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Basic concepts in the physiopathology of edema are reviewed. The mechanisms of fluid exchange across the capillary endothelium are explained. Interstitial flow and lymph formation are examined. Clinical disorders of tissue and lymphatic transport, microcirculatory derangements in venous disorders, protein disorders, and lymphatic system disorders are explored. Techniques for investigational imaging of the lymphatic system are explained.
MOTIVATION: Spaceflight countermeasures mitigate the harmful effects of the space environment on astronaut health and performance. Exercise has historically been used as a countermeasure to physical deconditioning, and additional countermeasures including lower body negative pressure, blood flow occlusion and artificial gravity are being researched as countermeasures to spaceflight-induced fluid shifts. The NASA Digital Astronaut Project uses computational models of physiological systems to inform countermeasure design and to predict countermeasure efficacy.OVERVIEW: Computational modeling supports the development of the exercise devices that will be flown on NASAs new exploration crew vehicles. Biomechanical modeling is used to inform design requirements to ensure that exercises can be properly performed within the volume allocated for exercise and to determine whether the limited mass, volume and power requirements of the devices will affect biomechanical outcomes. Models of muscle atrophy and bone remodeling can predict device efficacy for protecting musculoskeletal health during long-duration missions. A lumped-parameter whole-body model of the fluids within the body, which includes the blood within the cardiovascular system, the cerebral spinal fluid, interstitial fluid and lymphatic system fluid, estimates compartmental changes in pressure and volume due to gravitational changes. These models simulate fluid shift countermeasure effects and predict the associated changes in tissue strain in areas of physiological interest to aid in predicting countermeasure effectiveness. SIGNIFICANCE: Development and testing of spaceflight countermeasure prototypes are resource-intensive efforts. Computational modeling can supplement this process by performing simulations that reduce the amount of necessary experimental testing. Outcomes of the simulations are often important for the definition of design requirements and the identification of factors essential in ensuring countermeasure efficacy.
Lymphatics are necessary for the generation and regulation of lymph flow. Lymphatics use phasic contractions and extrinsic compressions to generate flow; tonic contractions alter resistance. Lymphatic muscle exhibits important differences from typical vascular smooth muscle. In this study, the thoracic duct exhibited significant functional differences from mesenteric lymphatics. To understand the molecular basis for these differences, we examined the profiles of contractile proteins and their messages in mesenteric lymphatics, thoracic duct, and arterioles. Results demonstrated that mesenteric lymphatics express only SMB smooth muscle myosin heavy chain (SM-MHC), whereas thoracic duct and arterioles expressed both SMA and SMB isoforms. Both SM1 and SM2 isoforms of SM-MHC were detected in arterioles and mesenteric and thoracic lymphatics. In addition, the fetal cardiac/skeletal slow-twitch muscle-specific beta-MHC message was detected only in mesenteric lymphatics. All four actin messages, cardiac alpha-actin, vascular alpha-actin, enteric gamma-actin, and skeletal alpha-actin, were present in both mesenteric lymphatics and arterioles. However, in thoracic duct, predominantly cardiac alpha-actin and vascular alpha-actin were found. Western blot and immunohistochemical analyses corroborated the mRNA studies. However, in arterioles only vascular alpha-actin protein was detected. These data indicate that lymphatics display genotypic and phenotypic characteristics of vascular, cardiac, and visceral myocytes, which are needed to fulfill the unique roles of the lymphatic system.
In this work, we present mixed dimensional models for simulating blood flow and transport processes in breast tissue and the vascular tree supplying it. These processes are considered, to start from the aortic inlet to the capillaries and tissue of the breast. Large variations in biophysical properties and flow conditions exist in this system necessitating the use of different flow models for different geometries and flow regimes. In total, we consider four different model types. First, a system of 1D nonlinear hyperbolic partial differential equations (PDEs) is considered to simulate blood flow in larger arteries with highly elastic vessel walls. Second, we assign 1D linearized hyperbolic PDEs to model the smaller arteries with stiffer vessel walls. The third model type consists of ODE systems (0D models). It is used to model the arterioles and peripheral circulation. Finally, homogenized 3D porous media models are considered to simulate flow and transport in capillaries and tissue within the breast volume. Sink terms are used to account for the influence of the venous and lymphatic systems. Combining the four model types, we obtain two different 1D–0D–3D coupled models for simulating blood flow and transport processes: The first model results in a fully coupled 1D–0D–3D model covering the complete path from the aorta to the breast combining a generic arterial network with a patient specific breast network and geometry. The second model is a reduced one based on the separation of the generic and patient specific parts. The information from a calibrated fully coupled model is used as inflow condition for the patient specific sub-model allowing a significant computational cost reduction. Several numerical experiments are conducted to calibrate the generic model parameters and to demonstrate realistic flow simulations compared to existing data on blood flow in the human breast and vascular system. Moreover, we use two different breast vasculature and tissue data sets to illustrate the robustness of our reduced sub-model approach.
Terrestrial animals have adapted to a constant gravitational stress over millions of years. Tissues of the cardiovascular system and lumbar spine in tall species of animals such as the giraffe are particularly well adapted to high and variable vectors of gravitational force. Swelling of the leg tissues in the giraffe is prevented by a variety of physiological mechanisms including (1) a natural 'antigravity suit', (2) impermeable capillaries, (3) arterial-wall hypertrophy, (4) variable blood pressures during normal activity, and (5) a large-capacity lymphatic system. These adaptations, as well as a natural hypertension, maintain blood perfusion to the giraffe's brain. The intervertebral disk is another tissue that is uniquely adapted to gravitational stress. Tall and large terrestrial animals have higher swelling pressures than their smaller or aquatic counterparts. Finally, the meniscus of the rabbit knee provides information on the effects of aging and load-bearing on cartilaginous tissues. Such tissues within the joints of animals are important for load-bearing on Earth; these connective tissues may degenerate during long-duration space flight.
Subcutaneous injection of biotherapeutics has attracted considerable attention in the pharmaceutical industry. However, there is limited understanding of the mechanisms underlying the absorption of drugs with different molecular weights and the delivery of drugs from the injection site to the targeted tissue. Here, we propose the MPET 2 -mPBPK model to address this issue. This multiscale model couples the MPET 2 model, which describes subcutaneous injection at the local tissue scale from a biomechanical view, with a post-injection absorption model at injection site and a minimal physiologically-based pharmacokinetic (mPBPK) model at whole-body scale. Utilizing the principles of tissue biomechanics and fluid dynamics, the local MPET 2 model provides solutions that account for tissue deformation and drug absorption in local blood vessels and initial lymphatic vessels during injection. Additionally, we introduce a model accounting for the molecular weight effect on the absorption by blood vessels, and a nonlinear model accounting for the absorption in lymphatic vessels. The post-injection model predicts drug absorption in local blood vessels and initial lymphatic vessels, which are integrated into the whole-body mPBPK model to describe the pharmacokinetic behaviors of the absorbed drug in the circulatory and lymphatic system. We establish a numerical model which links the biomechanical process of subcutaneous injection at local tissue scale and the pharmacokinetic behaviors of injected biotherapeutics at whole-body scale. With the help of the model, we propose an explicit relationship between the reflection coefficient and the molecular weight and predict the bioavalibility of biotherapeutics with varying molecular weights via subcutaneous injection. The considered drug absorption mechanisms enable us to study the differences in local drug absorption and whole-body drug distribution with varying molecular weights. This model enhances the understanding of drug absorption mechanisms and transport routes in the circulatory system for drugs of different molecular weights, and holds the potential to facilitate the application of computational modeling to drug formulation.
Enzyme and hormonal concentrations in renal lymph fluid, discussing renal lymphatics as active fluid transport system
Interest in recapitulating in vivo phenomena in vitro using organ-on-a-chip technology has grown rapidly and with it, attention to the types of fluid flow experienced in the body has followed suit. These platforms offer distinct advantages over in vivo models with regards to human relevance, cost, and control of inputs (e.g., controlled manipulation of biomechanical cues from fluid perfusion). Given the critical role biophysical forces play in several tissues and organs, it is therefore imperative that engineered in vitro platforms capture the complex, unique flow profiles experienced in the body that are intimately tied with organ function. In this review, we outline the complex and unique flow regimes experienced by three different organ systems: blood vasculature, lymphatic vasculature, and the intestinal system. Here, we highlight current state-of-the-art platforms that strive to replicate physiological flows within engineered tissues while introducing potential limitations in current approaches.
Study of renal lymph fluid transport system
Background To determine if construction and trades workers formerly employed at US Department of Energy (DOE) nuclear weapons sites are at significant risk for occupational diseases, we studied the mortality experience of participants in the Building Trades National Medical Screening Program (BTMed). Methods The cohort included 26,922 participants enrolled between 1998 and 2021 and 8367 deaths. Standardized mortality ratios were calculated based on US death rates. Cox models compared construction workers (n = 22,747; 7487 deaths) to two nonconstruction subpopulations: administrative, scientific and security workers (n = 1894; 330 deaths), and all other nonconstruction workers (n = 2218; 550 deaths). Results Mortality was elevated for all causes, all cancers, cancers of the trachea, bronchus, lung, kidneys, and lymphatic and hematopoietic system, mesothelioma, chronic obstructive pulmonary disease (COPD), asbestosis, transportation injuries, and other injuries, particularly accidental poisonings. There were 167 deaths from coronavirus disease 2019 (COVID-19), which was lower than expected using US death rates. Overall cause-specific mortality was significantly higher among construction workers than for internal comparison groups. Conclusions Construction workers employed at DOE sites have a significantly increased risk for occupational illnesses. Apart from COVID-19 deaths, this update: (1) found that mortality among construction workers is significantly elevated compared to the US population and significantly higher than in the internal comparison populations, and (2) confirmed excess risk for these workers for first employment after 1990. Cancer mortality risks are similar to the cancers identified for DOE compensation from radiation exposures. In conclusion, the high lung cancer risk supports the value of early lung cancer detection. Continued medical surveillance is important.
There is a need for better predictive models of the human immune system to evaluate safety and efficacy of immunomodulatory drugs and biologics for successful product development and regulatory approvals. Current in vitro models, which are often tested in two-dimensional (2D) tissue culture polystyrene, and preclinical animal models fail to fully recapitulate the function and physiology of the human immune system. Microphysiological systems (MPSs) that can model key microenvironment cues of the human immune system, as well as of specific organs and tissues, may be able to recapitulate specific features of the in vivo inflammatory response. This minireview provides an overview of MPS for modeling lymphatic tissues, immunity at tissue interfaces, inflammatory diseases, and the inflammatory tumor microenvironment in vitro and ex vivo. Broadly, these systems have utility in modeling how certain immunotherapies function in vivo, how dysfunctional immune responses can propagate diseases, and how our immune system can combat pathogens.
Effective treatment of serious burns is dependent on early recognition of the extent of dead tissue and its removal to minimize the risk of infection and hasten healing. To meet the need for precise determination of burn depth, two physicists from Langley's Nondestructive Measurement Science Branch in cooperation with the Medical College of Virginia, Richmond, the University of Aberdeen, Scotland, and the NASA Technology Application Team, Research Triangle Institute, developed a prototype system that used ultrasound technology (originally developed as a means of detecting microscopic flaws in materials) for immediate assessment of burn depth. The system was commercialized by Westminster Supra Scanner, Inc., Orangeburg, NY, is produced under a NASA license, and was granted Food and Drug Administration approval in December 1990. It can be applied to the diagnosis of lymphatic disorders.
Immunity relies on the circulation of lymphocytes through many different tissues including blood vessels, lymphatic channels, and lymphoid organs. The ability of lymphocytes to traverse the interstitium in both nonlymphoid and lymphoid tissues can be determined in vitro by assaying their capacity to locomote through Type I collagen. In an attempt to characterize potential causes of microgravity-induced immunosuppression, we investigated the effects of simulated microgravity on human lymphocyte function in vitro using a specialized rotating-wall vessel culture system developed at the Johnson Space Center. This very low shear culture system randomizes gravitational vectors and provides an in vitro approximation of microgravity. In the randomized gravity of the rotating-wall vessel culture system, peripheral blood lymphocytes did not locomote through Type I collagen, whereas static cultures supported normal movement. Although cells remained viable during the entire culture period, peripheral blood lymphocytes transferred to unit gravity (static culture) after 6 h in the rotating-wall vessel culture system were slow to recover and locomote into collagen matrix. After 72 h in the rotating-wall vessel culture system and an additional 72 h in static culture, peripheral blood lymphocytes did not recover their ability to locomote. Loss of locomotory activity in rotating-wall vessel cultures appears to be related to changes in the activation state of the lymphocytes and the expression of adhesion molecules. Culture in the rotating-wall vessel system blunted the ability of peripheral blood lymphocytes to respond to polyclonal activation with phytohemagglutinin. Locomotory response remained intact when peripheral blood lymphocytes were activated by anti-CD3 antibody and interleukin-2 prior to introduction into the rotating-wall vessel culture system. Thus, in addition to the systemic stress factors that may affect immunity, isolated lymphocytes respond to gravitational changes by ceasing locomotion through model interstitium. These in vitro investigations suggest that microgravity induces non-stress-related changes in cell function that may be critical to immunity. Preliminary analysis of locomotion in true microgravity revealed a substantial inhibition of cellular movement in Type I collagen. Thus, the rotating-wall vessel culture system provides a model for analyzing the microgravity-induced inhibition of lymphocyte locomotion and the investigation of the mechanisms related to lymphocyte movement.