Interstitial Flow Research Articles

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.

Towards a 3D-Printed Millifluidic Device for Investigating Cellular Processes

Microfluidic devices (µFDs) have been explored extensively in drug screening and studying cellular processes such as migration and metastasis. However, the fabrication and implementation of microfluidic devices pose cost and logistical challenges that limit wider-spread adoption. Despite these challenges, light-based 3D printing offers a potential alternative to device fabrication. This study reports on the development of millifluidic devices (MiFDs) for disease modeling and elucidates the methods and implications of the design, production, and testing of 3D-printed MiFDs. It further details how such millifluidic devices can be cost-efficiently and effortlessly produced. The MiFD was developed through an iterative process with analytical tests (flow tests, leak tests, cytotoxicity assays, and microscopic analyses), driving design evolution and determination of the suitability of the devices for disease modeling and cancer research. The design evolution also considered flow within tissues and replicates interstitial flow between the main flow path and the modules designed to house and support organ-mimicking cancer cell spheroids. Although the primary stereolithographic (SLA) resin used in this study showed cytotoxic potential despite its biocompatibility certifications, the MiFDs possessed essential attributes for cell culturing. In summary, SLA 3D printing enables the production of MiFDs as a cost-effective, rapid prototyping alternative to standard µFD fabrication for investigating disease-related processes.

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

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.

Use microfluidics to study cell migration in response to fluid shear stress gradients

Cells respond not only to biological regulatory factors but also to physical stimuli such as electric fields, light, and shear stress in their environment. These stimuli can lead to cell migration and morphological changes. In the human body, cells encounter fluid shear stress induced by interstitial flow, lymphatic flow, blood flow, or organ-specific conditions within their micro-environments. Therefore, fluid shear stress, a classic mechanical force, has gained significant attention in wound healing and cancer metastasis. In this study, a microfluidic chip was developed to both culture cells and generate a shear stress gradient to direct cell migration. The design of this device’s geometry allows the generation of a shear stress gradient perpendicular to the direction of medium flow. This greatly eliminates the influence of flow-induced cell responses. Using mouse fibroblast cells (NIH3T3) and human lung cancer cells (CL1-5) as models, their migration directionality, migration rates, and alignment in response to the shear stress gradient were investigated. Within the stress range of 0.095–0.155 Pa and a gradient of 0.015 Pa/mm, NIH3T3 cells did not exhibit significant directional migration, differences in migration rates, or specific alignment patterns. In contrast, CL1-5 cells preferred higher shear stress environments and alignment parallel to the medium flow, suggesting that these conditions could induce higher mobility in these cancer cells.

A modular finite element approach to saturated poroelasticity dynamics: Fluid–solid coupling with Neo-Hookean material and incompressible flow

Several methods have been developed to model the dynamic behavior of saturated porous media. However, most of them are suitable only for small strain and small displacement problems and are built in a monolithic way, so that individual improvements in the solution of the solid or fluid phases can be difficult. This study shows a macroscopic approach through a partitioned fluid–solid coupling, in which the skeleton solid is considered to behave as a Neo-Hookean material and the interstitial flow is incompressible following the Stokes–Brinkman model. The porous solid is numerically modeled with a total Lagrangian position-based finite element formulation, while an Arbitrary Lagrangian-Eulerian stabilized finite element approach is employed for the porous medium flow dynamics. In both fields, an averaging procedure is applied to homogenize the problem, resulting in a macroscopic continuous phase. The solid and fluid homogenized domains are overlapped and strongly coupled, based on a block-iterative solution scheme. Two-dimensional simulations of wave propagation in saturated porous media are employed to validate the proposed formulation through a comprehensive comparison with analytical and numerical results from the literature. The analyses underscore the proposed formulation as a robust and precise modular approach for addressing dynamic problems in poroelasticity.

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.

Clogging of Noncohesive Suspension Flows

Abstract When flowing through narrow channels or constrictions, many-body systems exhibit various flowing patterns, yet they can also get stuck. In many of these systems, the flowing elements remain as individuals (they do not aggregate or merge), sharing strong analogies among each other. This is the case for systems as contrasting as grains in a silo and pedestrians passing through tight spaces. Interestingly, when these entities flow within a fluid medium, numerous similarities persist. However, the fluid dynamics aspects of such clogging events, such as interstitial flow, liquid pressure, and hydrodynamic interactions, has only recently begun to be explored. In this review, we describe parallels with dry granular clogging and extensively analyze phenomena emerging when particles coexist with fluid in the system. We discuss the influence of diverse flow drive, particle propulsion mechanisms, and particle characteristics, and we conclude with examples from nature.

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.

Construction of multilayered small intestine-like tissue by reproducing interstitial flow

Recent advances have made modeling human small intestines invitro possible, but it remains a challenge to recapitulate fully their structural and functional characteristics. We suspected interstitial flow within the intestine, powered by circulating blood plasma during embryonic organogenesis, to be a vital factor. We aimed to construct an invivo-like multilayered small intestinal tissue by incorporating interstitial flow into the system and, in turn, developed the micro-small intestine system by differentiating definitive endoderm and mesoderm cells from human pluripotent stem cells simultaneously on a microfluidic device capable of replicating interstitial flow. This approach enhanced cell maturation and led to the development of a three-dimensional small intestine-like tissue with villi-like epithelium and an aligned mesenchymal layer. Our micro-small intestine system not only overcomes the limitations of conventional intestine models but also offers a unique opportunity to gain insights into the detailed mechanisms underlying intestinal tissue development.

Characterization of 3D oxygen concentrations in microfluidic systems combining astigmatic particle tracking with phosphorescence decay measurements

In this work, we combine astigmatic particle tracking with phosphorescence decay measurements to determine 3D-resolved oxygen concentration in microfluidic systems. In our experiments we achieve uncertainties in the out-of-plane position of less than 1 µm and uncertainties in oxygen concentration of less than 2 ppm. The calibrated measurement range covers oxygen concentrations of 0.6 ppm to 27.6 ppm. A method is presented to correct for measurement errors caused by photobleaching. For this, the excitation energy, the cumulative exposure time and the spatially varying intensity profile of the laser are taken into account in the correction. With this method, low measurement errors of less than 2ppm at ambient oxygen levels can be achieved even after thousands of excitation cycles. Hence, 3D oxygen concentrations are measured in an agarose hydrogel filled microfluidic chamber across which different pressure and oxygen gradients can be set independently. The results show that oxygen diffusion is superposed by an interstitial flow, which significantly alters the resulting oxygen concentration.

Transient Macular Edema after Uncomplicated Cataract Surgery: Below the Surface

To present analysis of 17 case reports of 17 patients who had an acute transient macular edema appeared after uneventful cataract surgery. Observations: In literature about 12 case series of toxic macular edema development after cataract surgery are described and all of them were accompanied by the cefuroxime intracameral usage. Also, there are reports of macular edema development after several weeks after uncomplicated phacoemulsification due to pseudophakic cystoid macular edema (Irvine-Gass syndrome) or due to vitreomacular traction syndrome. We observed a series of transient acute macular edema with 3,8% incidence occurring on the first days after uncomplicated phacoemulsification with IOL implantation that had no signs of vitreomacular traction or acute inflammation. Optical coherence tomography (OCT) was performed on patients complaining on blur vision and who had signs of macular edema by ophthalmoscopy. By OCT high and often extensive neuroepithelium and local pigment epithelium detachments were observed on the first day after surgery in 17 patients with quiet postoperative condition of the eye. The edema resolved on the 3-6-th day by standard phaco accompanying pharmacological treatment. In most cases posterior vitreous cortex was adjacent to the retina except 3 patients with posterior vitreous detachment in macular area. We found a paper by Costen M.T.J. et al. (2007) about the same striking appearance of maculopathy called by authors “A-sign” maculopathy because of A-shaped pattern on OCT images in 3 patients after routine cataract surgery. Yaman A (2008) and Panagiotidis D (2010) also reported same findings after uncomplicated cataract surgery. We compared our findings with 3 papers mentioned above, as well as with typical pseudophakic cystoid macular edema (CME) and vitreomacular traction syndrome. Conclusion: It’s obvious that observed case series are cefuroxime induced. But its comparison with CME in terms of morphology of the macula could improve our understanding of mechanisms of the interstitial fluid flow in the eye tissues.

Investigating mechanisms of debris removal in ultrasonic vibration-assisted EDM drilling

In traditional electrical discharge machining (EDM) of micro-holes, the debris removal becomes increasingly challenging as hole depth increases, significantly affecting the machining of difficult-to-machine materials. To address this issue,we first developed a micro-hole gap flow field model for a novel longitudinal–torsional ultrasonic vibration (LTV) electrode EDM drilling method. We analyzed the effects of three types of electrodes — rotation electrodes, longitudinal ultrasonic vibration (LUV) electrodes, and LTV electrodes — on the flow velocity in the micro-hole interstitial flow field. Next, we simulated the motion of fluid and debris in the interstitial flow field of micro-holes, theoretically verifying the advantage of electrode ultrasonic vibration in enhancing debris removal efficiency. Additionally, we observed the electrode tip morphology, the elemental composition on the electrode surface, and the morphology of the micro-hole inlet/outlet and inner wall to further elucidate the debris removal mechanism and confirm the superior drilling performance of the ultrasonic vibration electrodes. At an optimal ultrasonic amplitude (AL=4μm), the LUV electrode demonstrated improved consistency in the micro-hole inlet/outlet and achieved a micro-hole taper of 0.014°. The material removal rate (MRR) using the LTV electrode reached 5.14 × 105μm3/s, nearly 1.5 times higher rotation electrode. This method successfully produced a positively tapered hole suitable for injector nozzles.

The morphology of cell spheroids in simple shear flow

Cell spheroids are a widely used model to investigate cell-cell and cell-matrix interactions in a 3D microenvironment in vitro. Most research on cell spheroids has been focused on their response to various stimuli under static conditions. Recently, the effect of flow on cell spheroids has been investigated in the context of tumor invasion in interstitial space. In particular, microfluidic perfusion of cell spheroids embedded in a collagen matrix has been shown to modulate cell-cell adhesion and to represent a possible mechanism promoting tumor invasion by interstitial flow. However, studies on the effects of well-defined flow fields on cell spheroids are lacking in the literature. Here, we apply simple shear flow to cell spheroids in a parallel plate apparatus while observing their morphology by optical microscopy. By using image analysis techniques, we show that cell spheroids rotate under flow as rigid prolate ellipsoids. As time goes on, cells from the outer layer detach from the sheared cell spheroids and are carried away by the flow. Hence, the size of cell spheroids declines with time at a rate increasing with the external shear stress, which can be used to estimate cell-cell adhesion. The technique proposed in this work allows one to correlate flow-induced effects with microscopy imaging of cell spheroids in a well-established shear flow field, thus providing a method to obtain quantitative results which are relevant in the general field of mechanobiology.