Rheology and Lymphatic Physiokogy 2025 HD

The lymphatic system has important roles in body fluid regulation, macromolecular homeostasis, lipid absorption , and immune function. To accomplish these roles, lymphatics must move fluid and its other contents (macromolecules, lipids=chylomicra, immune cells) from the interstitium through the lymphatics, across the nodes, and into the great veins. Thus, the principal task of the lymphatic vascular system is transport. The body must impart energy to the lymph via pumping mechanisms to propel it along the lymphatic network and use pumps and valves to generate lymph flow and prevent its backflow. The lymphatic system utilizes both extrinsic pumps, which rely on the cyclical compression and expansion of lymphatics by surrounding tissue forces, and intrinsic pumps, which rely on the intrinsic rapid=phasic contractions of lymphatic muscle. The intrinsic lymph pump function can be modulated by neural, humoral, and physical factors. Generally, increased lymph pressure= stretch of the muscular lymphatics activates the intrinsic lymph pump, while increased lymph flow=shear in the muscular lymphatics can either activate or inhibit the intrinsic lymph pump depending on the pattern and magnitude of the flow. To regulate lymph transport, lymphatic pumping and resistance must be controlled. A better understanding of these mechanisms could provide the basis for the development of better diagnostic and treatment modalities for lymphatic dysfunction. The Lymphatic Transport System T he lymphatic system moves fluid from the interstitial spaces in the tissue parenchyma into the network of lymphatic vessels, through a series of lymph nodes into the postnodal lymph ducts that converge into the thoracic duct (for the lower half and upper left quadrant of the body) and right lymphatic duct (for the upper right quadrant of the body) before eventually emptying their lymph into the great veins. The unidirectional movement of lymph through this network is necessary for the transport of fluid, macromole-cules, lipids, antigens, immune cells, and particulate matter. Thus, all of the important functions that the lymphatic system must accomplish to maintain body homeostasis depend on the controlled transport of lymph from the initial lymphatics to the great veins. Over the last 10 years, great strides have been made in the molecular and cellular processes that drive the formation and=or regeneration of the lymphatic vessels. This has greatly advanced our understanding of the developmental and remodeling processes that govern some of the structural considerations of the lymphatic system, particularly those in the initial lymphatic vessels where lymph is formed. Much less recent effort has been placed into the study of the lymphatic structures at any level beyond the most peripheral parts of the lymphatic network. An understanding of the structure and function of the lymphatic architecture must go hand in hand if we are to develop a true appreciation of the impact of the lymphatic system in health and disease. When evaluating the lymphatic system it is crucial to remember that its principal purpose is the transport of lymph and it is by this regulated transport that ALL of the body's homeostatic functions that the lymphatic system participates in are served. Lastly but importantly, lymph transport includes not only the initial formation of lymph in the lym-phatic capillaries but also the movement of lymph along the rest of the lymphatic network on its route to the veins. Hydrodynamics of Lymph Transport Under steady states, most interstitial fluid pressures are either near atmospheric (i.e., near zero cm H 2 O relative pressure) or subatmospheric (À1 to À5 cm H 2 O, i.e., negative

Journal of Biomechanics, 1999

Interstitial #uid movement is intrinsically linked to lymphatic drainage. However, their relationship is poorly understood, and associated pathologies are mostly untreatable. In this work we test the hypothesis that bulk tissue #uid movement can be evaluated in situ and described by a linear biphasic theory which integrates the regulatory function of the lymphatics with the mechanical stresses of the tissue. To accomplish this, we develop a novel experimental and theoretical model using the skin of the mouse tail. We then use the model to demonstrate how interstitial}lymphatic #uid movement depends on a balance between the elasticity, hydraulic conductivity, and lymphatic conductance as well as to demonstrate how chronic swelling (edema) alters the equipoise between tissue #uid balance parameters. Speci"cally, tissue #uid equilibrium is perturbed with a continuous interstitial infusion of saline into the tip of the tail. The resulting gradients in tissue stress are measured in terms of interstitial #uid pressure using a servo-null system. These measurements are then "t to the theory to provide in vivo estimates of the tissue hydraulic conductivity, elastic modulus, and overall resistance to lymphatic drainage. Additional experiments are performed on edematous tails to show that although chronic swelling causes an increase in the hydraulic conductivity, its greatly increased distensibility (due to matrix remodeling) dampens the driving forces for #uid movement and leads to #uid stagnation. This model is useful for examining potential treatments for edema and lymphatic disorders as well as substances which may alter tissue #uid balance and/or lymphatic drainage.

Atlas of Lymphoscintigraphy and Sentinel Node Mapping, 2013

Quarterly Journal of Experimental Physiology and Cognate Medical Sciences, 1973

Intralymphatic pressures were monitored from plastic cannulas implanted in the thoracic, lumbar trunk and mesenteric lymphatics of conscious and anesthetized sheep, and in the thoracic duct of anaesthetized dogs. Extrinsic factors appeared to be important in the propulsion of lymph only in the thoracic duct of the dog. Intrinsic pulsatile pressure patterns were recorded from all lymphatics studied in sheep, and from the thoracic duct in one out of three dogs. The pulses ranged from about 1-15 mm Hg in amplitude and from about 2-20 pulses/min in frequency. A parameter of contractility was defined and used to establish the existence in sheep of a linear relationship between contractility and flow rate. This relationship was demonstrated when flow was increased by infusion into the lymphatic or into a vein, or, in the case of mesenteric lymphatics, by feeding fat. It was concluded that the intrinsic contractility is myogenic in origin and is the major factor responsible for lymph propulsion at least in sheep; the relationship between contractility and flow enables the rate of lymph flow to keep pace with the rate of lymph production.

To accomplish its normal roles in body fluid regulation/macromolecular homeostasis, immune function, and lipid absorption; the lymphatic system must transport lymph from the interstitial spaces, into and through the lymphatics, through the lymphatic compartment of the nodes, back into the nodal efferent lymphatics and eventually empty into the great veins. The usual net pressure gradients along this path do not normally favor the passive movement of lymph. Thus, lymph transport requires the input of energy to the lymph to propel it along this path. To do this, the lymphatic system uses a series of pumps to generate lymph flow. Thus to regulate lymph transport, both lymphatic pumping and resistance must be controlled. This review focuses on the regulation of the intrinsic lymph pump by hydrodynamic factors and how these regulatory processes are altered with age. Intrinsic lymph pumping is generated via the rapid/phasic contractions of lymphatic muscle, which are modulated by local physical factors (pressure/stretch and flow/shear). Increased lymph pressure/stretch will generally activate the intrinsic lymph pump up to a point, beyond which the lymph pump will begin to fail. The effect of increased lymph flow/shear is somewhat more complex, in that it can either activate or inhibit the intrinsic lymph pump, depending on the pattern and magnitude of the flow. The pattern and strength of the hydrodynamic regulation of the lymph transport is different in various parts of the lymphatic tree under normal conditions, depending upon the local hydrodynamic conditions. In addition, various pathophysiological processes can affect lymph transport. We have begun to evaluate the influence of the aging process on lymphatic transport characteristics in the rat thoracic duct. The pressure/stretch-dependent activation of intrinsic pumping is significantly impaired in aged rat thoracic duct (TD) and the flow/shear-dependent regulatory mechanisms are essentially completely lacking. The loss of shear-dependent modulation of lymphatic transport appears to be related to a loss of normal eNOS expression and a large rise in iNOS expression in these vessels. Therefore, aging of the lymph transport system significantly impairs its ability to transport lymph. We believe this will alter normal fluid balance as well as negatively impact immune function in the aged animals. Further studies are needed to detail the mechanisms that control and alter lymphatic transport during normal and aged conditions.

Scientific Reports, 2019

fluid homeostasis. Lymphatic vessels minimize contractions if existing fluid pressure gradients can drive flow, but actively pump to drive fluid otherwise 10,14,15. Our previous work has elucidated how these behaviors are coordinated throughout the lymphatic system by mechano-sensitive feedback 15,16. In summary, our model shows that + Ca 2 and NO concentrations establish complementary and oscillatory feedback loops that are self-regulating, maintaining normal lymphatic function, in agreement with experimental observations 12,17-19. However, in our previous work, the intraluminal valves were modeled by mathematically inserting a semi-permeable wall in the vessel when the flow reversed direction. Although this approach was able to reproduce the correct behaviors seen in vivo, it simplified valve performance and neglected valve leaflet structure and mechanics. The intraluminal valves that bias the flow in the direction away from the peripheral tissues are extremely important for lymphatic function, but little is known about their mechanical properties or how they influence lymph clearance or contraction efficiency. Previous studies have determined that lymphatic valves are biased to the open position, especially when the vessel is partially distended by a trans-wall pressure gradient 20. Experimental studies and mathematical models show that this property can increase flow efficiency by reducing flow resistance when the vessel is not actively contracting, even though it results in significant backflow as the downstream lymphangion contracts 21-24. The valve leaflets are also important as sources of biomolecules. Experiments have shown that the leaflets are a significant source of nitric oxide, presumably produced by dynamic shear stress on the leaflet structures themselves 25. Here, we extend our previous model of collecting lymphatic vessels by introducing realistic intraluminal valves. Furthermore, we embed the pumping vessel within a poro-elastic tissue that has fixed pressure boundaries in order to simulate fluid transport and edema at the tissue level. Model Description Figure 1 shows the model domain and dimensions. Fluid can enter the tissue from anywhere on the boundary except at the vessel outlet. Fluid percolates through the tissue to enter the initial lymphatic capillary at left (represented by the dashed line). The solid regions in this segment are impermeable, while the open regions are semipermeable, simulating the primary valves in the lymphatic capillaries. The collecting lymphatic vessel is downstream from the initial lymphatic, and fluid passes through it to exit at right. This vessel has two intraluminal valves that bias the flow toward the exit, and the walls can move to actively pump fluid. We use the lattice Boltzmann method (LBM) 26,27 to calculate the fluid flow, shear stresses and pressures in the tissue and lymphatic vessel. The endothelium on the inner wall of the vessel can generate nitric oxide (NO) 28-30 in response to increased shear stress, and contractions of the collecting lymphatic are determined by the concentration of + Ca 2 in the lymphatic muscle cells. Briefly, + Ca 2 can be depleted over time due to recharging of the cytoplasm ion concentrations, and can increase due to mechanical or chemical triggers. The self-regulating contraction dynamics that effect lymph drainage are governed by mutual mechanical feedback of the NO and + Ca 2 systems 15,16. The details of the model are given in the Methods section.

Kornuta JA, Nepiyushchikh Z, Gasheva OY, Mukherjee A, Zawieja DC, Dixon JB. Effects of dynamic shear and trans-mural pressure on wall shear stress sensitivity in collecting lym-phatic vessels..—Given the known mechanosen-sitivity of the lymphatic vasculature, we sought to investigate the effects of dynamic wall shear stress (WSS) on collecting lymphatic vessels while controlling for transmural pressure. Using a previously developed ex vivo lymphatic perfusion system (ELPS) capable of independently controlling both transaxial pressure gradient and average transmural pressure on an isolated lymphatic vessel, we imposed a multitude of flow conditions on rat thoracic ducts, while controlling for transmural pressure and measuring diameter changes. By gradually increasing the imposed flow through a vessel, we determined the WSS at which the vessel first shows sign of contraction inhibition, defining this point as the shear stress sensitivity of the vessel. The shear stress threshold that triggered a contractile response was significantly greater at a transmural pressure of 5 cmH2O (0.97 dyne/cm 2) than at 3 cmH2O (0.64 dyne/cm 2). While contraction frequency was reduced when a steady WSS was applied, this inhibition was reversed when the applied WSS oscillated, even though the mean wall shear stresses between the conditions were not significantly different. When the applied oscillatory WSS was large enough, flow itself synchronized the lymphatic contractions to the exact frequency of the applied waveform. Both transmural pressure and the rate of change of WSS have significant impacts on the contractile response of lymphatic vessels to flow. Specifically, time-varying shear stress can alter the inhibition of phasic contraction frequency and even coordinate contractions, providing evidence that dynamic shear could play an important role in the contractile function of collecting lymphatic vessels. endothelial cell; lymphatic; pump function; shear stress; thoracic duct THE LYMPHATIC SYSTEM SUPPORTS some of the human body's most critical functions, including maintaining tissue fluid balance (59), providing a route for immune cell and antigen transport to and from the lymph node (52), and transporting lipid from the gut to the blood (14), among others. Specifically, the network of vessels begins in the interstitial tissue spaces, subsequently merging downstream as it branches into larger vessels termed the collecting lymphatic vessels. These collecting vessels consist of luminal lymphatic endothelial cells (LECs) surrounded by muscle cells that actively contract to transport fluid toward the left subclavian vein (66). Like in the heart, these rapid phasic contractions are crucial in lymphatic transport, since interstitial fluid pressure alone is normally insufficient to move lymph against the adverse pressure gradient present in the system (4). However, like blood vessels, the collecting lym-phatic vessels also actively alter their tone on a slower time scale in a manner that promotes passive lymph transport from externally applied pressure gradients (19, 49). The collecting lymphatic vessels are separated by one-way valves into unit segments known as lymphangions, which close under adverse pressure gradients to minimize backflow (11). Together, these two features operate in synchrony to control lymph transport throughout the body, which recent estimates put at almost 8 l/day for humans (37), However, unlike most veins, these vessels can rapidly contract to quickly eject fluid from one lymphangion to another, sometimes up to 75% of their diameter (13), a phenomenon achieved through the specialized muscle cells surrounding the collecting lymphatic vessel (44). The contraction dynamics of collecting lymphatic vessels, which are categorized as either phasic or tonic and often referred to as the intrinsic pump, are highly sensitive to the mechanical forces imposed on the vessel (10, 19, 40, 42). Since lymph formation can vary widely, even during normal, physiological circumstances due to extrinsic factors (35) (such as digestion, skeletal muscle contraction, respiration, and intersti-tial fluid formation), it has been hypothesized that the lym-phatic vessel's sensitivity to the local mechanical environment aids in optimizing lymph transport (19). This ability to sense and respond to local mechanical forces would certainly be beneficial to the vessels' intrinsic pumping, allowing it to optimize its performance for the rapidly varying loads in vivo. For instance, like the heart, collecting lymphatic vessels have been shown to quickly react to different levels of transmural pressure (23, 40) and preload/afterload (12, 57), parameters that change continuously on the basis of levels of lymph formation, body position, skeletal muscle activity, etc. Much like in the heart, the lymphangions' response to these loads appears tuned in such a way to maximize fluid output and minimize energy expenditure (21). In addition to a contractile dependency on transmural pressure , isolated vessel and in vivo studies have also demonstrated inhibition of lymphatic pump function in response to luminal fluid shear stress (3, 18, 19, 30, 50). In isolated vessel studies, higher magnitudes of applied transaxial pressure gradient re

American Journal of Physiology-Heart and Circulatory Physiology, 2007

The lymphatic system returns interstitial fluid to the central venous circulation, in part, by the cyclical contraction of a series of “lymphangion pumps” in a lymphatic vessel. The dynamics of individual lymphangions have been well characterized in vitro; their frequencies and strengths of contraction are sensitive to both preload and afterload. However, lymphangion interaction within a lymphatic vessel has been poorly characterized because it is difficult to experimentally alter properties of individual lymphangions and because the afterload of one lymphangion is coupled to the preload of another. To determine the effects of lymphangion interaction on lymph flow, we adapted an existing mathematical model of a lymphangion (characterizing lymphangion contractility, lymph viscosity, and inertia) to create a new lymphatic vessel model consisting of several lymphangions in series. The lymphatic vessel model was validated with focused experiments on bovine mesenteric lymphatic vessels i...

The lymphatic system is vital to a proper maintenance of fluid and solute homeostasis. Collecting lym-phatics 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 o1 ml/h and pressures of a few cmH 2 O, 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 4 1.39, the average resistance to forward flow was 0.95 Â 10 6 [g/(cm 4 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.

The Journal of Physiology, 2011

Regulation of fluid and material movement between the vascular space of microvessels penetrating functioning organs and the cells therein has been studied extensively. Unanswered questions as to the regulatory mechanisms and routes remain. Significantly less is known about the lymphatic vascular system given the difficulties in seeing, no less isolating, these vessels lying deeper in these same tissues. It has become evident that the exchange microvasculature is not simply a passive biophysical barrier separating the vascular and interstitial compartments but a dynamic, multicellular structure subject to acute regulation and chronic adaptation to stimuli including inflammation, sepsis, diabetes, injury, hypoxia and exercise. Similarly lymphatic vessels range, in their simplest form, from lymphatic endothelium attached to the interstitial matrix, to endothelia and phasic lymphatic smooth muscle that act as Starling resistors. Recent work has demonstrated that among the microvascular lymphatic elements, the collecting lymphatics have barrier properties similar to venules, and thus participate in exchange. As with venules, vasoactive agents can alter both the permeability and contractile properties thereby setting up previously unanticipated gradients in the tissue space and providing potential targets for the pharmacological prevention and/or resolution of oedema.