Nonlinear Analysis for Shear Augmented Dispersion of Solutes in Blood Flow through Narrow Arteries

The shear augmented dispersion of solutes in blood flow (i) through circular tube and (ii) between parallel flat plates is analyzed mathematically, treating blood as Herschel-Bulkley fluid model. The resulting system of nonlinear differential equations are solved with the appropriate boundary conditions, and the expressions for normalized velocity, concentration of the fluid in the core region and outer region, flow rate, and effective axial diffusivity are obtained. It is found that the normalized velocity of blood, relative diffusivity, and axial diffusivity of solutes are higher when blood is modeled by Herschel-Bulkley fluid rather than by Casson fluid model. It is also noted that the normalized velocity, relative diffusivity, and axial diffusivity of solutes are higher when blood flows through circular tube than when it flows between parallel flat plates

Herschel-Bulkley model of blood flow through a stenosed artery with the effect of chemical reaction on solute dispersion

A non-Newtonian mathematical model of blood flow described as the Hershel- Bulkley fluid model in a stenosed artery is studied together with the effect of its chemical reaction. The expressions of the shear stress, velocity, mean velocity, and relative velocity in the plug and non-plug flow field were evaluated. The convective-diffusion equation was solved using the Taylor-Aris technique subjected to the relevant boundary condition in determining the concentration as well as the relative and effective axial diffusivity of the solute. The efficiency of the dispersion process was affected by the presence of chemical reactions and stenosis in blood flow. The normalised velocity decreased as the power-law index and yield stress increased. The height and length of the stenosis, as well as the power-law index, increased with an increase in the parameters of the chemical reaction rate. In contrast, the relative axial diffusivity and effective axial diffusivity showed a reverse behaviour. The existence of stenosis restricted the blood flow and drug dispersion. In short, this study improved the understanding of the physiological processes involved in the dispersion of drugs and nutrients in the circulatory system. Furthermore, it proved that the dispersion of a solute in the blood flow happened at a low shear rate through narrow arteries

Mathematical modeling of unsteady solute dispersion in bingham fluid model of blood flow through an overlapping stenosed artery

An artery narrowing referred to as atherosclerosis or stenosis causes a reduction in the diameter of the artery. When blood flow through an artery consists of stenosis, the issue of solute dispersion is more challenging to solve. A mathematical model is developed to examine the unsteady solute dispersion in an overlapping stenosed artery portraying blood as Bingham fluid model. The governing of the momentum equation and the constitutive equation is solved analytically. The generalized dispersion model is imposed to solve the convective-diffusion equation and to describe the entire dispersion process. The dispersion function at steady-state decreases at the center of an artery as the stenosis height increase. A reverse behavior is shown at an unsteady-state. As the plug core radius, time and stenosis height increase, the dispersion function decreases at the center of an artery. There is a high amount of red blood cells at the center of the artery but no influences near the wall. Hence, this model is useful in transporting the drug or nutrients to the targeted stenosed region in the treatment of diseases and in understanding many physiological processes

Moment analysis of unsteady bi-component species (drug) transport with coupled chemical reaction in non-Newtonian blood flow

Motivated by exploring the fluid dynamics of dual drug delivery systems in biomedicine, a mathematical analysis of the bi-component species transport (convective-diffusion) in rheological blood flow with bulk chemical reaction through a two-dimensional rigid vessel is presented. Two different bulk degradation reaction rates are included for the dual species (pharmacological agents, A, B). An analytical expression for axial velocity is derived using a perturbation method. The decoupled convection-diffusion equations are then analyzed with the Aris – Barton approach. The mean concentration of the species is estimated using the first five concentration moments with the aid of fourth order Hermite polynomials. A finite difference technique based on the Crank Nicholson implicit scheme is employed to handle the pth order moment of the general concentration. The analysis reveals that increasing reversible transfer rate and irreversible bulk degradation result in a reduction in the total mass of the species over time. The mass of both species decreases with an increase in reversible transfer rate, even though the mass of species A depletes faster than the mass of species B. The skewness of the concentration distribution decreases as yield stress increases and the distributions in all scenarios are positively skewed and tend to zero over time, implying that the distribution tends to symmetry over time. The kurtosis decreases over time from positive to negative values and eventually approaches zero. Mean concentration peaks for both species A and B are elevated with increasing yield stress, although magnitudes are significantly higher for species A. With increasing values of the distribution coefficient between two species, mean concentration peaks are elevated for species (component) A whereas they are depleted for species B, although substantially greater magnitudes are computed for species B. Good correlation of the skewness with earlier Newtonian results is achieved. The results provide some useful insight into the bi-component drug transport in smaller vessel pharmacodynamics where hemorheology is important

Mechanical loading impacts intramuscular drug transport : impact on local drug delivery

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.Includes bibliographical references (leaves 152-166).Controlled-release drug-delivery systems enable efficient and defined administration of therapeutic agents to target tissues. However, ultimate drug distribution and pharmacologic effect are determined by target tissue pharmacokinetics. In muscular tissues, complex architecture that is further augmented by dynamic motion and contraction can alter the pharmacokinetics and deposition of locally delivered macromolecules. We developed a system and applied a quantitative schema to investigate the impact of controlled mechanical loads applied to skeletal and cardiac muscle tissue on intramuscular transport of locally delivered drug. In a series of studies, we examined how the interaction between architectural configuration and functional mechanics alters the transport of drugs across both physicochemical and binding properties. We correlated these pharmacokinetic effects with characteristic parameters in the physiologic range of the tissue to derive mechanistic insight into the fundamental structural and dynamic elements that underlie these effects. While previous studies have revealed the unilateral scaling of substrate uptake with mechanical influences, we elucidated an architecturally defined pharmacokinetic setpoint whereby maximal drug penetration corresponds with optimal muscle function. Our findings elucidate basic biologic design in muscle that optimizes the interface between tissue and its physical environment. The unique insights from our investigations have broad impact on current understanding of the pharmacokinetic influences of biologic form and function, and elucidate new clinical strategies for controlled release and local delivery of a wide range of therapeutic compounds to mechanically active tissues.by Peter I-Kung Wu.Ph.D

Mechanical and failure mechanisms of descending thoracic aorta: implications for health and disease

Structural organization of the extracellular matrix components of the aorta is critical to its loading-bearing capacity and homeostasis. Aortic elastic fibers form concentric lamellar layers with a closely interwoven three-dimensional network of collagen and elastic fibers in the narrow interlamellar space. Aging and cardiovascular diseases are closely associated with disrupted microstructural organization, integrity, as well as altered mechanical and failure properties of the aortic wall. The overall goal of this research is to advance the current understanding of the mechanical and failure mechanisms of human descending thoracic aorta and provide insights for aortic remodeling during aging and disease progression using integrated biomechanical testing, imaging, and computational modeling approaches. Biaxial tensile tests revealed anisotropic stiffening of the aortic wall with aging with a more drastic stiffening behavior in the longitudinal direction. A newly developed constitutive model considering collagen crosslinking suggested that collagen crosslinking has an increasing contribution to the stress-stretch behavior and elastic energy storage in aortic senescence. The aorta relies on interlamellar structural components, mainly elastic and collagen fibers, for maintaining its structural and mechanical integrity. Our study using peeling and direct tension tests demonstrated that elastic and collagen fibers both play an important role in bonding of the arterial wall, while collagen fibers dominate the interlamellar stiffness, strength and toughness. Our study further reveals that the interlamellar strength and toughness both increase due to nonenzymatic glycation, which is in accordance with the reported inverse relation between diabetes and a reduced risk of aortic dissection. On the other hand, however, our study showed decreasing interlamellar bonding toughness of the medial layer of human descending thoracic aorta with aging. Avalanches and power-law behavior in dissection propagation was found for all age groups investigated. Finite element simulations incorporating discrete interlamellar collagen fibers successfully recapitulates the power-law behavior and points to prominent structural alterations in interlamellar collagen fibers with aging including reduced fiber density and higher degree of dispersion. In aging and diseases, changes to the extracellular matrix microstructure can trigger a cascade of effects on tissue and cellular function. The knowledge gained from this research provide insights into the microstructural mechanisms in determining the physiological and failure properties of aorta and will potentially generate clinical impact on the developments of new diagnostics and interventions

Material-Induced Platelet and Leukocyte Activation: A Systems Approach

A systems approach in the study of blood-biomaterial interactions (BBI) is likely to provide better insight into the transient behaviors of complex biological systems. Although some attempts have been made to apply a systems approach in blood-biomaterial studies, a good framework for applying a systems approach has not yet been achieved. In this thesis, the case for a systems approach is presented and a framework is proposed. As a demonstration, the systems approach is applied to the development of an in vitro model for BBI. In vitro models play an important role in the initial investigation of BBI. Therefore, careful consideration of their parameters to mimic physiological parameters is crucial for results that can be translated to physiological conditions. The parameters of the in vitro model used in this thesis were determined using a systems approach method. The fluid dynamics of the model were characterized, to account for the model blood sample always including air, and an improved time-averaged wall shear stress was proposed. Since wall shear stress is an important parameter that determines cell activation and adhesion, in vitro studies were performed to investigate and validate the model with experiments. In line with a systems approach and clinical relevance, whole blood samples were used in the in vitro experiments. Platelet activation was investigated, as characterized by platelet microparticle (PMP) formation and expression of both P-selectin and the integrin glycoprotein receptor GPIIb/IIIa. For whole blood, in the absence of model stents, there was no significant sample volume or shear effect on PMP formation for wall shear stress up to 56 dyn/cm2. However, in the presence of model stents, combined volume and shear-dependent PMP formation was observed. While GPIIb/IIIa expression was reduced, P-selectin, on the other hand, did not generally show significant change after 2 hours of incubation. Leukocyte activation was also investigated, as characterized by the expression of tissue factor (TF), Mac-1, C3aR and toll-like receptor 4 (TLR-4). In the absence of model stents, sample volume had minimal effect on leukocyte activation but in the presence of model stents, a sample volume effect was observed at high shear rates, especially on Mac-1 expression. The other markers, TF, C3aR and TLR-4 did not show sensitivity to the volume effect. However, under combined volume-stent-shear, all markers were down-regulated at high shear. Correspondingly, platelet-leukocyte aggregation was also generally reduced. Leukocytes, as well as platelets, were sensitive to surface-area-to-volume ratio. The use of low surface area-to-volume ratio, below the ISO Standard recommended limit, resulted in reduced platelet and leukocyte sensitivity to shear and/or material. However, sensitivity to shear was still high on platelet-leukocyte aggregation. Also cell surface adhesion was shear-dependent but could not be linked to a sample volume effect. Complement inhibitor FUT-175 reduced PMP formation but had less effect on GPIIb/IIIa expression. Complement inhibition also reduced leukocyte activation, especially under shear conditions. Considerable reduction in leukocyte activation was observed under shear in the presence of model stents. These conditions would normally be expected to produce high complement activation. Furthermore, the conditions with the most reduction in platelet and leukocyte activation corresponded with the most reduction in platelet-leukocyte aggregation in the fluid phase. On the stent surface, FUT-175 inhibited leukocyte adhesion but allowed some platelet adhesion. Thus, complement inhibition with FUT-175 has the potential to reduce thrombosis while possibly retaining platelet function in hemostasis. The effect of surface roughness was investigated with inhomogeneous multiscale roughness surfaces. Although the unetched and acid-etched stent surfaces had similar average surface roughness values, the acid-etched surface resulted in increased platelet activation and platelet-leukocyte aggregation. In addition, platelet-leukocyte aggregates seemed to be more resistant to shear-induced disaggregation. However, when complement inhibitor FUT-175 was introduced, platelet and leukocyte activation and aggregation were reduced to similar levels as for unetched stents. This suggests that complement inhibition with FUT-175 has the potential to reduce material-induced thrombosis in the presence of nano/micro-structured stent surfaces such as those used for drug-eluting stents

Development of small-scale fluidised bed bioreactor for 3D cell culture

Three-dimensional cell culture has gained significant importance by producing physiologically relevant in vitro models with complex cell-cell and cell-matrix interactions. However, current constructs lack vasculature, efficient mass transport and tend to reproduce static or short-term conditions. The work presented aimed to design a benchtop fluidised bed bioreactor (sFBB) for hydrogel encapsulated cells to generate perfusion for homogenous diffusion of nutrients and, host substantial biomass for long-term evolution of tissue-like structures and “per cell” performance analysis. The sFBB induced consistent fluidisation of hydrogel spheres while maintaining their shape and integrity. Moreover, this system expanded into a multiple parallel units’ setup with equivalent performances enabling simultaneous comparisons. Long term culture of alginate encapsulated hepatoblastoma cells under dynamic environment led to proliferation of highly viable cell spheroids with a 2-fold increase in cellular density over static (27.3 vs 13.4 million cells/mL beads). Upregulation of hepatic phenotype markers (transcription factor C/EBP-α and drug-metabolism CYP3A4) was observed from an early stage in dynamic culture. This environment also affected ERK1/2 signalling pathway, progressively reducing its activation while increasing it in static conditions. Furthermore, culture of primary human mesenchymal stem cells was evaluated. Cell proliferation was not observed but continuous perfusion sustained their viability and undifferentiated phenotype, enabling differentiation into chondrogenic and adipogenic lineages after de-encapsulation. These biological readouts validated the sFBB as a robust dynamic platform and the prototype design was optimised using computer-aided design and computational fluid dynamics, followed by experimental tests. This thesis proved that dynamic environment promoted by fluidisation sustains biomass viability in long-term cell culture and leads 3D cell constructs with physiologically relevant phenotype. Therefore, this bioreactor would constitute a simple and versatile tool to generate in vitro tissue models and test their response to different agents, potentially increasing the complexity of the system by modifying the scaffold or co-culturing relevant cell types

Book of Abstracts 15th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering and 3rd Conference on Imaging and Visualization

In this edition, the two events will run together as a single conference, highlighting the strong connection with the Taylor & Francis journals: Computer Methods in Biomechanics and Biomedical Engineering (John Middleton and Christopher Jacobs, Eds.) and Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization (JoãoManuel R.S. Tavares, Ed.). The conference has become a major international meeting on computational biomechanics, imaging andvisualization. In this edition, the main program includes 212 presentations. In addition, sixteen renowned researchers will give plenary keynotes, addressing current challenges in computational biomechanics and biomedical imaging. In Lisbon, for the first time, a session dedicated to award the winner of the Best Paper in CMBBE Journal will take place. We believe that CMBBE2018 will have a strong impact on the development of computational biomechanics and biomedical imaging and visualization, identifying emerging areas of research and promoting the collaboration and networking between participants. This impact is evidenced through the well-known research groups, commercial companies and scientific organizations, who continue to support and sponsor the CMBBE meeting series. In fact, the conference is enriched with five workshops on specific scientific topics and commercial software.info:eu-repo/semantics/draf