Interstitial Transport Research Articles

Exploring Tissue Permeability of Brain Tumours in Different Grades: Insights from Pore-scale Fluid Dynamics Analysis

Interstitial fluid (ISF) flow is identified as an essential physiological process that plays an important role in the development and progression of brain tumours. However, the relationship between the permeability of the tumour tissue, a complex porous medium, and the interstitial fluid flow around the tumour cells at the microscale is not well understood. To shed light on this issue, and in the absence of experimental techniques that can provide direct measurements, we develop a computational model to predict the tissue permeability of brain tumours in different grades by analysing the ISF flow at the pore scale. The 3-D geometrical models of tissue extracellular spaces are digitally reconstructed for each grade tumour based on their morphological properties measured from microscopic images. The predictive accuracy of the framework is validated by experimental results reported in the literature. Our results indicate that high-grade brain tumours are less permeable despite their higher porosity, whereas necrotic areas of glioblastoma are more permeable than the viable tumour areas. This implies that tissue permeability is primarily governed by both tissue porosity and the deposition of hyaluronic acid (HA), a key component of the extracellular matrix, while the HA deposition can have a greater effect than macro-level porosity. Parametric studies show that tissue permeability falls exponentially with increasing HA concentration in all grades of brain tumours, and this can be captured using an empirically derived relationship in a quantitative manner. These findings provide an improved understanding of the hydraulic properties of brain tumours and their intrinsic links to tumour microstructure. This work can be used to reveal the intratumoural physiochemical processes that rely on fluid flow and offer a powerful tool to tune textured and porous biomaterials for desired transport properties. Statement of SignificanceInterstitial fluid flow in the extracellular space of brain tumours plays a crucial role in their progression, development, and response to drug treatments. However, the mechanisms of interstitial fluid transport around tumour cells and the characterization of these microscale transports at the tissue scale to meet clinical requirements are largely unknown. In the absence of advanced experimental techniques to capture these pore-scale transport phenomena, we have developed and validated a computational framework to successfully reveal these phenomena across all grades of brain tumours. For the first time, we have quantitatively determined the tissue permeability of all grades of brain tumours as a function of the concentration of hyaluronic acid, a key component of the extracellular matrix. This framework will enhance our ability to capture the intratumoural physicochemical processes in brain tumours and correlate them with tumour tissue-scale behaviours.

Enhanced transport of brain interstitial solutes mediated by stimulation of sensorimotor area in rats.

Solute transport in the brain is essential for maintaining cerebral homeostasis. Recent studies have shown that neuronal activity enhances the transport of cerebrospinal fluid solutes, but its impact on interstitial solute transport has not been established. In this study, we investigated whether neuronal activity affects the transport of interstitial solutes. Fluorescent Texas Red ovalbumin was injected intracortically into the unilateral sensorimotor area of the Sprague-Dawley rats. Regional neuronal activity around the injection site was elicited by transdermal electrical stimulation of a corresponding forelimb for 90 min ( n = 6). The control group of rats ( n = 6) did not receive any electrical stimulation. Subsequently, the spatial distributions of the tracer over the cortical surface and from the brain sections were imaged and compared between two groups. The ovalbumin fluorescence from the cervical lymph nodes was also compared between the groups to evaluate the effect of neuronal activity on solute clearance from the brain. Tracer distribution over the brain surface/sections revealed a significantly higher uptake of ovalbumin in the hemisphere ipsilateral to the injection among the stimulated animals compared to the unstimulated group. This difference, however, was not seen in the hemisphere contralateral to injection. A trace amount of ovalbumin in the lymph nodes was equivalent between the groups, which indicated a considerable time needed for interstitial solutes to be drained from the brain. The results suggest that neuronal activity enhances interstitial solute transport, calling for further examination of ultimate routes and mechanisms for brain solute clearance.

Abstract PO5-25-02: Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes

Abstract The tumour microenvironment (TME) includes physical forces from interstitial fluid flow and cell-cell interactions that modulate cancer development and progression through activation of multiple oncogenic pathways leading to tumor growth and metastatic spreading. We previously reported on the role of physical forces on epithelial to mesenchymal transition (EMT) and S100 gene family expression and cell to cell adhesion properties with implications to normal breast development and cancer. Signals from the tumor exit the local tumor environment through interstitial fluid transport and cell migration where they can be found in the blood stream. We developed a whole blood RNA gene expression biomarker panel coupled with proprietary software capable of identifying the presence of an active breast cancer signature at early stages of disease with clinical study results previously reported. Here we report on results from transcriptomic and function studies with cell interaction models. Cancer cells can influence immune cells through direct contact or via secreted molecules causing the immune cells to undergo functional changes. To investigate mechanisms involved in the induction of these alterations in a model system, we performed co-culture studies with human monocytic cells and breast cancer cells. Interaction of human monocytic cells with the breast cancer cells caused significant changes in both behavior and transcriptomes. Moreover, using RNAseq and pathway analysis we demonstrated that the changes induced through the exposure to the more aggressive triple negative (TNBC) phenotype were distinct from the alterations triggered upon contact with an ER+ breast cancer cell line. We also show that cancer-immune crosstalk triggers EMT as well as activation of multiple oncogenic pathways associated with cell migration and invasion, cell chemotaxis and cell-to-cell interactions. As the interplay between cancer and immune cells plays an important role in cancer progression, these findings provide important insight into key mechanisms controlling these outcomes. Citation Format: Karen Norek, Jacob Kennard, Kenneth Fuh, Robert Shepherd, Kristina Rinker, Olesya Kharenko. Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-02.

Model discovery approach enables noninvasive measurement of intra-tumoral fluid transport in dynamic MRI.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to noninvasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamics in situ and in vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that our method will contribute to the better understanding of cancer progression and therapeutic response.

Interstitial fluid transport in cortical bone porosities: Effects of blood pressure and mass exchange using porous media theory

This research focuses on the importance of understanding bone adaptation for gaining insights into diseases such as osteoporosis. The study investigates the role of fluid flow in cortical bone adaptation, with a specific focus on the network of osteocyte canaliculi and the chemical reactions involved in bone resorption. Prior studies have implemented methods such as poroelasticity theory and dual porosity, but these models did not account for mass exchange between the solid and fluid phases within the bone or the pressure exerted by arteries. The movement of interstitial fluid between the vascular porosity and lacuno-canalicular porosity in cortical bone, as well as the velocity of the fluid, are affected by both the pressure exerted by arteries and the exchange of mass between the solid and fluid components of the bone. To incorporate these effects in the model, the authors propose a dual porosity model based on the theory of porous media. The model considers the transfer of mass between vascular and lacunar-canalicular porosities, as well as between solid and fluid phases, while also accounting for blood pressure variations. To verify the proposed model, a numerical example is solved and compared with the results of previous studies. The model enables the measurement and analysis of the interstitial fluid velocity and the pressure in the respective porosities. The results reveal that accounting for blood pressure pulses and mass exchange between solid and fluid phases can alter the velocity and pressure fields of interstitial fluid within cortical bone. In addition, this study investigates transient examples and various scenarios of the bone remodeling. Overall, this research provides a more accurate understanding of the bone remodeling and the effects of blood pressure variation and mass exchange between solid and fluid phases of cortical bone.

Computational Multi-Scale Modeling of Drug Delivery into an Anti-Angiogenic Therapy-Treated Tumor.

The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the anti-angiogenesis effect. This paper simulates intravascular blood flow and interstitial fluid flow using a dynamic model. The model accounts for the non-Newtonian behavior of blood and incorporates the adaptation of the diameter of a heterogeneous microvascular network derived from modeling the evolution of endothelial cells toward a circular tumor sprouting from two-parent vessels, with and without imposing the inhibitory effect of angiostatin on a modified discrete angiogenesis model. The average solute exposure and its uniformity in solid tumors of different sizes are studied by numerically solving the convection-diffusion equation. Three different methodologies are considered for simulating anti-angiogenesis: modifying the capillary network, updating the transport properties, and considering both microvasculature and transport properties modifications. It is shown that anti-angiogenic therapy decreases drug wash-out in the periphery of the tumor. Results show the decisive role of microvascular structure, particularly its distribution, and interstitial transport properties modifications induced via vascular normalization on the quality of drug delivery, such that it is improved by 39% in uniformity by the second approach in R = 0.2 cm.

Neural activity induces strongly coupled electro-chemo-mechanical interactions and fluid flow in astrocyte networks and extracellular space-A computational study.

The complex interplay between chemical, electrical, and mechanical factors is fundamental to the function and homeostasis of the brain, but the effect of electrochemical gradients on brain interstitial fluid flow, solute transport, and clearance remains poorly quantified. Here, via in-silico experiments based on biophysical modeling, we estimate water movement across astrocyte cell membranes, within astrocyte networks, and within the extracellular space (ECS) induced by neuronal activity, and quantify the relative role of different forces (osmotic, hydrostatic, and electrical) on transport and fluid flow under such conditions. We find that neuronal activity alone may induce intracellular fluid velocities in astrocyte networks of up to 14μm/min, and fluid velocities in the ECS of similar magnitude. These velocities are dominated by an osmotic contribution in the intracellular compartment; without it, the estimated fluid velocities drop by a factor of ×34-45. Further, the compartmental fluid flow has a pronounced effect on transport: advection accelerates ionic transport within astrocytic networks by a factor of ×1-5 compared to diffusion alone.

Non-invasive imaging of interstitial fluid transport parameters in solid tumors in vivo

In this paper, new and non-invasive imaging methods to assess interstitial fluid transport parameters in tumors in vivo are developed, analyzed and experimentally validated. These parameters include extracellular volume fraction (EVF), interstitial fluid volume fraction (IFVF) and interstitial hydraulic conductivity (IHC), and they are known to have a critical role in cancer progression and drug delivery effectiveness. EVF is defined as the volume of extracellular matrix per unit volume of the tumor, while IFVF refers to the volume of interstitial fluid per unit bulk volume of the tumor. There are currently no established imaging methods to assess interstitial fluid transport parameters in cancers in vivo. We develop and test new theoretical models and imaging techniques to assess fluid transport parameters in cancers using non-invasive ultrasound methods. EVF is estimated via the composite/mixture theory with the tumor being modeled as a biphasic (cellular phase and extracellular phase) composite material. IFVF is estimated by modeling the tumor as a biphasic poroelastic material with fully saturated solid phase. Finally, IHC is estimated from IFVF using the well-known Kozeny–Carman method inspired by soil mechanics theory. The proposed methods are tested using both controlled experiments and in vivo experiments on cancers. The controlled experiments were performed on tissue mimic polyacrylamide samples and validated using scanning electron microscopy (SEM). In vivo applicability of the proposed methods was demonstrated using a breast cancer model implanted in mice. Based on the controlled experimental validation, the proposed methods can estimate interstitial fluid transport parameters with an error below 10% with respect to benchmark SEM data. In vivo results demonstrate that EVF, IFVF and IHC increase in untreated tumors whereas these parameters are observed to decrease over time in treated tumors. The proposed non-invasive imaging methods may provide new and cost-effective diagnostic and prognostic tools to assess clinically relevant fluid transport parameters in cancers in vivo.

Convection and extracellular matrix binding control interstitial transport of extracellular vesicles.

Extracellular vesicles (EVs) influence a host of normal and pathophysiological processes in vivo. Compared to soluble mediators, EVs can traffic a wide range of proteins on their surface including extracellular matrix (ECM) binding proteins, and their large size (∼30-150nm) limits diffusion. We isolated EVs from the MCF10 series-a model human cell line of breast cancer progression-and demonstrated increasing presence of laminin-binding integrins α3β1 and α6β1 on the EVs as the malignant potential of the MCF10 cells increased. Transport of the EVs within a microfluidic device under controlled physiological interstitial flow (0.15-0.75μm/s) demonstrated that convection was the dominant mechanism of transport. Binding of the EVs to the ECM enhanced the spatial concentration and gradient, which was mitigated by blocking integrins α3β1 and α6β1. Our studies demonstrate that convection and ECM binding are the dominant mechanisms controlling EV interstitial transport and should be leveraged in nanotherapeutic design.

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method.

Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, pFDR-corrected = 0.04) in pediatric ALL. Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, pFDR-corrected = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Interstitial fluid transport in a multi-compartment model of cerebral blood flow

Abstract Whole brain models are a valuable tool to gain a better understanding of cerebral blood flow and metabolism. Recent work has developed multi-compartment models of blood flow and oxygen transport that can be used in a finite element framework to simulate whole brain behaviour with low computational expense, helping to move such tools towards clinical application. However, the transport of fluid between the vascular space and the interstitial space has not yet been considered in detail in this context, despite this playing an important role in several cerebrovascular diseases. In this study, an extended framework is proposed to include this transport, coupled with a linear elastic model of tissue displacement to simulate the movement of fluid and the resulting displacement of brain tissue. This framework is compared in detail with previous models. The resulting equations are found to exhibit multiple time scales, and a separation of scales is performed to analyse the behaviour at different time scales. Finally, a simplified model is proposed that can be easily implemented within existing computational frameworks, providing a valuable extension of the pathological conditions that can be simulated.

Temperature-affected nano-deformation behavior of nanometals in ultrahigh-strain-rate formation processes.

As metal forming processes move toward high speed, high throughput, high precision and small scale with temperature dependence, clarifying the fundamental nano-deformation behavior of metals is critical for the optimization of manufacturing processes, and the control of nano-optical, electrical, mechanical or surface properties. Unfortunately, limited by the time scale and sample size, the effect of temperature on the deformation behavior of nano-metals during the ultrahigh-strain-rate forming process remains largely unexplored. This study demonstrates the nonlinear effect of temperature on the formability of nano-metals for the first time. Temperatures below 673 K facilitated the formability of nano-metals benefiting from the temperature-promoted dislocation proliferation process, whereas temperatures above 673 K weakened the plasticity of the nano-metal due to the activation of phase transformation. Frequent phase transition activation and accelerated dislocation annihilation at high temperatures reduced interstitial transport channels and delayed atomic transfer. Based on the temperature response of nano-metals in deformation mechanisms, defect evolution behavior and formability, the constitutive model and nano-deformation mechanism map of nano-metals in ultrahigh-strain-rate forming processes are proposed. The objective of this work is to provide basic support for the reasonable matching of nano-forming technology and processing temperature, and the determination of the optimal process window through fundamental nano-deformation behavior exploration.

Coupled Diffusion-Binding-Deformation Modelling for Phase-Transition Microneedles-Based Drug Delivery

Phase-transition microneedles (PTMNs)-based transdermal drug delivery (TDD) is gaining popularity due to its non-invasiveness and ability to deliver a wide range of drugs. PTMNs absorb interstitial skin fluid (ISF) and transport drugs from microneedle (MNs) domain to the skin without polymer dissolution. To establish PTMNs for practical use, one needs to understand and optimise the key parameters governing drug transport mechanisms to achieve controlled drug delivery. In addressing this point, we have developed a coupled diffusion-binding-deformation model to understand the effect of physicochemical parameters (e.g., swelling capacity, drug binding) of MN and skin mechanical properties on overall drug transport behaviour. The contact mechanics at the MN and skin interface is introduced to account for the resistive force exerted by the deformed skin to MN swelling. The model is validated with the reported data of in vitro insulin delivery using polyvinyl alcohol (PVA) MN. The drug binding parameters are estimated from the fitting of the cumulative release of insulin within 6 hours of MN insertion. To predict the in vivo data of insulin delivery using the PVA MN, one-compartment model of drug pharmacokinetics is incorporated. It is shown in the paper that the model is able to predict the final insulin concentration in blood and in good agreement with the reported experimental data. The proposed model is concluded to be a tool for the predictive design and development of PTMNs-based TDD systems.

Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow -- meshes used for the simulations

Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow -- meshes used for the simulations

Numerical calculation of interstitial dumbbell-mediated transport coefficients in dilute crystalline systems with non-truncated correlations

ABSTRACT Interstitial dumbbell-mediated diffusion can affect segregation and precipitation properties of solutes in alloys under irradiated conditions. Accurate computation of transport coefficients for dumbbell-mediated diffusion thus becomes essential for modelling solute segregation under irradiation. In this work, we extend the Green's function approach, a general numerical approach, to compute accurate transport coefficients for interstitial dumbbell-mediated mechanisms in the dilute limit for arbitrary crystalline systems with non-truncated correlations in atomic diffusion. We also present results of tracer correlation factors, solute drag ratios and partial diffusion coefficient ratios in iron and nickel-based alloys computed with our approach, compare our results with existing results in the literature, and discuss some aspects of correlated solute-dumbbell motion.

Enhancement of cerebrospinal fluid tracer movement by the application of pulsed transcranial focused ultrasound

Efficient transport of solutes in the cerebrospinal fluid (CSF) plays a critical role in their clearance from the brain. Convective bulk flow of solutes in the CSF in the perivascular space (PVS) is considered one of the important mechanisms behind solute movement in the brain, before their ultimate drainage to the systemic lymphatic system. Acoustic pressure waves can impose radiation force on a medium in its path, inducing localized and directional fluidic flow, known as acoustic streaming. We transcranially applied low-intensity focused ultrasound (FUS) to rats that received an intracisternal injection of fluorescent CSF tracers (dextran and ovalbumin, having two different molecular weights–Mw). The sonication pulsing parameter was determined on the set that propelled the aqueous solution of toluidine blue O dye into a porous media (melamine foam) at the highest level of infiltration. Fluorescence imaging of the brain showed that application of FUS increased the uptake of ovalbumin at the sonicated plane, particularly around the ventricles, whereas the uptake of high-Mw dextran was unaffected. Numerical simulation showed that the effects of sonication were non-thermal. Sonication did not alter the animals’ behavior or disrupt the blood-brain barrier (BBB) while yielding normal brain histology. The results suggest that FUS may serve as a new non-invasive means to promote interstitial CSF solute transport in a region-specific manner without disrupting the BBB, providing potential for enhanced clearance of waste products from the brain.

Sensitivity analysis on a network model of glymphatic flow.

Intracranial cerebrospinal and interstitial fluid (ISF) flow and solute transport have important clinical implications, but limited in vivo access to the brain interior leaves gaping holes in human understanding of the nature of these neurophysiological phenomena. Models can address some gaps, but only insofar as model inputs are accurate. We perform a sensitivity analysis using a Monte Carlo approach on a lumped-parameter network model of cerebrospinal and ISF in perivascular and extracellular spaces in the murine brain. We place bounds on model predictions given the uncertainty in input parameters. Péclet numbers for transport in penetrating perivascular spaces (PVSs) and within the parenchyma are separated by at least two orders of magnitude. Low permeability in penetrating PVSs requires unrealistically large driving pressure and/or results in poor perfusion and are deemed unlikely. The model is most sensitive to the permeability of penetrating PVSs, a parameter whose value is largely unknown, highlighting an important direction for future experiments. Until the value of the permeability of penetrating PVSs is more accurately measured, the uncertainty of any model that includes flow in penetrating PVSs is so large that absolute numbers have little meaning and practical application is limited.

Interstitial proton transport through defective MXenes

Proton transport across nanometer-thick membranes in an aqueous medium is important for applications in energy and molecular sieving. Recently, Hu et al. [Nature 516(7530), 227–230 (2014)] experimentally demonstrated proton tunneling through 2D materials like graphene and hexagonal boron nitride, opening up a wide range of applications in hydrogen-based technologies such as fuel cells. Here, we demonstrate proton transport in an aqueous medium across a 2D cubic Ti2C membrane, a representative defective MXene, from ab initio molecular dynamics simulations. We observe bidirectional translocation of protons, which occurs through the interstitial vacancies in the surface. We show from our simulations that water dissociates on the membrane and the dissociated proton moves into the interstitial sites in the membrane. The proton hops from interstitial-to-interstitial and transports across the membrane. We also show that this interstitial proton transport is associated with an induced electric field that is modulated with bidirectional transport of protons across the membrane.

The effects of gravity and compression on interstitial fluid transport in the lower limb

Edema in the limbs can arise from pathologies such as elevated capillary pressures due to failure of venous valves, elevated capillary permeability from local inflammation, and insufficient fluid clearance by the lymphatic system. The most common treatments include elevation of the limb, compression wraps and manual lymphatic drainage therapy. To better understand these clinical situations, we have developed a comprehensive model of the solid and fluid mechanics of a lower limb that includes the effects of gravity. The local fluid balance in the interstitial space includes a source from the capillaries, a sink due to lymphatic clearance, and movement through the interstitial space due to both gravity and gradients in interstitial fluid pressure (IFP). From dimensional analysis and numerical solutions of the governing equations we have identified several parameter groups that determine the essential length and time scales involved. We find that gravity can have dramatic effects on the fluid balance in the limb with the possibility that a positive feedback loop can develop that facilitates chronic edema. This process involves localized tissue swelling which increases the hydraulic conductivity, thus allowing the movement of interstitial fluid vertically throughout the limb due to gravity and causing further swelling. The presence of a compression wrap can interrupt this feedback loop. We find that only by modeling the complex interplay between the solid and fluid mechanics can we adequately investigate edema development and treatment in a gravity dependent limb.

Interstitial Fluid Behavior and Diseases.

Living things comprise a typical hierarchical and porous medium, and their most fundamental logical architectures are interstitial structures encapsulating parenchymal structures. The recent discovery of the efficient transport mechanisms of interstitial streams has provided a new understanding of these complex activities. The substance transport of interstitial streams follows mesoscopic fluid behavior dynamics, which is intimately associated with material transfer in nanoconfined spaces and a unique signal transmission. Accordingly, the evaluation of interstitial stream transport behavior at the mesoscopic scale is essential. In this review, recent advances in physical and chemical properties, the substance transport model, and the characterization methods of interstitial streams at the mesoscopic scale, as well as the relationships between interstitial streams and disease are summarized. Interstitial stream transport can be used as a basis to fully mine hierarchal behavior in images to expand imaging behavior into an omics field. By starting from the perspective of soft matter, a new understanding can be gained of health and disease and quantitative physical markers for research, clinical diagnosis, and treatment can be provided, as well as prognosis evaluation in complex diseases such as cancer and Alzheimer's disease. This will provide a foundation for the development of medicine of soft matter.