Interstitial Pressure Research Articles

Transport and distribution of biotherapeutics in different tissue layers after subcutaneous injection

The subcutaneous injection is the main route of administration for monoclonal antibodies (mAbs) and several other biotherapeutics due to the patient comfort and cost-effectiveness. However, their transport and distribution after subcutaneous injection is poorly understood. Here, we exploit a three-dimensional poroelastic model to find the biomechanical response of the tissue, including interstitial pressure and tissue deformation during the injection. We quantify the drug concentration inside the tissue. We start with a single-layer model of the tissue. We show that during the injection, the difference between the permeability of the solvent and solute will result in a higher drug concentration proportional to the inverse permeability ratio. Then we study the role of tissue layered properties with primary layers, including epidermis, dermis, subcutaneous (SQ), and muscle layers, on tissue biomechanical response to injection and drug transport. We show that the drug will distribute mainly in the SQ layer due to its lower elastic moduli. Finally, we study the effect of secondary tissue elements like the deep fascia layer and the network of septa fibers inside the SQ tissue. We use the Voronoi tessellation algorithm to create random geometry of the septa network. We show how drugs accumulate around these tissue components as observed in the experimental SQ injection. Next, we study the effect of injection rate on drug concentration. We show how higher injection rates will slightly increase the drug concentration around septa fibers. Finally we demonstrate how the concentration dependent viscosity will increase the concentration of biotherapeutics in the direction of septa fibers.

The interstitial compartment as a therapeutic target in heart failure.

Congestion is the single most important contributor to heart failure (HF) decompensation. Most of the excess volume in patients with HF resides in the interstitial compartment. Inadequate decongestion implies persistent interstitial congestion and is associated with worse outcomes. Therefore, effective interstitial decongestion represents an unmet need to improve quality of life and reduce clinical events. The key processes that underlie incomplete interstitial decongestion are often ignored. In this review, we provide a summary of the pathophysiology of the interstitial compartment in HF and the factors governing the movement of fluids between the interstitial and vascular compartments. Disruption of the extracellular matrix compaction occurs with edema, such that the interstitium becomes highly compliant, and large changes in volume marginally increase interstitial pressure and allow progressive capillary filtration into the interstitium. Augmentation of lymph flow is required to prevent interstitial edema, and the lymphatic system can increase fluid removal by at least 10-fold. In HF, lymphatic remodeling can become insufficient or maladaptive such that the capacity of the lymphatic system to remove fluid from the interstitium is exceeded. Increased central venous pressure at the site of the thoracic duct outlet also impairs lymphatic drainage. Owing to the kinetics of extracellular fluid, microvascular absorption tends to be transient (as determined by the revised Starling equation). Therefore, effective interstitial decongestion with adequate transcapillary plasma refill requires a substantial reduction in plasma volume and capillary pressure that are prolonged and sustained, which is not always achieved in clinical practice. The critical importance of the interstitium in the congestive state underscores the need to directly decongest the interstitial compartment without relying on the lowering of intracapillary pressure with diuretics. This unmet need may be addressed by novel device therapies in the near future.

Thermal conductivity of planetary regoliths: The effects of grain-size distribution

The thermal properties of a planet's regolith are of primary importance in solar system exploration. Thermal conductivity and the related parameter thermal inertia are often used to decipher the regolith's structure, grain size, and areal distribution. In this work we utilize a guarded-heat-flow apparatus to measure the thermal conductivity of mono-dispersed and bimodal size populations of regolith analogs (borosilicate-glass beads and terrestrial soils) under a range of interstitial gas pressures from 10−5 to 103 mb, at 20 °C. From these measurements we further develop a physically based analytical model for use as a predictive tool for planetary research.While our results for mono-dispersed grains agree well with previous studies, our findings for bimodal grain-size mixtures do not. Our results demonstrate that the functional dependence of thermal conductivity on interstitial gas pressure closely follows that of the fine-grained component of the mixture, but uniformly offset to higher conductivity values depending only on the volume fraction of the coarse component. The grain size of the coarse fraction plays no role. The reason for the difference with previous studies appears to be related to limitations with the transient-heated-wire method in previous work. Our results suggest that, on Mars, large quantities of coarse grain material, such as sand or cobbles, could be hidden in regional dust deposits. Additionally, variations in the thermal properties of aeolian dune fields may result from differences between age-related dust infiltration and self-cleansing sand migration, rather than any real differences in local grain size. On Earth, at high gas pressures, grain size mixtures result in higher thermal conductivity than any component alone, consistent with field observations.

Haemodynamic predisposition to acute kidney injury: Shadow and light!

Acute kidney injury (AKI) could well be regarded as a sentinel complication given it is relatively common and associated with a substantial risk of subsequent morbidity and mortality. On the aegis of 'prevention is better than cure', there has been a wide interest in evaluating haemodynamic predisposition to AKI so as to provide a favourable renoprotective haemodynamic milieu to the subset of patients presenting a significant risk of developing AKI. In this context, the last decade has witnessed a series of evaluation of the hypotension value and duration cut-offs associated with risk of AKI across diverse non-operative and operative settings. Nevertheless, a holistic comprehension of the haemodynamic predisposition to AKI has been a laggard with only few reports highlighting the potential of elevated central venous pressure, intra-abdominal hypertension and high mean airway pressures in considerably attenuating the effective renal perfusion, particularly in scenarios where kidneys are highly sensitive to any untoward elevation in the afterload. Despite the inherent autoregulatory mechanisms, the effective renal perfusion pressure (RPP) can be modulated by a number of haemodynamic factors in addition to mean arterial pressure (MAP) as the escalation of renal interstitial pressure, in particular hampers kidney perfusion which in itself is a dynamic interplay of a number of innate pressures. The present article aims to review the subject of haemodynamic predisposition to AKI centralising the focus on effective RPP (over and above the conventional 'tunnel-vision' for MAP) and discuss the relevant literature accumulating in this area of ever-growing clinical interest.

Recent Advances in Nanotheranostic Agents for Tumor Microenvironment-Responsive Magnetic Resonance Imaging.

Nanomaterials integrating a variety of excellent properties (such as controllable/suitable size, surface modifier, and multifunctionality) have attracted increasing attention in the biomedical field and have been considered a new generation of magnetic resonance imaging (MRI) contrast agents (CAs). In recent years, stimuli-responsive nanomaterials with specifically responsive ability have been synthesized as MRI CAs, which can significantly improve the diagnostic sensitivity and accuracy depending on their outstanding performance. Furthermore, the inherent tumor microenvironment (TME) of malignant tumor is considered to possess several unique features, such as low extracellular pH, redox condition, hypoxia, and high interstitial pressure, that are significantly different from healthy tissues. Hence, constructing nanomaterials for TME-responsive MRI as an emerging strategy is expected to overcome the current obstacles to precise diagnosis. This review focuses on recent advances of nanomaterials in their application of TME-responsive MRI that trigger the diagnostic function in response to various endogenous stimulations, including pH, redox, enzyme, and hypoxia. Moreover, the future challenges and trends in the development of nanomaterials serving as TME-responsive MRI CAs are discussed.

Abstract 6029: Long-term three-dimensional (3D) tumor culture models using a universal well-plate platform

Abstract Generating 3D tumor spheroid in vitro has been a straightforward method not only to replicate in vivo like cytoarchitecture and also to study complex interactions to the 3D milieu. Although various approaches have been developed to date, most of the in vitro techniques were hampered by the limitations like small-volume, non-uniformity, irregular sphericity, short-term culture, labor-intensive and studies’ complexities. Here, we have developed very intuitive methods to generate 3D tumor spheroid models and scaffold-based 3D culture models in a single well of universal plate for long-term cultivation. Experimental Procedures: The prototype of 3D printed chamber was designed by Sketchup software (Trimble) and printed at Illinois MakerLab (http://makerlab.illinois.edu) for this study. The human colon cancer cell (HCT116), obtained from American Type Culture Collection (ATCC), were cultured in DMEM medium containing 10% FBS and stored in a humidified incubator of 5% CO 2 at 37 °C. Five universal 96 well plates (Corning, Thermo Scientific, CytoOne, Advangene, and Genesee Scientific), Elisa 96 well strip (Corning), Black 96-well plate (Thermo scientific) were used without any modification (Not a type of ultra-low attachment (ULA) plate). The prototype designs are flexible to be modified and will be utilized to develop a product beyond conceptual frameworks in the market. Results: Recently, microfabricated approaches have been intensively studied for micro 3D tumor models (< 300 µm in diameter) implemented with high-throughput analysis. However, the micro tumor model incubated in a short-term might not effectively develop tumor heterogeneity such as a non-perfusion core, diffusion gradient and increased interstitial pressure. We intentionally generated a tumor spheroid model incubated over 1 month with appropriate media replacement to supply nutrients. The spheroid in the system grew over 1.5mm of diameter with an excellent sphericity (> 0.95). Besides, our methodology can perform various in-situ spheroid assays in basic cancer research and also generate scaffold-free/based 3D tumor culture models in the system. To replicate in vivo like cytoarchitecture more physiologically relevant, decellularized tissue scaffold-based 3D culture was conceptually demonstrated. Conclusions: We developed a simple and effective process that generates 3D tumor culture models in millimeter size and allows long-term incubation to develop local heterogeneity. Importantly, this approach does not require additional hidden costs and any specialized instruments. We believe the present strategy satisfies all essential criteria (i.e., easiness, accessibility, reproducibility, effectiveness, and applicability) to appeal to general researchers compared to other available methods by far. Citation Format: Yoon Jeong, Ashley Tin, Joseph Irudayaraj. Long-term three-dimensional (3D) tumor culture models using a universal well-plate platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6029.

Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue.

Simple SummaryScientists have been working on the development of nanomedicine-based tumor therapy, rather than conventional treatment, to treat cancer for several years. Unfortunately, biological barriers hinder the delivery of nanomedicine to tumors. There are different strategies applied by researchers to improve the nanomedicine penetration to tumors, such as the modification of nanoparticle features and controlling the cancer micro-environment. However, complicated cancer micro-environments and delivery problems prevent these approaches from achieving optimal results. Changes in the extra-cellular matrix or blood vessels modify tumor microenvironments in a way that provides improved nanomedicine penetration and distribution but not to an optimal level. Herein, we reviewed the challenges of nanomedicine penetration to tumors along with possible approaches to deal with this concern.Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review.

Mathematical modelling of haemorrhagic transformation within a multiscale microvasculature network

Objective. Haemorrhagic transformation (HT) is one of the most common complications after ischaemic stroke, caused by damage to the blood–brain barrier (BBB) that could be the result of stroke progression or a complication of stroke treatment with reperfusion therapy. The aim of this study is to develop further a previous simple HT mathematical model into an enlarged multiscale microvasculature model in order to investigate the effects of HT on the surrounding tissue and vasculature. In addition, this study investigates the relationship between tissue displacement and vascular geometry. Approach. By modelling tissue displacement, capillary compression, hydraulic conductivity in tissue and vascular permeability, we establish a mathematical model to describe the change of intracranial pressure (ICP) surrounding the damaged vascular bed after HT onset, applied to a 3D multiscale microvasculature. The use of a voxel-scale model then enables us to compare our HT simulation with available clinical imaging data for perfusion and cerebral blood volume () in the multiscale microvasculature network. Main results. We showed that the haematoma diameter and the maximum tissue displacement are approximately proportional to the diameter of the breakdown vessel. Based on the voxel-scale model, we found that perfusion reduces by approximately and reduces by around after HT onset due to the effect of capillary compression caused by increased interstitial pressure. The results are in good agreement with the limited experimental data. Significance. This model, by enabling us to bridge the gap between the microvascular scale and clinically measurable parameters, providing a foundation for more detailed validation and understanding of HT in patients.

Photocatalysis/enzymolysis-based biomimetic Schottky junction reduces tumor interstitial solid and fluid phases for deep-penetrating tumor therapy

Tumor interstitial solid phase-induced physical obstacles and fluid phase-induced hydrostatic pressure are regarded as the two main intractable barriers of drug delivery, leading to the survive of deep-seated tumor stem cells. Herein, a rational strategy is presented based on near-infrared light-stimuli enzymolysis and photocatalysis to decompose the tumor interstitial solid and fluid phases for boosting the tumor penetration of nanomedicine. In detail, a cuprous oxide/sliver nano-photocatalyst (Cu2O/Ag) is designed, which is covered with the thermosensitive papain-loaded tumor-homing homologous cytomembrane to form the nanomedicine (Cu2O/Ag-P@M). With the light irradiation, the heat generated by Cu2O/Ag promote the enzymolysis of extracellular matrix by papain, which eliminate the physical obstacles. Moreover, the photocatalytic water splitting of Cu2O/Ag reduce the volume of tumor interstitial fluid, which decrease the elevated hydrostatic pressure to boost the tumor penetration of nanomedicine. Additionally, during the intratumoral delivery, Cu2O/Ag-P@M is able to realize anti-tumor photothermal therapy and chemotherapy. The results indicate that the Cu2O/Ag-P@M decompose a majority of tumor extracellular matrix and interstitial fluid under light irradiation. The tumor interstitial hydrostatic pressure is reduced by 69.7%. The tumor penetration of Cu2O/Ag-P@M + L treated group is 5.03-fold than the Cu2O/Ag@M−L group, leading to the 95.19% of tumor inhibition rate.

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis.

Movement-induced forces are critical to correct joint formation, but it is unclear how cells sense and respond to these mechanical cues. To study the role of mechanical stimuli in the shaping of the joint, we combined experiments on regenerating axolotl (Ambystoma mexicanum) forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a transient receptor potential vanilloid 4 (TRPV4) agonist during joint morphogenesis. We quantified growth and shape in regrown humeri from whole-mount light sheet fluorescence images of the regenerated limbs. Results revealed significant differences in morphology and cell proliferation between groups, indicating that TRPV4 desensitization has an effect on joint shape. To link TRPV4 desensitization with impaired mechanosensitivity, we developed a finite element model of a regenerating humerus. Local tissue growth was the sum of a biological contribution proportional to chondrocyte density, which was constant, and a mechanical contribution proportional to fluid pressure. Computational predictions of growth agreed with experimental outcomes of joint shape, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.

Variations in weathering characteristics of soil profiles and response of the Atterberg limits in the granite hilly area of South China

Red loam hills with granitic parent material are susceptible to gully erosion under continuous runoff. Laterite soils from granitic parent material in South China are continuously weathered. Soil profile weathering and Atterberg limits, as indirect indicators of soil erosion resistance, are often neglected. Here, three typical granite weathering profiles in Hubei (HB), Fujian (FJ) and Guangxi (GX) were selected to investigate the granite weathering zonation characteristics and their relationships with the Atterberg limits. The main soil profile oxides were SiO2, Fe2O3 and Al2O3, and their total content exceeded 80.00%. Moreover, the chemical weathering indicators consistently showed highly weathered states and increase in weathering degree from bottom to top in the soil profiles; the weathering degree had zonal characteristics from north to south, and the weathering mantle thickness gradually increased. The liquid limit (LL), plastic limit (PL), shrinkage limit (SL), plasticity index (PI) and shrinkage index (SI) decreased as the soil profile depth increased, while the liquidity index (LI) decreased, indicating more stability and less susceptibility to erosion in the surface soil layers. During heavy rainfall, the soil moisture content in the sandy layer was more likely to approach the PL or even LL, which easily cause soil loss. Further, the red soil layers tended to shrink under higher moisture contents, thereby forming fissures and leading to preferential flow, which increased the interstitial pressure of the soil and led to a reduction in shear strength, and resulted in gully erosion. Regression analyses showed that Si mobility was significantly positively correlated with LL (R2 = 0.712), PL (R2 = 0.732), SL (R2 = 0.669), SI (R2 = 0.709), and PI (R2 = 0.592) and significantly negatively correlated with LI (R2 = 0.554). The correlations between Fe mobility and Atterberg limits were the opposite of those for Si. According to path analysis, the Fe2O3 content and Atterberg limits had the largest decision coefficients, indicating that the weathering intensity was significantly correlated with the Atterberg limits.

Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity

Due to the abnormal vasculation and proliferation, the tumor microenvironment is hypoxic, lacking nutrients, and under high interstitial pressure. Compared to oxygen and nutrients, the effect of pressure on cancer biology remains poorly studied. Here we constructed αROR1-CAR T cells and co-cultured with A549 cells with and without elevated pressure. We then measured apoptosis and cell death by flow cytometry and luciferase activity. We also measured cytokine (IL-2, IFN-γ, and TNF-α) release by ELISA. The results show that pressure-preconditioned A549 cells are much resistant to αROR1-CAR T cell-mediated cytotoxicity. Pressure preconditioning does not appear to affect the expression of αROR1-CAR or cytokine production. However, pressure preconditioning upregulates PD-L1 expression in A549 cells and decreases cytokine release from αROR1-CAR T cells. In addition, Pembrolizumab and Cemiplimab that block PD-1::PD-L1 interaction increase the cytokine production in αROR1-CAR T cells, increase the apoptotic cell death in A549 cells, and improve the αROR1-CAR T-mediated cytotoxicity. In xenograft mice, pressure preconditioning increases tumorigenesis of A549 cells, which can be blocked by a combined therapy using Pembrolizumab and αROR1-CAR T cells. Together, our studies suggest that elevated pressure in the tumor microenvironment could blunt the T cell therapy by upregulating PD-L1 expression, which could be overcome by combining CAR T therapy with immune checkpoint inhibitors.

Hydrostatic pressure induces profibrotic properties in hepatic stellate cells via the RhoA/ROCK signaling pathway.

Elevated interstitial fluid hydrostatic pressure is commonly observed in diseased livers. We herein examined the hypothesis that hydrostatic pressure induces hepatic stellate cells to acquire profibrotic properties under pathological conditions. Human hepatic stellate cells were exposed to 50 mmHg pressure for 24 h. Although we observed few changes of cell growth and morphology, PCR array data on the expression of fibrosis‐associated genes suggested the acquisition of profibrotic properties. The exposure of hepatic stellate cells to 50 mmHg pressure for 24 h also significantly enhanced the expression of RhoA, ROCK1, α‐SMA, TGF‐β1, p‐MLC, and p‐Smad2, and this was effectively attenuated by the ROCK inhibitor Y‐27632. Our ex vivo experimental data suggest that elevated interstitial fluid hydrostatic pressure under pathological conditions may promote liver fibrosis by inducing acquisition of profibrotic properties of hepatic stellate cells through the RhoA/ROCK signaling pathway.

P2. FAT GRAFT PULMONARY EMBOLISM: IN FAVOUR OF A LYMPHATIC ROUTE

PURPOSE: Fat Pulmonary Embolism Syndrome (F-PES) complicates high-volume fat grafting. Adipocyte disruption generates triglyceride (TGC) oil dispersed in lipoaspirate (lipocrit). TGC plasma concentration ([TGC]p) was compared with lipocrit during liposuction-lipografting procedures. 1 buttock grafting case suffered a F-PES that required ICU support. METHODS: n=27 (19 breast, 8 buttocks) lipocrit recorded and ([TGC]p) measured in peripheral blood samples preoperatively, intra and 24h postoperatively. F-PES patient underwent right subclavian vein access (SVC) and Inferior Vena Cava (IVC) at ICU admission RESULTS: Lipocrit (200-600 cc graft volume) ranged 19-27%.Peripheral [TGC]p pre-, intra- post- and at 24h displayed no significant differences for all cases. In the F-PES case, SVC drawn [TGC]p was 7-fold higher than that from simultaneously drawn IVC or peripheral samples and returned to normal peripheral levels 48 h later. These unexpected data prompted measurement of:Critical Micelle Concentration (CMC) of fat graft oil when mixed in either lymphatic (chylous, CMCc) or plasmatic (CMCp) fluids. CMCp was consistently higher than CMCc (CMCc=110 mg/dL, CMCp=320 mg/dL, n=17, P<0.001).Interstitial Pressures (IP) both intramuscular (im) and subcutaneous (sc) at recipient sites. IPsc raised to pressures below 50 mmHg and returned to baseline within 24 h. IPim raised above 50 mmHg and persisted CONCLUSION: F-PES appears associated to increased [TGC]p detectable at the SVC only. TGC micelle formation is thermodynamically adverse in plasma versus chyle, suggesting a preferential lymphatic uptake of grafted oil at the recipient site. This lymphatic uptake could be favored when graft oil is implanted im, where IP-im reach pressures that prevent venous drainage.

Vascular Permeability in Diseases.

Vascular permeability is a selective mechanism that maintains the exchange between vessels, tissues, and organs. The regulation was mostly studied during the nineteenth century by physiologists who defined physical laws and equations, taking blood, tissue interstitial, and oncotic pressure into account. During the last decades, a better knowledge of vascular cell functions and blood-vessel interactions opens a new area of vascular biology. Endothelial cell receptors vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule (ICAM), vascular endothelial growth factor receptor (VEGFR-2), receptor for advanced glycation end products (RAGE), and mediators were identified and their role in homeostasis and pathological situations was described. The molecular differences of endothelial cell junctions (tight, gap, and adherens junctions) and their role in vascular permeability were characterized in different organs. The main mediators of vasomotricity and permeability, such as prostaglandins, nitric oxide (NO), prostacyclin, vascular growth factor (VEGF), and cytokines, have been demonstrated to possess major functions in steady state and pathological situations. Leukocytes were shown to adhere to endothelium and migrate during inflammatory situations and infectious diseases. Increased vascular permeability is linked to endothelium integrity. Glycocalyx, when intact, may limit cancer cell metastasis. Biological modifications of blood and tissue constituents occurring in diabetes mellitus were responsible for increased permeability and, consequently, ocular and renal complications. Vascular pressure and fluidity are major determinants of pulmonary and cerebral edema. Beside the treatment of the infectious disease, of the blood circulation dysfunction and inflammatory condition, drugs (cyclooxygenase inhibitors) and specific antibodies anti-cytokine (anti-VEGF) have been demonstrated to reduce the severity and the mortality in diseases that exhibited enhanced vascular permeability.

Two-Phase Lung Damage Mechanisms For COVID-19 Disease, and Driving Force and Selectivity in Leukecyte Recruitment and Migration

To understand lung damages caused by COVID-19, we deduced two phases lung damage mechanisms. After the lungs are infected with COVID-19, the affected lung tissue swells and surface properties of pulmonary capillaries change, both contributing to an increased flow resistance of the capillaries. The initial damages are mainly fluid leakage in a limited number of involved alveoli. The increased vascular resistance results in retaining more white blood cells (“WBCs”) in pulmonary capillaries. Some of the WBCs may get into interstitial spaces. When more and more WBCs are dynamically retained, the vascular resistance of pulmonary capillaries further rises; and thus the overall vascular resistance of the lungs rises and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When pulmonary capillary pressures around the alveoli are sufficiently high, the elevated pressure causes interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alvoeli and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and occupation of alvoelar spaces by leaked water result in reduced deformable and compressible spaces, and thus causes a further rise of the vascular resistance of the lungs. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. Among potential influencing factors, the available space in the thorax cage, temperature, and humid are expected to have great impacts. The free space in the thorax cage, lung usable capacity, and other organ usable capacities are the major factors that determine the arrival time of last- phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain how leukecytes are “recruited and migrated” into inflamed tissues by dynamic retention.

Myocardial Edema Provides a Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.

Myocardial Edema Provides a Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.

Characteristics of Venous Leg Ulcer Patients at a Tertiary Wound Care Center

Venous leg ulcers (VLU) are defined as “open skin lesions of the leg or foot that occur in an area affected by venous hypertension” and is the most common cause of chronic leg wounds. However, the clinical presentation and characteristics of VLUs are not well-defined. Causes for venous hypertension can include venous reflux, obstruction, elevated central venous pressures owing to obesity, increased interstitial pressures, compromised lymphatics, dependent edema, and calf muscle dysfunction. This study was performed to characterize the multifactorial VLUs in patients being treated at a tertiary wound care center.

Multilayer microfluidic platform for the study of luminal, transmural, and interstitial flow

Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures (IFPs), and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MμLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and IFPs. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics (CFD) models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.

The Development of Peritoneal Metastasis from Gastric Cancer and Rationale of Treatment According to the Mechanism.

In the present article, we describe the normal structure of the peritoneum and review the mechanisms of peritoneal metastasis (PM) from gastric cancer (GC). The structure of the peritoneum was studied by a double-enzyme staining method using alkaline-phosphatase and 5′-nucreotidase, scanning electron microscopy, and immunohistological methods. The fundamental structure consists of three layers, mesothelial cells and a basement membrane (layer 1), macula cribriformis (MC) (layer 2), and submesothelial connective tissue containing blood vessels and initial lymphatic vessels, attached to holes in the MC (layer 3). Macro molecules and macrophages migrate from mesothelial stomata to the initial lymphatic vessels through holes in the MC. These structures are characteristically found in the diaphragm, omentum, paracolic gutter, pelvic peritoneum, and falciform ligament. The first step of PM is spillage of cancer cells (peritoneal free cancer cells; PFCCs) into the peritoneal cavity from the serosal surface of the primary tumor or cancer cell contamination from lymphatic and blood vessels torn during surgical procedures. After PFCCs adhere to the peritoneal surface, PMs form by three processes, i.e., (1) trans-mesothelial metastasis, (2) trans-lymphatic metastasis, and (3) superficial growing metastasis. Because the intraperitoneal (IP) dose intensity is significantly higher when generated by IP chemotherapy than by systemic chemotherapy, IP chemotherapy has a great role in the treatment of PFCCs, superficial growing metastasis, trans-lymphatic metastasis and in the early stages of trans-mesothelial metastasis. However, an established trans-mesothelial metastasis has its own interstitial tissue and vasculature which generate high interstitial pressure. Accordingly, it is reasonable to treat established trans-mesothelial metastasis by bidirectional chemotherapy from both IP and systemic chemotherapy.