software environment, code, and data that produced the result. This implies new workflows, in particular in peer-reviews. Existing journals have been slow to adapt: source codes are rarely requested and are hardly ever actually executed to check that they produce the results advertised in the article. ReScience is a peer-reviewed journal that targets computational research and encourages the explicit replication of already published research, promoting new and open-source implementations in order to ensure that the original research can be replicated from its description. To achieve this goal, the whole publishing chain is radically different from other traditional scientific journals. ReScience resides on GitHub where each new implementation of a computational study is made available together with comments, explanations, and software tests.

A Simulation Model of Periarterial Clearance of Amyloid-ß from the Brain.

The accumulation of soluble and insoluble amyloid-ß (Aß) in the brain indicates failure of elimination of Aß from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aß from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aß into the blood and periarterial lymphatic drainage of Aß. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aß, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aß in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aß diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aß occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.

Peristalsis with Oscillating Flow Resistance: A Mechanism for Periarterial Clearance of Amyloid Beta from the Brain.

Alzheimer's disease is characterized by accumulation of amyloid-ß (Aß) in the brain and in the walls of cerebral arteries. The focus of this work is on clearance of Aß along artery walls, the failure of which may explain the accumulation of Aß in Alzheimer's disease. Periarterial basement membranes form continuous channels from cerebral capillaries to major arteries on the surface of the brain. Arterial pressure pulses drive peristaltic flow in the basement membranes in the same direction as blood flow. Here we forward the hypothesis that flexible structures within the basement membrane, if oriented such they present greater resistance to forward than retrograde flow, may cause net reverse flow, advecting Aß along with it. A solution was obtained for peristaltic flow with low Reynolds number, long wavelength compared to channel height and small channel height compared to vessel radius in a Darcy-Brinkman medium representing a square array of cylinders. Results show that retrograde flow is promoted by high cylinder volume fraction and low peristaltic amplitude. A decrease in cylinder concentration and/or an increase in amplitude, both of which may occur during ageing, can reduce retrograde flow or even cause a transition from retrograde to forward flow. Such changes may explain the accumulation of Aß in the brain and in artery walls in Alzheimer's disease.