Interstitial Fluid Flow Research Articles

Mathematical modelling of hollow microneedle-mediated transdermal drug delivery.

Hollow microneedles represent a promising approach for overcoming the protective barrier of the stratum corneum, facilitating direct drug infusion into viable skin tissue and thereby enhancing the efficacy of transdermal delivery. However, delivery outcomes across different skin layers and into the systemic circulation can vary substantially due to the diverse properties of drug delivery systems, clinical settings, and environmental factors. The optimal strategies for enhancing the efficiency of hollow microneedle-mediated transdermal drug delivery remain to be elucidated. This study employs mathematical modelling and a reconstructed skin model with realistic anatomical structures to investigate drug transport and accumulation across different skin layers and into the bloodstream under different delivery conditions. The modelling results reveal the crucial role of interstitial fluid flow in determining drug transport in this transdermal delivery. Delivery outcomes of each skin layer and blood exhibit distinct responses to changes in delivery conditions. Specifically, increasing the vascular permeability or nanocarrier diffusivity raises drug concentration in the blood or reticular dermis, respectively, while leading to reductions in other skin layers. The use of microneedles with narrower infusion channels can only enhance drug availability in the viable epidermis. Optimisation requires a tailored approach to several parameters depending on the target skin layer, including drug release rate, infusion rate, infusion duration, and microneedle length. Environmental factors that promote trans-epidermal water loss can increase drug concentration in the viable epidermis but have a limited impact on deeper skin tissues. The findings support the selection or customisation of hollow microneedles and nanocarriers to address specific therapeutic needs, such as targeting specific skin layers or systemic circulation, while minimising the risk of side effects from high drug concentrations in normal tissues. This study provides guidance for optimising transdermal drug delivery systems.

Image-guided patient-specific prediction of interstitial fluid flow and drug transport in solid tumors.

Tumor fluid dynamics and drug delivery simulations in solid tumors are highly relevant topics in clinical oncology. The current study introduces a novel method combining computational fluid dynamics (CFD) modeling, quantitative magnetic resonance imaging (MRI; including dynamic contrast-enhanced (DCE) MRI and diffusion-weighted (DW) MRI), and a novel ex-vivo protocol to generate patient-specific models of solid tumors in four patients with peritoneal metastases. DCE-MRI data were analyzed using the extended Tofts model to estimate the spatial distribution of tumor capillary permeability using the Ktrans parameter. DW-MRI data analysis provided a 3D representation of drug diffusivity, and DW-MRI coupled to an ex-vivo measurement protocol informed the spatial heterogeneity of the hydraulic conductivity of tumor tissue. The patient-specific data were subsequently incorporated into a computational fluid dynamics (CFD) model to simulate individualized tumor perfusion and drug transport maps. The results on interstitial fluid flow demonstrated noticeable heterogeneity of interstitial fluid pressure and velocity within the tumor, along with heterogeneous drug penetration profiles among different tumors, even with a similar drug administration regimen.

Probing the physical hallmarks of cancer.

The physical microenvironment plays a crucial role in tumor development, progression, metastasis and treatment. Recently, we proposed four physical hallmarks of cancer, with distinct origins and consequences, to characterize abnormalities in the physical tumor microenvironment: (1) elevated compressive-tensile solid stresses, (2) elevated interstitial fluid pressure and the resulting interstitial fluid flow, (3) altered material properties (for example, increased tissue stiffness) and (4) altered physical micro-architecture. As this emerging field of physical oncology is being advanced by tumor biologists, cell and developmental biologists, engineers, physicists and oncologists, there is a critical need for model systems and measurement tools to mechanistically probe these physical hallmarks. Here, after briefly defining these physical hallmarks, we discuss the tools and model systems available for probing each hallmark in vitro, ex vivo, in vivo and in clinical settings. We finally review the unmet needs for mechanistic probing of the physical hallmarks of tumors and discuss the challenges and unanswered questions associated with each hallmark.

Convective forces contribute to post‐traumatic degeneration after spinal cord injury

AbstractSpinal cord injury (SCI) initiates a complex cascade of chemical and biophysical phenomena that result in tissue swelling, progressive neural degeneration, and formation of a fluid‐filled cavity. Previous studies show fluid pressure above the spinal cord (supraspinal) is elevated for at least 3 days after injury and contributes to a phase of damage called secondary injury. Currently, it is unknown how fluid forces within the spinal cord itself (interstitial) are affected by SCI and if they contribute to secondary injury. We find spinal interstitial pressure increases from −3 mmHg in the naive cord to a peak of 13 mmHg at 3 days post‐injury (DPI) but relatively normalizes to 2 mmHg by 7 DPI. A computational fluid dynamics model predicts interstitial flow velocities up to 0.9 μm/s at 3 DPI, returning to near baseline by 7 DPI. By quantifying vascular leakage of Evans Blue dye after a cervical hemi‐contusion in rats, we confirm an increase in dye infiltration at 3 DPI compared to 7 DPI, suggestive of higher fluid velocities at the time of peak fluid pressure. In vivo expression of the apoptosis marker caspase‐3 is strongly correlated with regions of interstitial flow at 3 DPI, and exogenously enhancing interstitial flow exacerbates tissue damage. In vitro, we show overnight exposure of neuronal cells to low pathological shear stress (0.1 dynes/cm2) significantly reduces cell count and neurite length. Collectively, these results indicate that interstitial fluid flow and shear stress may play a detrimental role in post‐traumatic neural degeneration.

Modelling Hollow Microneedle-Mediated Drug Delivery in Skin Considering Drug Binding.

Background/Objectives: Microneedle(MN)-based drug delivery is one of the potential approaches to overcome the limitations of oral and hypodermic needle delivery. An in silico model has been developed for hollow microneedle (HMN)-based drug delivery in the skin and its subsequent absorption in the blood and tissue compartments in the presence of interstitial flow. The drug's reversible specific saturable binding to its receptors and the kinetics of reversible absorption across the blood and tissue compartments have been taken into account. Methods: The governing equations representing the flow of interstitial fluid, the transport of verapamil in the viable skin and the concentrations in the blood and tissue compartments are solved using combined Marker and Cell and Immersed Boundary Methods to gain a quantitative understanding of the model under consideration. Results: The viscoelastic skin is predicted to impede the transport of verapamil in the viable skin and, hence, reduce the concentrations of all forms in the blood and the tissue compartments. The findings reveal that a higher mean concentration in the viable skin is not always associated with a longer MN length. Simulations also predict that the concentrations of verapamil in the blood and bound verapamil in the tissue compartment rise with decreasing tip diameters. In contrast, the concentration of free verapamil in the tissue increases with increasing injection velocities. Conclusions: The novelty of this study includes verapamil metabolism in two-dimensional viscoelastic irregular viable skin and the nonlinear, specific, saturable, and reversible binding of verapamil in the tissue compartment. The tip diameter and the drug's injection velocity are thought to serve as regulatory parameters for the effectiveness and efficacy of MN-mediated therapy if the MN is robust enough to sustain the force needed to penetrate a wider tip into the skin.

CXCL12 impact on glioblastoma cells behaviors under dynamic culture conditions: Insights for developing new therapeutic approaches

Glioblastoma multiforme (GBM) is the most prevalent malignant brain tumor, with an average survival time of 14 to 20 months. Its capacity to invade brain parenchyma leads to the failure of conventional treatments and subsequent tumor recurrence. Recent studies have explored new therapeutic strategies using a chemoattracting gradient to attract GBM cells into a soft hydrogel trap where they can be exposed to higher doses of radiation or chemotherapy. It has been demonstrated in vitro under static conditions, that nanoparticles (NPs) encapsulating the chemoattractant CXCL12 can create a gradient to attract GBM cell. However, GBM cell invasion is also largely dependent on interstitial fluid flow (IFF). In the present study, a custom-made in vitro 3D model with indirect perfusion to mimic IFF at flow rates of 0.5 μL/min and 3 μL/min was used to examine the invasive behavior of F98-rodent-derived and U87-human-derived GBM cells. This model simulated IFF and CXCL12 gradient within an alginate:matrigel-based hydrogel mimicking brain parenchyma. Findings revealed that CXCL12 (1600 ng/mL) released from NPs significantly increased the migration of F98 GBM cells after 72 hours under IFF conditions at both 0.5 and 3 μL/min. In contrast, U87 GBM cells required a higher CXCL12 concentration (2400 ng/mL) and longer incubation time for migration (120 hours). Unlike the F98 cells, U87 GBM cells showed a CXCL12 dose-dependent proliferation. Semi-quantitative qPCR showed higher CXCR4 mRNA levels in F98 cells than in U87 cells. CXCL12 significantly increased intracellular calcium levels via CXCR4 activation, with a 2.3-fold rise in F98 cells compared to U87, consistent with observed cell behavior during perfusion. This highlights the combined influence of IFF and CXCL12 on cell migration, dependent on cell line. This 3D dynamic model is a valuable tool to analyze parameters like interstitial fluid flow (IFF) and chemokine gradients, influenced by GBM tumor diversity.

Decoding complex transport patterns in flow-induced autologous chemotaxis of multicellular systems.

Cell migration via autologous chemotaxis in the presence of interstitial fluid flow is important in cancer metastasis and embryonic development. Despite significant recent progress, our understanding of flow-induced autologous chemotaxis of multicellular systems remains poor. The literature presents inconsistent findings regarding the effectiveness of collective autologous chemotaxis of densely packed cells under interstitial fluid flow. Here, we present a high-fidelity computational model to analyze the migration of multicellular systems performing autologous chemotaxis in the presence of interstitial fluid flow. Our simulations show that the details of the complex transport dynamics of the chemoattractant and fluid flow patterns that occur in the extracellular space, previously overlooked, are essential to understand this cell migration mechanism. We find that, although flow-induced autologous chemotaxis is a robust migration mechanism for individual cells, the cell-cell interactions that occur in multicellular systems render autologous chemotaxis an inefficient mechanism of collective cell migration. Our results offer new perspectives on the potential role of autologous chemotaxis in the tumor microenvironment, where fluid flow is an important modulator of transport.

Models of Hydration Dependent Lymphatic Opening, Interstitial Fluid Flows and Ambipolar Diffusion.

A theoretical understanding of fluid exchange and the role of initial lymph formation in tissues through mathematical/physical modeling is lacking. Here, we present three models for tissues rich in negative fixed charges due to glycosaminoglycans interacting with the extracellular matrix. We first model a lymphatic opening mechanism at relevant hydrations of the interstitium. At each hydration affecting tissue strain, two equations coupled in time are developed and solved with the new lymphatic opening and particle draining mechanism. The lymphatic opening mechanism is then included in a new model of interstitial fluid and macromolecular flow where the influence of different exclusion and available volumes for charged and neutral particles are quantified. For therapeutic interactions with cells, essential differences are found between electrically charged and neutral therapeutic substances. The interstitial fluid hydrostatic pressure gradient and flow are expressed through an extended Darcy equation, derived using similar methods as in kinetic theory of dense gases and fluid flows. Finally, a model for ambipolar diffusion of electrically charged macromolecules in tissue is developed. Our study will inform transport of charged and neutral macromolecules between the vasculature, interstitium, and the lymphatic system, thus having implications for tissue uptake of therapeutic agents.

DDEL-02. PRECLINICAL EFFICACY OF IL13RΑ2-TARGETING POLYPEPTIDE-DRUG CONJUGATE (SELF-DEPOTTM ONCOPDC) IN GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are currently incurable cancers. Systemic chemotherapy shows limited efficacy because of the intact blood-brain barrier. Convection-enhanced delivery (CED) offers promise by concentrating high doses of chemotherapeutics directly within these tumors. However, drugs administered via CED often face challenges in confirming precise target delivery and are quickly cleared by increased interstitial fluid flow and drug efflux transporters. This highlights the urgent need for innovative drugs that demonstrate target specificity and prolonged retention capabilities. Intrinsically disordered polypeptides (IDPs), derived from tropoelastin, self-assemble into water-insoluble structures with extended retention properties triggered by body temperature. IL13Rα2, differentially amplified in U87MG GBM and SF8628 DIPG cells, serves as a target for therapeutic intervention. An IL13Rα2-targeting IDP (XM161) was developed by incorporating IL13Rα2 binding sequences into the IDP domains. XM161 demonstrated high selectivity in binding to IL13Rα2, with Kd values of 1,786 nM for IL13Rα1 and 12.8 nM for IL13Rα2. Conjugation of XM161 with SN38, a potent topoisomerase I inhibitor, resulted in XM161-SN38, which remained in a dissolved state up to 50°C but formed insoluble aggregates above 27°C in the presence of cerebrospinal fluid. XM161-SN38 exhibited strong cytotoxicity against U87MG and SF8628 cells, with IC50 values of 14.2 nM and 0.48 nM, respectively. Importantly, XM161-SN38 demonstrated efficacy in overcoming Temozolomide resistance in T98G GBM cells, with IC50 values of 3.35 nM compared to 10.87 nM for unconjugated SN38. In orthotopic xenograft models established in BALB/cSlc-nu/nu male mice using U87MG-Luc2 cells, three doses (3 x 0.95 μg SN38 equivalents) of XM161-SN38 delivered via CED were well tolerated and significantly extended median survival to over 65 days, providing a notable survival benefit compared to untreated controls (42 days) and Topotecan-treated group (42.5 days). These findings validate the feasibility and therapeutic potential of XM161-SN38 for GBM treatment. Ongoing studies are underway to investigate the safety and pharmacokinetics of XM161-SN38 in tumor-naive mouse brains.

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.

A Photopolymerizable Hyaluronic Acid-Collagen Model of the Invasive Glioma Microenvironment with Interstitial Flow.

Glioblastoma recurrence is a major hindrance to treatment success and is driven by the invasion of glioma stem cells (GSCs) into healthy tissue that are inaccessible to surgical resection and are resistant to existing chemotherapies. Tissue-level fluid movement, or interstitial fluid flow (IFF), regulates GSC invasion in a manner dependent on the tumor microenvironment (TME), highlighting the need for model systems that incorporate both IFF and the TME. We present an accessible method for replicating the invasive TME in glioblastoma: a hyaluronan-collagen I hydrogel composed of human GSCs, astrocytes, and microglia seeded in a tissue culture insert. Elevated IFF can be represented by applying a fluid pressure head to the hydrogel. Additionally, this model can be tuned to replicate inter- or intra-patient differences in cellular ratios, flow rates, or matrix stiffnesses. Invasion can be quantified, while gels can be harvested for a variety of outcomes, including GSC invasion, flow cytometry, protein or RNA extraction, or imaging.

Towards a framework for predicting immunotherapy outcome: a hybrid multiscale mathematical model of immune response to vascular tumor growth.

Studying tumor immune microenvironment (TIME) is pivotal to understand the mechanism and predict the outcome of cancer immunotherapy. Systems biology mathematical models can consider and control various factors of TIME and therefore explore the anti-tumor immune response meticulously. However, the role of tumor vasculature in the recruitment of T cells and the mechanism of T cell migration through TIME have not been studied comprehensively. In this work, we developed a hybrid discrete-continuum multi-scale model to study TIME. The mathematical model includes angiogenesis and T cell recruitment via tumor vasculature. Moreover, solid tumor growth, vascular growth and remodeling, interstitial fluid flow, hemodynamics, and blood rheology are all considered in the model. In addition, different aspects of T cells, including their migration, proliferation, subtype conversion, and interaction with tumor cells are thoroughly included. The model reproduces spatiotemporal distribution of tumor infiltrating T cells that mimics histopathological patterns. Furthermore, TIME model robustly recapitulates different phases of tumor immunoediting. We also examined a number of biomarkers to predict the outcome of immune checkpoint blockade (ICB) treatment. The results demonstrated that although tumor mutational burden (TMB) may predict non-responders to ICB, a combination of different biomarkers is essential to predict the majority of the responders. Based on our results, the ICB response rate varies significantly from 28 to 89% depending on the values of different parameters, even in the cases with high TMB.

A theoretical model to study of influence of an external tilted magnetic field on interstitial fluid flow inside a cylindrical tumor with capillaries

A theoretical model to study of influence of an external tilted magnetic field on interstitial fluid flow inside a cylindrical tumor with capillaries

Effect of infusion direction on convection-enhanced drug delivery to anisotropic tissue.

Convection-enhanced delivery (CED) can effectively overcome the blood-brain barrier by infusing drugs directly into diseased sites in the brain using a catheter, but its clinical performance still needs to be improved. This is strongly related to the highly anisotropic characteristics of brain white matter, which results in difficulties in controlling drug transport and distribution in space. In this study, the potential to improve the delivery of six drugs by adjusting the placement of the infusion catheter is examined using a mathematical model and accurate numerical simulations that account simultaneously for the interstitial fluid (ISF) flow and drug transport processes in CED. The results demonstrate the ability of this direct infusion to enhance ISF flow and therefore facilitate drug transport. However, this enhancement is highly anisotropic, subject to the orientation of local axon bundles and is limited within a small region close to the infusion site. Drugs respond in different ways to infusion direction: the results of our simulations show that while some drugs are almost insensitive to infusion direction, this strongly affects other compounds in terms of isotropy of drug distribution from the catheter. These findings can serve as a reference for planning treatments using CED.

Early Improvement in Interstitial Fluid Flow in Patients With Severe Carotid Stenosis After Angioplasty and Stenting.

This study aimed to investigate early changes in interstitial fluid (ISF) flow in patients with severe carotid stenosis after carotid angioplasty and stenting (CAS). We prospectively recruited participants with carotid stenosis ≥80% undergoing CAS at our institute between October 2019 and March 2023. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), and the Mini-Mental State Examination (MMSE) were performed 3 days before CAS. MRI with DTI and MMSE were conducted within 24 hours and 2 months after CAS, respectively. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated from the DTI data to determine the ISF status. Increments were defined as the ratio of the difference between post- and preprocedural values to preprocedural values. In total, 102 participants (age: 67.1±8.9 years; stenosis: 89.5%±5.7%) with longitudinal data were evaluated. The DTI-ALPS index increased after CAS (0.85±0.15; 0.85 [0.22] vs. 0.86±0.14; 0.86 [0.21]; P=0.022), as did the MMSE score (25.9±3.7; 24.0 [4.0] vs. 26.9±3.4; 26.0 [3.0]; P<0.001). Positive correlations between increments in the DTI-ALPS index and MMSE score were found in all patients (rs=0.468; P<0.001). An increased 24-hour post-CAS DTI-ALPS index suggests early improvement in ISF flow efficiency. The positive correlation between the 24-hour DTI-ALPS index and 2-month MMSE score increments suggests that early ISF flow improvement may contribute to long-term cognitive improvement after CAS.

A novel methodology for mapping interstitial fluid dynamics in murine brain tumors using DCE-MRI

We present a comprehensive methodology for measuring heterogeneous interstitial fluid flow in murine brain tumors using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) coupled with the computational tool, Lymph4D. This four-part protocol encompasses glioma cell preparation, tumor inoculation, MRI imaging protocol, and histological verification using Evans Blue. While conventional DCE-MRI analysis primarily focuses on vascular perfusion, our methods reveal untapped potential to extract crucial information about interstitial fluid dynamics, including directions, velocities, and diffusion coefficients. This methodology extends beyond glioma research, with applicability to conditions routinely imaged with DCE-MRI, thereby offering a versatile tool for investigating interstitial fluid dynamics across a wide range of diseases and conditions. Our methodology holds promise for accelerating discoveries and advancements in biomedical research, ultimately enhancing diagnostic and therapeutic strategies for a wide range of diseases and conditions.

A Mathematical Model of Interstitial Fluid Flow and Retinal Tissue Deformation in Macular Edema.

This study aims to develop a mathematical model to elucidate fluid circulation in the retina, focusing on the movement of interstitial fluid (comprising water and albumin) to understand the mechanisms underlying exudative macular edema (EME). The model integrates physiological factors such as retinal pigment epithelium (RPE) pumping, osmotic pressure gradients, and tissue deformation. It accounts for spatial variability in hydraulic conductivity (HC) across the retina and incorporates the structural role of Müller cells (MCs) in maintaining retinal stability. The model predicts that tissue deformation is maximal at the center of the fovea despite fluid exudation from blood capillaries occurring elsewhere, aligning with clinical observations. Additionally, the model suggests that spatial variability in HC across the thickness of the retina plays a protective role against fluid accumulation in the fovea. Despite inherent simplifications and uncertainties in parameter values, this study represents a step toward understanding the pathophysiology of EME. The findings provide insights into the mechanisms underlying fluid dynamics in the retina and fluid accumulation in the foveal region, showing that the specific conformation of Müller cells is likely to play a key role.

Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma.

Microphysiological systems (MPSs) reconstitute tissue interfaces and organ functions, presenting a promising alternative to animal models in drug development. However, traditional materials like polydimethylsiloxane (PDMS) often interfere by absorbing hydrophobic molecules, affecting drug testing accuracy. Additive manufacturing, including 3D bioprinting, offers viable solutions. GlioFlow3D, a novel microfluidic platform combining extrusion bioprinting and stereolithography (SLA) is introduced. GlioFlow3D integrates primary human cells and glioblastoma (GBM) lines in hydrogel-based microchannels mimicking vasculature, within an SLA resin framework using cost-effective materials. The study introduces a robust protocol to mitigate SLA resin cytotoxicity. Compared to PDMS, GlioFlow3D demonstrated lower small molecule absorption, which is relevant for accurate testing of small molecules like Temozolomide (TMZ). Computational modeling is used to optimize a pumpless setup simulating interstitial fluid flow dynamics in tissues. Co-culturing GBM with brain endothelial cells in GlioFlow3D showed enhanced CD133 expression and TMZ resistance near vascular interfaces, highlighting spatial drug resistance mechanisms. This PDMS-free platform promises advanced drug testing, improving preclinical research and personalized therapy by elucidating complex GBM drug resistance mechanisms influenced by the tissue microenvironment.

Heterogeneous Mechanical Stress and Interstitial Fluid Flow Predictions Derived from DCE-MRI for Rat U251N Orthotopic Gliomas.

Mechanical stress and fluid flow influence glioma cell phenotype in vitro, but measuring these quantities in vivo continues to be challenging. The purpose of this study was to predict these quantities in vivo, thus providing insight into glioma physiology and potential mechanical biomarkers that may improve glioma detection, diagnosis, and treatment. Image-based finite element models of human U251N orthotopic glioma in athymic rats were developed to predict structural stress and interstitial flow in and around each animal's tumor. In addition to accounting for structural stress caused by tumor growth, our approach has the advantage of capturing fluid pressure-induced structural stress, which was informed by in vivo interstitial fluid pressure (IFP) measurements. Because gliomas and the brain are soft, elevated IFP contributed substantially to tumor structural stress, even inverting this stress from compressive to tensile in the most compliant cases. The combination of tumor growth and elevated IFP resulted in a concentration of structural stress near the tumor boundary where it has the greatest potential to influence cell proliferation and invasion. MRI-derived anatomical geometries and tissue property distributions resulted in heterogeneous interstitial fluid flow with local maxima near cerebrospinal fluid spaces, which may promote tumor invasion and hinder drug delivery. In addition, predicted structural stress and interstitial flow varied markedly between irradiated and radiation-naïve animals. Our modeling suggests that relative to tumors in stiffer tissues, gliomas experience unusual mechanical conditions with potentially important biological (e.g., proliferation and invasion) and clinical consequences (e.g., drug delivery and treatment monitoring).

Using Microfluidics to Align Matrix Architecture and Generate Chemokine Gradients Promotes Directional Branching in a Model of Epithelial Morphogenesis.

The mechanical cue of fiber alignment plays a key role in the development of various tissues in the body. The ability to study the effect of these stimuli in vitro has been limited previously. Here, we present a microfluidic device capable of intrinsically generating aligned fibers using the microchannel geometry. The device also features tunable interstitial fluid flow and the ability to form a morphogen gradient. These aspects allow for the modeling of complex tissues and to differentiate cell response to different stimuli. To demonstrate the abilities of our device, we incorporated luminal epithelial cysts into our device and induced growth factor stimulation. We found the mechanical cue of fiber alignment to play a dominant role in cell elongation and the ability to form protrusions was dependent on cadherin-3. Together, this work serves as a springboard for future potential with these devices to answer questions in developmental biology and complex diseases such as cancers.