The role of diffusion tensor imaging in characterizing injury patterns on athletes with concussion and subconcussive injury: a systematic review.

Traumatic brain injury (TBI) is a major public health problem. The majority of TBIs are in the form of mild TBI (also known as concussion) with sports-related concussion (SRC) receiving public attention in recent years.Here we have performed a systematic review of the literature on the use of Diffusion Tensor Imaging (DTI) on sports-related concussion and subconcussive injuries. Our review found different patterns of change in DTI parameters between concussed and subconcussed groups. The Fractional Anisotropy (FA) was either unchanged or increased for the concussion group, while the subconcussed group generally experienced a decrease in FA. A reverse pattern was observed for Mean Diffusivity (MD) - where the concussed group experienced a decrease in MD while the subconcussed group showed an increase in MD. However, in general, discrepancies were observed in the results reported in the literature - likely due to the huge variations in DTI acquisition parameters, and image processing and analysis methods used in these studies. This calls for more comprehensive and well-controlled studies in this field, including those that combine the advanced brain imaging with biomechancial modeling and kinematic sensors - to shed light on the underlying mechanisms behind the structural changes observed from the imaging studies.

In Vitro Models of Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) is a major public health challenge that is also the third leading cause of death worldwide. It is also the leading cause of long-term disability in children and young adults worldwide. Despite a large body of research using predominantly in vivo and in vitro rodent models of brain injury, there is no medication that can reduce brain damage or promote brain repair mainly due to our lack of understanding in the mechanisms and pathophysiology of the TBI. The aim of this review is to examine in vitro TBI studies conducted from 2008-2018 to better understand the TBI in vitro model available in the literature. Specifically, our focus was to perform a detailed analysis of the in vitro experimental protocols used and their subsequent biological findings. Our review showed that the uniaxial stretch is the most frequently used way of load application, accounting for more than two-thirds of the studies reviewed. The rate and magnitude of the loading were varied significantly from study to study but can generally be categorized into mild, moderate, and severe injuries. The in vitro studies reviewed here examined key processes in TBI pathophysiology such as membrane disruptions leading to ionic dysregulation, inflammation, and the subsequent damages to the microtubules and axons, as well as cell death. Overall, the studies examined in this review contributed to the betterment of our understanding of TBI as a disease process. Yet, our review also revealed the areas where more work needs to be done such as: 1) diversification of load application methods that will include complex loading that mimics in vivo head impacts; 2) more widespread use of human brain cells, especially patient-matched human cells in the experimental set-up; and 3) need for building a more high-throughput system to be able to discover effective therapeutic targets for TBI.

A computational modeling of blood flow in asymmetrically bifurcating microvessels and its experimental validation.

Microvascular transport is complex due to its heterogeneity. Many researchers have been developing mathematical and computational models in predicting microvascular geometries and blood transport. However, previous works were focused on developing simulation models, not on validating suggested models with microvascular geometry and blood flow in the real microvasculature. In this paper, we suggest a computational model for microvascular transport with experimental validation in its geometry and blood flow. The geometry is generated by controlling asymmetric conditions of microvascular network. Also, the blood flow in microvascular networks is predicted by considering in vivo viscosity, Poiseuille flow model, and hematocrit redistribution by plasma skimming. The suggested model is validated by the measured data in rat mesentery. Also, the microvascular transport in a case of mouse cortex is predicted and compared against experimental data to check applicability of the suggested model.

Effect of fractional blood flow on plasma skimming in the microvasculature.

Although redistribution of red blood cells at bifurcated vessels is highly dependent on flow rate, it is still challenging to quantitatively express the dependence of flow rate in plasma skimming due to nonlinear cellular interactions. We suggest a plasma skimming model that can involve the effect of fractional blood flow at each bifurcation point. To validate the model, it is compared with in vivo data at single bifurcation points, as well as microvascular network systems. In the simulation results, the exponential decay of the plasma skimming parameter M along fractional flow rate shows the best performance in both cases.

Generalized plasma skimming model for cells and drug carriers in the microvasculature.

In microvascular transport, where both blood and drug carriers are involved, plasma skimming has a key role on changing hematocrit level and drug carrier concentration in capillary beds after continuous vessel bifurcation in the microvasculature. While there have been numerous studies on modeling the plasma skimming of blood, previous works lacked in consideration of its interaction with drug carriers. In this paper, a generalized plasma skimming model is suggested to predict the redistributions of both the cells and drug carriers at each bifurcation. In order to examine its applicability, this new model was applied on a single bifurcation system to predict the redistribution of red blood cells and drug carriers. Furthermore, this model was tested at microvascular network level under different plasma skimming conditions for predicting the concentration of drug carriers. Based on these results, the applicability of this generalized plasma skimming model is fully discussed and future works along with the model's limitations are summarized.

Predicting bifurcation angle effect on blood flow in the microvasculature.

Since blood viscosity is a basic parameter for understanding hemodynamics in human physiology, great amount of research has been done in order to accurately predict this highly non-Newtonian flow property. However, previous works lacked in consideration of hemodynamic changes induced by heterogeneous vessel networks. In this paper, the effect of bifurcation on hemodynamics in a microvasculature is quantitatively predicted. The flow resistance in a single bifurcation microvessel was calculated by combining a new simple mathematical model with 3-dimensional flow simulation for varying bifurcation angles under physiological flow conditions. Interestingly, the results indicate that flow resistance induced by vessel bifurcation holds a constant value of approximately 0.44 over the whole single bifurcation model below diameter of 60µm regardless of geometric parameters including bifurcation angle. Flow solutions computed from this new model showed substantial decrement in flow velocity relative to other mathematical models, which do not include vessel bifurcation effects, while pressure remained the same. Furthermore, when applying the bifurcation angle effect to the entire microvascular network, the simulation results gave better agreements with recent in vivo experimental measurements. This finding suggests a new paradigm in microvascular blood flow properties, that vessel bifurcation itself, regardless of its angle, holds considerable influence on blood viscosity, and this phenomenon will help to develop new predictive tools in microvascular research.

A physical sciences network characterization of circulating tumor cell aggregate transport.

Circulating tumor cells (CTC) have been implicated in the hematogenous spread of cancer. To investigate the fluid phase of cancer from a physical sciences perspective, the multi-institutional Physical Sciences-Oncology Center (PS-OC) Network performed multidisciplinary biophysical studies of single CTC and CTC aggregates from a patient with breast cancer. CTCs, ranging from single cells to aggregates comprised of 2-5 cells, were isolated using the high-definition CTC assay and biophysically profiled using quantitative phase microscopy. Single CTCs and aggregates were then modeled in an in vitro system comprised of multiple breast cancer cell lines and microfluidic devices used to model E-selectin mediated rolling in the vasculature. Using a numerical model coupling elastic collisions between red blood cells and CTCs, the dependence of CTC vascular margination on single CTCs and CTC aggregate morphology and stiffness was interrogated. These results provide a multifaceted characterization of single CTC and CTC aggregate dynamics in the vasculature and illustrate a framework to integrate clinical, biophysical, and mathematical approaches to enhance our understanding of the fluid phase of cancer.

Quantifying uncertainties in the microvascular transport of nanoparticles.

The character of nanoparticle dispersion in the microvasculature is a driving factor in nanoparticle-based therapeutics and bio-sensing. It is difficult, with current experimental and engineering capability, to understand dispersion of nanoparticles because their vascular system is more complex than mouse models and because nanoparticle dispersion is so sensitive to in vivo environments. Furthermore, uncertainty cannot be ignored due to the high variation of location-specific vessel characteristics as well as variation across patients. In this paper, a computational method that considers uncertainty is developed to predict nanoparticle dispersion and transport characteristics in the microvasculature with a three step process. First, a computer simulation method is developed to predict blood flow and the dispersion of nanoparticles in the microvessels. Second, experiments for nanoparticle dispersion coefficients are combined with results from the computer model to suggest the true values of its unknown and unmeasurable parameters-red blood cell deformability and red blood cell interaction-using the Bayesian statistical framework. Third, quantitative predictions for nanoparticle transport in the tumor microvasculature are made that consider uncertainty in the vessel diameter, flow velocity, and hematocrit. Our results show that nanoparticle transport is highly sensitive to the microvasculature.

On the near-wall accumulation of injectable particles in the microcirculation: smaller is not better.

Although most nanofabrication techniques can control nano/micro particle (NMP) size over a wide range, the majority of NMPs for biomedical applications exhibits a diameter of ~100 nm. Here, the vascular distribution of spherical particles, from 10 to 1,000 nm in diameter, is studied using intravital microscopy and computational modeling. Small NMPs (≤100 nm) are observed to move with Red Blood Cells (RBCs), presenting an uniform radial distribution and limited near-wall accumulation. Larger NMPs tend to preferentially accumulate next to the vessel walls, in a size-dependent manner (~70% for 1,000 nm NMPs). RBC-NMP geometrical interference only is responsible for this behavior. In a capillary flow, the effective radial dispersion coefficient of 1,000 nm particles is ~3-fold larger than Brownian diffusion. This suggests that sub-micron particles could deposit within diseased vascular districts more efficiently than conventional nanoparticles.

A statistical study on nanoparticle movements in a microfluidic channel.

Microfluidic channels have received much attention because they can be used to control and transport nanoscale objects such as nanoparticles, nanowires, carbon nanotubes, DNA and cells. However, so far, practical channels have not been easy to design because they require very expensive fabrication and sensitive experiments. Numerical approaches can be alternatives or supplementary measures to predict the performance of new channels because they efficiently explain nanoscale multi-physics phenomena and successfully solve nanowire alignment and cell adhesion problems. In this paper, a newly updated immersed finite element method that accounts for collision force and Brownian motion as well as fluid-solid interaction is proposed, and is applied to simulate nanoparticle movements in a microfluidic channel. As part of the simulation, Brownian motion effects in a single nanoparticle focusing lens system are examined under different temperature conditions, and the resulting transport efficiencies are discussed. Furthermore, nanoparticle movements in a double focusing lens system are predicted to show the enhancement of focusing efficiency.

Numerical simulation of a nanoparticle focusing lens in a microfluidic channel by using immersed finite element method.

Lap-on-a-chip system is one of challenging parts in nano and bio engineering fields, for instance, microfluidic channels on the chip are useful for selecting a target particle and mass transferring of boiomolecules in fluid. However, since experimental approach is highly expensive both in time and cost, alternative reliable methods are required to conceive optimized channels. The purpose of this research is to simulate a nanoparticle focusing lens in a microfluidic channel from nanoparticle control point of view. A promising immersed finite element method is expanded to estimate the path of randomly moving nanoparticles through a focusing lens. The channel flow is assumed as incompressible viscous fluid and Brownian motion effects as well as initial position of particle are quantitatively examined. As a representative result, while the nanoparticles with/without Brownian motion were focused along the center of the channel, the concentration factor representing focusing efficiency was calculated. Therefore, it is expected that the newly proposed numerical method considering Brownian motion will be efficiently applicable to design the microfluidic channel containing various particles, molecules and so forth in the near future.