119 results found
Xu Q, Moore JE, 2020, Ex vivo perfusion of human lymph nodes, JOURNAL OF PATHOLOGY, Vol: 251, Pages: 225-227, ISSN: 0022-3417
Kalogiros D, Russell M, Bonneuil W, et al., 2019, An Integrated Pipeline for Combining In Vitro Data and Mathematical Models Using a Bayesian Parameter Inference Approach to Characterize Spatio-temporal Chemokine Gradient Formation, Frontiers in Immunology, Vol: 10, Pages: 1-15, ISSN: 1664-3224
All protective and pathogenic immune and inflammatory responses rely heavily on leukocyte migration and localization. Chemokines are secreted chemoattractants that orchestrate the positioning and migration of leukocytes through concentration gradients. The mechanisms underlying chemokine gradient establishment and control include physical as well as biological phenomena. Mathematical models offer the potential to both understand this complexity and suggest interventions to modulate immune function. Constructing models that have powerful predictive capability relies on experimental data to estimate model parameters accurately, but even with a reductionist approach, most experiments include multiple cell types, competing interdependent processes and considerable uncertainty. Therefore, we propose the use of reduced modelling and experimental frameworks in complement, to minimize the number of parameters to be estimated. We present a Bayesian optimization framework that accounts for advection and diffusion of a chemokine surrogate and the chemokine CCL19, transport processes that are known to contribute to the establishment of spatio temporal chemokine gradients. Two examples are provided that demonstrate the estimation of the governing parameters as well as the underlying uncertainty. This study demonstrates how a synergistic approach between experimental and computational modelling benefits from the Bayesian approach to provide a robust analysis of chemokine transport. It provides a building block for a larger research effort to gain holistic insight and generate novel and testable hypotheses in chemokine biology and leukocyte trafficking.
Moore Jr J, 2019, Quantification of the Whole Lymph Node Vasculature Based on Tomography of the Vessel Corrosion Casts, Scientific Reports, Vol: 9, Pages: 1-11, ISSN: 2045-2322
Lymph nodes (LN) are crucial for immune function, and comprise an important interface between the blood and lymphatic systems. Blood vessels (BV) in LN are highly specialized, featuring high endothelial venules across which most of the resident lymphocytes crossed. Previous measurements of overall lymph and BV flow rates demonstrated that fluid also crosses BV walls, and that this is important for immune function. However, the spatial distribution of the BV in LN has not been quantified to the degree necessary to analyse the distribution of transmural fluid movement. In this study, we seek to quantify the spatial localization of LNBV, and to predict fluid movement across BV walls. MicroCT imaging of murine popliteal LN showed that capillaries were responsible for approximately 75% of the BV wall surface area, and that this was mostly distributed around the periphery of the node. We then modelled blood flow through the BV to obtain spatially resolved hydrostatic pressures, which were then combined with Starling’s law to predict transmural flow. Much of the total 10 nL/min transmural flow (under normal conditions) was concentrated in the periphery, corresponding closely with surface area distribution. These results provide important insights into the inner workings of LN, and provide a basis for further exploration of the role of LN flow patterns in normal and pathological functions.
Wilson JT, Edgar LT, Prabhakar S, et al., 2018, A fully coupled fluid-structure interaction model of the secondary lymphatic valve., Comput Methods Biomech Biomed Engin, Vol: 21, Pages: 813-823
The secondary lymphatic valve is a bi-leaflet structure frequent throughout collecting vessels that serves to prevent retrograde flow of lymph. Despite its vital function in lymph flow and apparent importance in disease development, the lymphatic valve and its associated fluid dynamics have been largely understudied. The goal of this work was to construct a physiologically relevant computational model of an idealized rat mesenteric lymphatic valve using fully coupled fluid-structure interactions to investigate the relationship between three-dimensional flow patterns and stress/deformation within the valve leaflets. The minimum valve resistance to flow, which has been shown to be an important parameter in effective lymphatic pumping, was computed as 268 g/mm4-s. Hysteretic behavior of the lymphatic valve was confirmed by comparing resistance values for a given transvalvular pressure drop during opening and closing. Furthermore, eddy structures were present within the sinus adjacent to the valve leaflets in what appear to be areas of vortical flow; the eddy structures were characterized by non-zero velocity values (up to ∼4 mm/s) in response to an applied unsteady transvalvular pressure. These modeling capabilities present a useful platform for investigating the complex interplay between soft tissue motion and fluid dynamics of lymphatic valves and contribute to the breadth of knowledge regarding the importance of biomechanics in lymphatic system function.
Bertram CD, Macaskill C, Davis MJ, et al., 2018, Contraction of collecting lymphatics: organization of pressure-dependent rate for multiple lymphangions, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 17, Pages: 1513-1532, ISSN: 1617-7959
Moore Jr JE, Brook B, Nibbs RJB, 2018, Chemokine transport dynamics and emerging recognition of their role in immune function, Current Opinion in Biomedical Engineering, Vol: 5, Pages: 90-95, ISSN: 2468-4511
Leukocyte migration is critically important during all protective and pathological immune and inflammatory responses. Chemokines play fundamental roles in this process, and chemokine concentration gradients stimulate the directional migration of leukocytes. The formation and regulation of these gradients is poorly understood. These are complex processes that depend on the specific properties of each chemokine and interactions between physical, biological and biochemical processes, including production, diffusion, advection, scavenging, post-translational modification, and extracellular matrix (ECM) binding. While some of these mechanisms have been investigated in isolation or limited combinations, more integrative research is required to provide a quantitative knowledge base that explains how chemokine gradients are established and maintained, and how cells respond to, and modify, these gradients.
Moore JE, Bertram CD, 2018, Lymphatic System Flows., Annu Rev Fluid Mech, Vol: 50, Pages: 459-482, ISSN: 0066-4189
The supply of oxygen and nutrients to tissues is performed by the blood system, and involves a net leakage of fluid outward at the capillary level. One of the principal functions of the lymphatic system is to gather this fluid and return it to the blood system to maintain overall fluid balance. Fluid in the interstitial spaces is often at subatmospheric pressure, and the return points into the venous system are at pressures of approximately 20 cmH2O. This adverse pressure difference is overcome by the active pumping of collecting lymphatic vessels, which feature closely spaced one-way valves and contractile muscle cells in their walls. Passive vessel squeezing causes further pumping. The dynamics of lymphatic pumping have been investigated experimentally and mathematically, revealing complex behaviours indicating that the system performance is robust against minor perturbations in pressure and flow. More serious disruptions can lead to incurable swelling of tissues called lymphœdema.
Behringer EJ, Scallan JP, Jafarnejad M, et al., 2017, Calcium and electrical dynamics in lymphatic endothelium, The Journal of Physiology, Vol: 595, Pages: 7347-7368, ISSN: 0022-3751
Bertram CD, Macaskill C, Davis MJ, et al., 2017, Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 16, Pages: 1987-2003, ISSN: 1617-7959
Jamalian S, Jafarnejad M, Zawieja SD, et al., 2017, Demonstration and Analysis of the Suction Effect for Pumping Lymph from Tissue Beds at Subatmospheric Pressure, Scientific Reports, Vol: 7
Jafarnejad M, Zawieja DC, Brook BS, et al., 2017, A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4, JOURNAL OF IMMUNOLOGY, Vol: 199, Pages: 2291-2304, ISSN: 0022-1767
Walsh MT, Moore JE, 2017, Editorial: Special Issue on Vascular Access : Towards Improving Vascular Access., Cardiovasc Eng Technol, Vol: 8, Pages: 237-239
Athanasiou D, Edgar LT, Jafarnejad M, et al., 2017, The passive biomechanics of human pelvic collecting lymphatic vessels, PLOS One, Vol: 12, ISSN: 1932-6203
The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport.
Jafarnejad M, Zawieja DC, Brook BS, et al., 2017, A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4., Journal of Immunology, Vol: 199, Pages: 2291-2304, ISSN: 1550-6606
The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19-CCL21-CCR7-ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines.
Bertram CD, Macaskill C, Moore Jr JE, 2016, Pump function curve shape for a model lymphatic vessel, Medical Engineering & Physics, Vol: 38, Pages: 656-663, ISSN: 1873-4030
The transport capacity of a contractile segment of lymphatic vessel is defined by its pump function curve relating mean flow-rate and adverse pressure difference. Numerous system characteristics affect curve shape and the magnitude of the generated flow-rates and pressures. Some cannot be varied experimentally, but their separate and interacting effects can be systematically revealed numerically. This paper explores variations in the rate of change of active tension and the form of the relation between active tension and muscle length, factors not known from experiment to functional precision. Whether the pump function curve bends toward or away from the origin depends partly on the curvature of the passive pressure-diameter relation near zero transmural pressure, but rather more on the form of the relation between active tension and muscle length. A pump function curve bending away from the origin defines a well-performing pump by maximum steady output power. This behaviour is favoured by a length/active-tension relationship which sustains tension at smaller lengths. Such a relationship also favours high peak mechanical efficiency, defined as output power divided by the input power obtained from the lymphangion diameter changes and active-tension time-course. The results highlight the need to pin down experimentally the form of the active tension/length relationship.
Jamalian S, Davis MJ, Zawieja DC, et al., 2016, Network Scale Modeling of Lymph Transport and Its Effective Pumping Parameters, PLOS One, Vol: 11, ISSN: 1932-6203
he lymphatic system is an open-ended network of vessels that run in parallel to the blood circulation system. These vessels are present in almost all of the tissues of the body to remove excess fluid. Similar to blood vessels, lymphatic vessels are found in branched arrangements. Due to the complexity of experiments on lymphatic networks and the difficulty to control the important functional parameters in these setups, computational modeling becomes an effective and essential means of understanding lymphatic network pumping dynamics. Here we aimed to determine the effect of pumping coordination in branched network structures on the regulation of lymph flow. Lymphatic vessel networks were created by building upon our previous lumped-parameter model of lymphangions in series. In our network model, each vessel is itself divided into multiple lymphangions by lymphatic valves that help maintain forward flow. Vessel junctions are modeled by equating the pressures and balancing mass flows. Our results demonstrated that a 1.5 s rest-period between contractions optimizes the flow rate. A time delay between contractions of lymphangions at the junction of branches provided an advantage over synchronous pumping, but additional time delays within individual vessels only increased the flow rate for adverse pressure differences greater than 10.5 cmH2O. Additionally, we quantified the pumping capability of the system under increasing levels of steady transmural pressure and outflow pressure for different network sizes. We observed that peak flow rates normally occurred under transmural pressures between 2 to 4 cmH2O (for multiple pressure differences and network sizes). Networks with 10 lymphangions per vessel had the highest pumping capability under a wide range of adverse pressure differences. For favorable pressure differences, pumping was more efficient with fewer lymphangions. These findings are valuable for translating experimental measurements from the single lymphangion lev
Soares JS, Moore JE, 2016, Biomechanical Challenges to Polymeric Biodegradable Stents, ANNALS OF BIOMEDICAL ENGINEERING, Vol: 44, Pages: 560-579, ISSN: 0090-6964
Braakman ST, Moore JE, Ethier CR, et al., 2015, Transport across Schlemm's canal endothelium and the blood-aqueous barrier, Experimental Eye Research, Vol: 146, Pages: 17-21, ISSN: 0014-4835
The majority of trabecular outflow likely crosses Schlemm's canal (SC) endothelium through micron-sized pores, and SC endothelium provides the only continuous cell layer between the anterior chamber and episcleral venous blood. SC endothelium must therefore be sufficiently porous to facilitate outflow, while also being sufficiently restrictive to preserve the blood-aqueous barrier and prevent blood and serum proteins from entering the eye. To understand how SC endothelium satisfies these apparently incompatible functions, we examined how the diameter and density of SC pores affects retrograde diffusion of serum proteins across SC endothelium, i.e. from SC lumen into the juxtacanalicular tissue (JCT). Opposing retrograde diffusion is anterograde bulk flow velocity of aqueous humor passing through pores, estimated to be approximately 5 mm/s. As a result of this relatively large through-pore velocity, a mass transport model predicts that upstream (JCT) concentrations of larger solutes such as albumin are less than 1% of the concentration in SC lumen. However, smaller solutes such as glucose are predicted to have nearly the same concentration in the JCT and SC. In the hypothetical case that, rather than micron-sized pores, SC formed 65 nm fenestrae, as commonly observed in other filtration-active endothelia, the predicted concentration of albumin in the JCT would increase to approximately 50% of that in SC. These results suggest that the size and density of SC pores may have developed to allow SC endothelium to maintain the blood-aqueous barrier while simultaneously facilitating aqueous humor outflow.
Wilson J, van Loon R, Wang W, et al., 2015, Determining the combined effect of the lymphatic valve leaflets and sinus on resistance to forward flow, Journal of Biomechanics, Vol: 48, Pages: 3593-3599, ISSN: 1873-2380
The lymphatic system is vital to a proper maintenance of fluid and solute homeostasis. Collecting lymphatics are composed of actively contracting tubular vessels segmented by bulbous sinus regions that encapsulate bi-leaflet check valves. Valve resistance to forward flow strongly influences pumping performance. However, because of the sub-millimeter size of the vessels with flow rates typically<1 ml/hour and pressures of a few cmH2O, resistance is difficult to measure experimentally. Using a newly defined idealized geometry, we employed an uncoupled approach where the solid leaflet deflections of the open valve were computed and lymph flow calculations were subsequently performed. We sought to understand: 1) the effect of sinus and leaflet size on the resulting deflections experienced by the valve leaflets and 2) the effects on valve resistance to forward flow of the fully open valve. For geometries with sinus-to-root diameter ratios>1.39, the average resistance to forward flow was 0.95×106 [g/(cm4 s)]. Compared to the viscous pressure drop that would occur in a straight tube the same diameter as the upstream lymphangion, valve leaflets alone increase the pressure drop up to 35%. However, the presence of the sinus reduces viscous losses, with the net effect that when combined with leaflets the overall resistance is less than that of the equivalent continuing straight tube. Accurately quantifying resistance to forward flow will add to the knowledge used to develop therapeutics for treating lymphatic disorders and may eventually lead to understanding some forms of primary lymphedema.
Jafarnejad M, Woodruff MC, Zawieja DC, et al., 2015, Modeling lymph flow and fluid exchange with blood vessels in lymph nodes, Lymphatic Research and Biology, ISSN: 1557-8585
Background: Lymph nodes (LNs) are positioned strategically throughout the body as critical mediators of lymph filtration and immune response. Lymph carries cytokines, antigens, and cells to the downstream LNs, and their effective delivery to the correct location within the LN directly impacts the quality and quantity of immune response. Despite the importance of this system, the flow patterns in LN have never been quantified, in part because experimental characterization is so difficult. Methods and Results: To achieve a more quantitative knowledge of LN flow, a computational flow model has been developed based on the mouse popliteal LN, allowing for a parameter sensitivity analysis to identify the important system characteristics. This model suggests that about 90% of the lymph takes a peripheral path via the subcapsular and medullary sinuses, while fluid perfusing deeper into the paracortex is sequestered by parenchymal blood vessels. Fluid absorption by these blood vessels under baseline conditions was driven mainly by oncotic pressure differences between lymph and blood, although the magnitude of fluid transfer is highly dependent on blood vessel surface area. We also predict that the hydraulic conductivity of the medulla, a parameter that has never been experimentally measured, should be at least three orders of magnitude larger than that of the paracortex to ensure physiologic pressures across the node. Conclusions: These results suggest that structural changes in the LN microenvironment, as well as changes in inflow/outflow conditions, dramatically alter the distribution of lymph, cytokines, antigen and cells within the LN, with great potential for modulating immune response.
Jafarnejad M, Cromer WE, Kaunas RR, et al., 2015, Measurement of shear stress-mediated intracellular calcium dynamics in human dermal lymphatic endothelial cells, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 308, Pages: H697-H706, ISSN: 0363-6135
Bazigou E, Wilson JT, Moore JE, 2014, Primary and secondary lymphatic valve development: Molecular, functional and mechanical insights, MICROVASCULAR RESEARCH, Vol: 96, Pages: 38-45, ISSN: 0026-2862
Hayman D, Bergerson C, Miller S, et al., 2014, The Effect of Static and Dynamic Loading on Degradation of PLLA Stent Fibers, JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME, Vol: 136, ISSN: 0148-0731
Rahbar E, Akl T, Cote GL, et al., 2014, Lymph Transport in Rat Mesenteric Lymphatics Experiencing Edemagenic Stress, MICROCIRCULATION, Vol: 21, Pages: 359-367, ISSN: 1073-9688
Bertram CD, Macaskill C, Davis MJ, et al., 2014, Development of a model of a multi-lymphangion lymphatic vessel incorporating realistic and measured parameter values, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 13, Pages: 401-416, ISSN: 1617-7959
Bertram CD, Macaskill C, Moore JE, 2014, Incorporating measured valve properties into a numerical model of a lymphatic vessel, COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING, Vol: 17, Pages: 1519-1534, ISSN: 1025-5842
Zawieja D, Gashev A, Gasheva O, et al., 2014, Phenotypic characterization of lymphatic contractile activity, 11th International Symposium on Resistance Arteries from Molecular Machinery to Clinical Challenges, Publisher: KARGER, Pages: 61-61, ISSN: 1018-1172
Jafarnejad M, Cromer WE, Kaunas RR, et al., 2014, CALCIUM REGULATION IN LYMPHATIC ENDOTHELIAL CELLS UNDER FLOW, 15th American-Society-Mechanical-Engineering Summer Bioengineering Conference (SBC2013), Publisher: AMER SOC MECHANICAL ENGINEERS
Jamalian S, Bertram CD, Richardson WJ, et al., 2013, Parameter sensitivity analysis of a lumped-parameter model of a chain of lymphangions in series., Am J Physiol Heart Circ Physiol, Vol: 305, Pages: H1709-H1717
Any disruption of the lymphatic system due to trauma or injury can lead to edema. There is no effective cure for lymphedema, partly because predictive knowledge of lymphatic system reactions to interventions is lacking. A well-developed model of the system could greatly improve our understanding of its function. Lymphangions, defined as the vessel segment between two valves, are the individual pumping units. Based on our previous lumped-parameter model of a chain of lymphangions, this study aimed to identify the parameters that affect the system output the most using a sensitivity analysis. The system was highly sensitive to minimum valve resistance, such that variations in this parameter caused an order-of-magnitude change in time-average flow rate for certain values of imposed pressure difference. Average flow rate doubled when contraction frequency was increased within its physiological range. Optimum lymphangion length was found to be some 13-14.5 diameters. A peak of time-average flow rate occurred when transmural pressure was such that the pressure-diameter loop for active contractions was centered near maximum passive vessel compliance. Increasing the number of lymphangions in the chain improved the pumping in the presence of larger adverse pressure differences. For a given pressure difference, the optimal number of lymphangions increased with the total vessel length. These results indicate that further experiments to estimate valve resistance more accurately are necessary. The existence of an optimal value of transmural pressure may provide additional guidelines for increasing pumping in areas affected by edema.
Richardson WJ, van der Voort DD, Wilson E, et al., 2013, Differential Orientation of 10T1/2 Mesenchymal Cells on Non-Uniform Stretch Environments, MOLECULAR & CELLULAR BIOMECHANICS, Vol: 10, Pages: 245-265, ISSN: 1556-5297
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.