Thomas Michel Daniel Combriat

• Demir, Ali Aslan; Combriat, Thomas Michel Daniel; Heyward, Catherine Anne; Tiainen, Hanna; Carlier, Aurélie & Dysthe, Dag Kristian (2026). A cellular automaton model of osteogenic differentiation reveals identifiability limits of endpoint assays. Frontiers in Systems Biology. 6. doi: 10.3389/fsysb.2026.1872774. Full text in Research Archive Show summary

  Introduction Standard differentiation assays sample cell states only at discrete time points, while the underlying progression unfolds continuously and heterogeneously across cells. As a result, different combinations of proliferation, commitment, and maturation dynamics can converge to similar endpoint measurements. This many-to-one mapping between latent trajectories and observable readouts constitutes a partially observed inverse problem that limits mechanistic interpretation. Although this ambiguity is inherent to many experimental systems, it is rarely examined using models that connect cell-state dynamics to assay-level quantities. Methods We present OsteoMin, a coarse-grained cellular automaton that links stochastic transitions between pre-osteoblast and osteoblast states to experimentally measurable readouts of alkaline phosphatase activity, collagen deposition, and mineralization. Model parameters were constrained using literature-reported kinetics and evaluated against dexamethasone and menaquinone-4 perturbations. The framework enables systematic analysis of how cell-state progression, matrix maturation, and external perturbations shape differentiation outcomes. Results OsteoMin reproduces qualitative assay trends and quantifies the identifiability limits of endpoint assays. Distinct perturbation families often produce similar endpoint responses (macro-F1 ≈ 0.42$), indicating limited discriminative power. Incorporating temporal trajectories improves separability (macro-F1 ≈ 0.78$), demonstrating that most identifiable information resides in marker dynamics rather than terminal measurements. Sobol analysis shows that early markers depend on proliferation timing, whereas late mineralization is governed by nonlinear matrix maturation and parameter interactions. Discussion These results show that endpoint assays constrain overall progression but do not uniquely identify underlying mechanisms. OsteoMin provides a framework linking differentiation dynamics to assay observables and a basis for assessing identifiability in endpoint-driven systems.

• Låstad, Silja Borring; Abbasova, Nigar; Combriat, Thomas Michel Daniel & Dysthe, Dag Kristian (2026). Three Dimensional Dynamics of Epithelial Monolayers. BioaRxiv. doi: 10.64898/2026.03.10.710903. Full text in Research Archive Show summary

  Cells in epithelial monolayers are commonly quantified using a projected area and implicitly assuming constant cell volume and prism-shaped cells. These 2.5D assumptions ignore the volume and mass dynamics that may accompany density fluctuation in confluent space-filling tissues but remain inaccessible to the labelling- and intensity-based imaging techniques used to date. Here, we use time-lapse quantitative phase imaging (QPI) to obtain spatially and temporally resolved maps of height, volume, and dry mass in MDCK epithelial monolayers under physiological conditions. Three findings follow. (i) Cellular dry mass concentration is maintained to within ∼ 4.5 % across the monolayer and over time, even during large-amplitude pulsations, ruling out fluid (water) transport as the dominant driver of height and area dynamics. (ii) The mean height of the monolayer increases from ∼ 5.5 to ∼ 9 µm and the mean cell volume decreases by ∼ 25 % as the cell density doubles, evidence of contact inhibition of cell size rather than constant cell volume. Cell heights vary up to 30%, oscillate with a ∼ 5 h period, and follow gamma-shaped distributions. (iii) At cellular scales, both segmented-cell tracking and continuum mass-flux analysis show that projected cell volume is not conserved; mass conservation is recovered only after coarse-graining over ∼ 2 cell diameters and ∼ 1.6 h. Two non-exclusive mechanisms may explain this: non-prismatic cell geometry produces apparent volume fluctuations even at constant true volume, and periodic mass exchange between cells and the ECM produces genuine cyclic changes in cellular dry mass. A propagating elastic mode in the dry-mass structure factor ( c s ∼ 15 µm/h) further indicates that the monolayer behaves as a viscoelastic active medium rather than a plug-flow fluid. Each of these results requires simultaneous, time-resolved access to height and dry mass at the cellular scale and is therefore newly visible with QPI applied to epithelial monolayers. Together, they question the common 2.5D assumptions of prism-shaped cells, constant volume, plug-flow kinematics, and argue that quantitative continuum and cell-based models of epithelial dynamics must incorporate dry-mass-density regulation and 3D cell geometry.

• Låstad, Silja Borring; Abbasova, Nigar; Combriat, Thomas Michel Daniel & Dysthe, Dag Kristian (2026). Quantitative Phase Imaging of the Dynamics of Epithelial Monolayers. SPIE Quantitative Phase Imaging XII. 13861. doi: 10.1117/12.3084036. Full text in Research Archive Show summary

  This study uses two different quantitative phase imaging techniques (QPI) and for the first time measures the height, volume, and mass dynamics of Madin-Darby Canine Kidney (MDCK) monolayers. We demonstrate novel methods to determine the height of confluent monolayers of cells from 2D and 3D QPI data and validate that the two methods agree. We developed a novel cell segmentation method adapted to QPI images of confluent cell layers and present a robust measure of relative error. We also demonstrate that height statistics of cells can be obtained without segmenting the images. We obtain the following precisions of cell density (1 %), height (3 %), area (5 %) and volume (6 %). Cell height varies 15-25 % over a monolayer and increases 50-100 % when cell density doubles. The average refractive index and the dry mass fraction of the cells, on the other hand, are constant over the entire density range.

• Martinez, Mikel Amirola; Combriat, Thomas Michel Daniel; Ferencevic, Katharina; Wilhelmsen, Ingrid; Dalmao-Fernandez, Andrea & Olsen, Petter Angell [Show all 9 contributors for this article] (2025). Aspects of zone-like identity and holotomographic tracking of human stem cell-derived liver sinusoidal endothelial cells. Frontiers in Cell and Developmental Biology. 13. doi: 10.3389/fcell.2025.1528991. Full text in Research Archive Show summary

  Introduction: Liver sinusoidal endothelial cells (LSEC) are specialized endothelial cells with unique metabolic and barrier functions adapted to the needs of the liver sinusoid. LSECs are highly sensitive to their environment, and this fragile nature causes challenges in analyzing their phenotype under in vitro conditions. Methods: In this work, we first differentiated LSEC-like cells (scLSECs) from two human pluripotent stem cell lines and characterized them by a panel of qPCR markers, immunohistochemistry, substrate oxidation for energy metabolism, scavenger function, and nitric oxide secretion. We then introduced holotomography, a technique that allows to recover quantitative and three-dimensional information about the refractive indexes of cell components, as a tool to image and track scLSEC in vitro in a minimally intrusive, label-free manner. Results and discussion: Holotomography and developed machine learning-based algorithm for image processing allowed us to describe and monitor changes in intracellular pore-like structures over time. Finally, we tested the possibility of inducing aspects of zone-specific LSEC phenotype and metabolism using culture-based treatments, which resulted in modest shifts in marker expression and metabolic activity. The presented strategy provides an advanced tool kit for investigating liver endothelial cells.

• Nøvik, Steffen; Hirayama-Shoji, Kayoko; Combriat, Thomas; Sakalys, Domantas; Aashamar, Erik & Louch, William E. [Show all 9 contributors for this article] (2025). Bioimpedance and electrophysiology measurements of engineered heart tissues outside the culture medium. Biosensors and Bioelectronics. ISSN 0956-5663. 287, p. 117634–117634. doi: 10.1016/j.bios.2025.117634. Full text in Research Archive
• Combriat, Thomas Michel Daniel; Dysthe, Dag Kristian & Flekkøy, Eirik Grude (2024). Cavitation dynamics in creeping flow. Journal of Fluid Mechanics. ISSN 0022-1120. 999. doi: 10.1017/jfm.2024.937. Full text in Research Archive Show summary

  We investigate the heterogeneous cavitation phenomenon in water when a spherical surface is abruptly separated from a nearby flat substrate, at a distance of approximately 10 nm. By tracking the surface separation using Newton ring positions, and capturing the bubble evolution with a high-speed camera on a microscope, we compare our experimental findings with hydrodynamic predictions at low Reynolds numbers. Upon upward movement of the spherical surface, the resulting bubble develops branched fingers through the Saffman–Taylor instability. Simultaneously, negative liquid pressures in the range ∼ 10 atm are observed. These large tension values occasionally lead to secondary nucleation events. The bubble sizes satisfy a predicted Family–Vicsek scaling law where the bubble area is proportional to the inverse bubble lifetime. The fact that creeping flow cavitation bubbles are more short-lived the larger they are separates them from bubbles that are governed by inertial dynamics.

• Wilhelmsen, Ingrid; Combriat, Thomas Michel Daniel; Dalmao-Fernandez, Andrea; Stokowiec, Justyna; Wang, Chencheng & Olsen, Petter Angell [Show all 10 contributors for this article] (2024). The effects of TGF-β-induced activation and starvation of vitamin A and palmitic acid on human stem cell-derived hepatic stellate cells. Stem Cell Research & Therapy. 15(223). doi: 10.1186/s13287-024-03852-8. Full text in Research Archive Show summary

  Background Hepatic stellate cells (HSC) have numerous critical roles in liver function and homeostasis, while they are also known for their importance during liver injury and fibrosis. There is therefore a need for relevant in vitro human HSC models to fill current knowledge gaps. In particular, the roles of vitamin A (VA), lipid droplets (LDs), and energy metabolism in human HSC activation are poorly understood. Methods In this study, human pluripotent stem cell-derived HSCs (scHSCs), benchmarked to human primary HSC, were exposed to 48-hour starvation of retinol (ROL) and palmitic acid (PA) in the presence or absence of the potent HSC activator TGF-β. The interventions were studied by an extensive set of phenotypic and functional analyses, including transcriptomic analysis, measurement of activation-related proteins and cytokines, VA- and LD storage, and cell energy metabolism. Results The results show that though the starvation of ROL and PA alone did not induce scHSC activation, the starvation amplified the TGF-β-induced activation-related transcriptome. However, TGF-β-induced activation alone did not lead to a reduction in VA or LD stores. Additionally, reduced glycolysis and increased mitochondrial fission were observed in response to TGF-β. Conclusions scHSCs are robust models for activation studies. The loss of VA and LDs is not sufficient for scHSC activation in vitro, but may amplify the TGF-β-induced activation response. Collectively, our work provides an extensive framework for studying human HSCs in healthy and diseased conditions.

• Combriat, Thomas Michel Daniel; Olsen, Petter Angell; Låstad, Silja Borring; Malthe-Sørenssen, Anders; Krauss, Stefan Johannes Karl & Dysthe, Dag Kristian (2024). Acoustic Wave-Induced Stroboscopic Optical Mechanotyping of Adherent Cells. Advanced Science. 11(16). doi: 10.1002/advs.202307929. Full text in Research Archive Show summary

  In this study, a novel, high content technique using a cylindrical acoustic transducer, stroboscopic fast imaging, and homodyne detection to recover the mechanical properties (dynamic shear modulus) of living adherent cells at low ultrasonic frequencies is presented. By analyzing the micro-oscillations of cells, whole populations are simultaneously mechanotyped with sub-cellular resolution. The technique can be combined with standard fluorescence imaging allowing to further cross-correlate biological and mechanical information. The potential of the technique is demonstrated by mechanotyping co-cultures of different cell types with significantly different mechanical properties.

• Aizenshtadt, Aleksandra; Wang, Chencheng; Abadpour, Shadab; Menezes, Pedro Duarte; Wilhelmsen, Ingrid & Dalmao-Fernandez, Andrea [Show all 15 contributors for this article] (2024). Pump-Less, Recirculating Organ-on-Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver. Advanced Healthcare Materials. ISSN 2192-2640. 13(13). doi: 10.1002/adhm.202303785. Full text in Research Archive Show summary

  Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) are epidemiologically correlated disorders with a worldwide growing prevalence. While the mechanisms leading to the onset and development of these conditions are not fully understood, predictive tissue representations for studying the coordinated interactions between central organs that regulate energy metabolism, particularly the liver and pancreatic islets, are needed. Here, a dual pump-less recirculating organ-on-chip platform that combines human pluripotent stem cell (sc)-derived sc-liver and sc-islet organoids is presented. The platform reproduces key aspects of the metabolic cross-talk between both organs, including glucose levels and selected hormones, and supports the viability and functionality of both sc-islet and sc-liver organoids while preserving a reduced release of pro-inflammatory cytokines. In a model of metabolic disruption in response to treatment with high lipids and fructose, sc-liver organoids exhibit hallmarks of steatosis and insulin resistance, while sc-islets produce pro-inflammatory cytokines on-chip. Finally, the platform reproduces known effects of anti-diabetic drugs on-chip. Taken together, the platform provides a basis for functional studies of obesity, T2DM, and MASLD on-chip, as well as for testing potential therapeutic interventions.

• Kwak, Dongho; Combriat, Thomas Michel Daniel; Jensenius, Alexander Refsum & Olsen, Petter Angell (2023). Characterization of Mechanical and Cellular Effects of Rhythmic Vertical Vibrations on Adherent Cell Cultures. Bioengineering. 10(7), p. 1–19. doi: 10.3390/bioengineering10070811. Full text in Research Archive Show summary

  This paper presents an innovative experimental setup that employs the principles of audio technology to subject adherent cells to rhythmic vertical vibrations. We employ a novel approach that combines three-axis acceleration measurements and particle tracking velocimetry to evaluate the setup’s performance. This allows us to estimate crucial parameters such as root mean square acceleration, fluid flow patterns, and shear stress generated within the cell culture wells when subjected to various vibration types. The experimental conditions consisted of four vibrational modes: No Vibration, Continuous Vibration, Regular Pulse, and Variable Pulse. To evaluate the effects on cells, we utilized fluorescence microscopy and a customized feature extraction algorithm to analyze the F-actin filament structures. Our findings indicate a consistent trend across all vibrated cell cultures, revealing a reduction in size and altered orientation (2D angle) of the filaments. Furthermore, we observed cell accumulations in the G1 cell cycle phase in cells treated with Continuous Vibration and Regular Pulse. Our results demonstrate a negative correlation between the magnitude of mechanical stimuli and the size of F-actin filaments, as well as a positive correlation with the accumulations of cells in the G1 phase of the cell cycle. By unraveling these analyses, this study paves the way for future investigations and provides a compelling framework for comprehending the intricate cellular responses to rhythmic mechanical stimulation.

• Kwak, Dongho; Combriat, Thomas Michel Daniel; Wang, Chencheng; Scholz, Hanne; Danielsen, Anne & Jensenius, Alexander Refsum (2022). Music for Cells? A Systematic Review of Studies Investigating the Effects of Audible Sound Played Through Speaker-Based Systems on Cell Cultures. Music & Science. 5. doi: 10.1177/20592043221080965. Full text in Research Archive Show summary

  There have been several studies investigating whether musical sound can be used as cell stimuli in recent years. We systematically searched publications to get an overview of studies that have used audible sound played through speaker-based systems to induce mechanical perturbation in cell cultures. A total of 12 studies were identified. We focused on the experimental setups, the sounds that were used as stimuli, and relevant biological outcomes. The studies are categorized into simple and complex sounds depending on the type of sound employed. Some of the promising effects reported were enhanced cell migration, proliferation, colony formation, and differentiation ability. However, there are significant differences in methodologies and cell type-specific outcomes, which made it difficult to find a systematic pattern in the results. We suggest that future experiments should consider using: (1) a more controlled acoustic environment, (2) standardized sound and noise measurement methods, and (3) a more comprehensive range of controlled sound parameters as cellular stimuli.

• Busek, Mathias; Nøvik, Steffen; Aizenshtadt, Aleksandra; Martinez, Mikel Amirola; Combriat, Thomas Michel Daniel & Grünzner, Stefan [Show all 7 contributors for this article] (2021). Thermoplastic elastomer (Tpe)–poly(methyl methacrylate) (pmma) hybrid devices for active pumping pdms-free organ-on-a-chip systems. Biosensors. ISSN 2079-6374. 11(5). doi: 10.3390/bios11050162. Full text in Research Archive Show summary

  Polydimethylsiloxane (PDMS) has been used in microfluidic systems for years, as it can be easily structured and its flexibility makes it easy to integrate actuators including pneumatic pumps. In addition, the good optical properties of the material are well suited for analytical systems. In addition to its positive aspects, PDMS is well known to adsorb small molecules, which limits its usability when it comes to drug testing, e.g., in organ-on-a-chip (OoC) systems. Therefore, alternatives to PDMS are in high demand. In this study, we use thermoplastic elastomer (TPE) films thermally bonded to laser-cut poly(methyl methacrylate) (PMMA) sheets to build up multilayered microfluidic devices with integrated pneumatic micro-pumps. We present a low-cost manufacturing technology based on a conventional CO2 laser cutter for structuring, a spin-coating process for TPE film fabrication, and a thermal bonding process using a pneumatic hot-press. UV treatment with an Excimer lamp prior to bonding drastically improves the bonding process. Optimized bonding parameters were characterized by measuring the burst load upon applying pressure and via profilometer-based measurement of channel deformation. Next, flow and long-term stability of the chip layout were measured using microparticle Image Velocimetry (uPIV). Finally, human endothelial cells were seeded in the microchannels to check biocompatibility and flow-directed cell alignment. The presented device is compatible with a real-time live-cell analysis system.

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• Låstad, Silja Borring; Abbasova, Nigar; Combriat, Thomas Michel Daniel & Dysthe, Dag Kristian (2026). Three Dimensional Dynamics of Epithelial Monolayers. Full text in Research Archive
• Låstad, Silja Borring; Abbasova, Nigar; Ho, Richard David Jun-Geet; Combriat, Thomas Michel Daniel & Dysthe, Dag Kristian (2025). Segmentation-free measurement of cell motion from quantitative phase imaging. Full text in Research Archive
• Låstad, Silja Borring; Abbasova, Nigar; Combriat, Thomas Michel Daniel & Dysthe, Dag Kristian (2025). Cell height, area and volume fluctuations in MDCK monolayers. Full text in Research Archive

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