bims-ecemfi 2026-08-23 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–08–23
nine papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Matrix stress relaxation drives glioblastoma cell response in viscoelastic biomaterials.
Contributions of single-cell mechanics and cell-cell adhesion to multicellular spheroid mechanics.
Mechanical memory of confinement pressure governs expansion size in epithelial monolayers.
Deformation Microscopy: A Protocol for Full-Field, Micro- to Nano-Scale Imaging of Mechanics in Extracellular Matrix, Cells, and Nuclei.
Engineering Multilayer Poly(ethylene glycol) Hydrogels via Off-Stoichiometry Thiol-Ene Chemistry.
Initiation of rotational collective migration in Drosophila through tissue geometry and mechanochemical feedback.
Tumor microenvironment and its implications for atomic force microscopy-based nanomechanics of cancer cells: a perspective.
Effects of Concentration, Cross-Linking, and Compression on Macromolecular Partitioning in Biological Hydrogels.
EnView: a tunable microphysiological platform with human crypt-scale topography and independent apical-basal flow for long-term culture and imaging of colonic epithelial monolayers.

Sci Adv. 2026 Aug 21. 12(34): eaef7087

Matrix stress relaxation drives glioblastoma cell response in viscoelastic biomaterials.

Sadegh Ghorbani, Michelle S Huang, Daiyao Zhang, Yueming Liu, Christopher Long, Riley Zwetsloot, Esther A T Mozipo, Rameshwar R Rao, Annika Enejder, Sarah C Heilshorn.

The extracellular matrix (ECM) of glioblastoma (GBM) is known to modulate cell behavior, yet the specific contributions of matrix biochemical and biomechanical signaling remain poorly understood. To address this, we engineer a tunable hyaluronan-elastin-like protein (HELP) hydrogel to independently control ligand presentation and matrix viscoelasticity. Two peptides mimicking fibronectin (FBN) and tenascin-C (TNC) are incorporated into HELP along with hyaluronan, all of which are highly up-regulated in GBM. Using dynamic covalent chemistry, we develop hydrogels with matched stiffness but distinct stress relaxation profiles. Slow stress-relaxing matrices promote cell clustering and elevated expression of P-selectin, a GBM invasion marker. These matrices also result in increased nascent ECM production, increased lipid droplet storage, and altered cytokine secretion. Our results highlight the benefit of protein-engineered, viscoelastic biomaterials for modeling the tumor microenvironment and reveal matrix viscoelasticity as a critical regulator of GBM cell state, offering a tool for identifying previously unrecognized therapeutic targets.

DOI: https://doi.org/10.1126/sciadv.aef7087
bioRxiv. 2026 Aug 08. pii: 2026.08.04.742605. [Epub ahead of print]

Contributions of single-cell mechanics and cell-cell adhesion to multicellular spheroid mechanics.

David Dolgitzer, Eleana Parajón, Douglas N Robinson, Pablo A Iglesias.

Tumor spheroid mechanics arise from both the mechanical properties of individual cells and the adhesive interactions that organize them into tissues. The relative contribution of these two factors to the bulk mechanical behavior, however, remains difficult to disentangle experimentally. Here, we develop a computational model of micropipette aspiration to compare the mechanical response of isolated cells and multicellular spheroids within a common computational framework. By independently varying single-cell stiffness and cell-cell adhesion, we quantify their effects on aspiration dynamics, effective elastic modulus, and viscoelastic relaxation. Our results show that increasing single-cell stiffness substantially alters the mechanics of isolated cells but has limited influence on the effective elastic modulus of multicellular spheroids. In contrast, changes in cell-cell adhesion produce pronounced effects on spheroid effective elastic modulus. Nevertheless, both parameters increase the retardation time governing the transition from the initial elastic response to long-time viscous deformation. These findings suggest that multicellular elasticity is governed primarily by intercellular mechanical coupling, whereas the dynamical response to applied stress depends jointly on cell-scale mechanics and cell-cell adhesion.

DOI: https://doi.org/10.64898/2026.08.04.742605
Life Sci Alliance. 2026 Oct;pii: e202603831. [Epub ahead of print]9(10):

Mechanical memory of confinement pressure governs expansion size in epithelial monolayers.

Linn Engström, Simon K Schnyder, Johannes K Ahnlide, Valeriia Grudtsyna, Martijn Gloerich, Pontus Nordenfelt, Amin Doostmohammadi, Vinay S Swaminathan.

Epithelial tissues undergo rapid expansion during development, repair, and morphogenesis, yet how tissue-scale growth is coordinated to re-establish homeostasis remains unclear. Here, we show that large epithelial monolayers confined at a wide range of initial densities and mechanochemical states robustly converge to the same final size and density upon release, despite differences in initial cell size, YAP activity, and cell number dynamics. To investigate the underlying mechanism, we combined quantitative experiments with a mechanochemical agent-based model in which mechanical pressure arising from confinement acts as a tissue-scale signal that modulates intracellular cell-cycle activity over time. Using this framework, we show that transient mechanical relaxation during confinement selectively elevates cell-cycle activity in higher density tissues at the time of release, accelerating early expansion without disrupting final homeostatic outcomes. Together, these results reveal how epithelial tissues coordinate collective growth and robustly restore homeostasis during expansion.

DOI: https://doi.org/10.26508/lsa.202603831
Curr Protoc. 2026 Aug;6(8): e70421

Deformation Microscopy: A Protocol for Full-Field, Micro- to Nano-Scale Imaging of Mechanics in Extracellular Matrix, Cells, and Nuclei.

Emily Y Miller, Skyler Hochmuth, Hongtian Zhu, Stephanie E Schneider, Soham Ghosh, Corey P Neu.

  The internal mechanics of living tissues, cells, and nuclei exhibit exquisite complexity, depend on dynamic structural changes, and influence biological functions such as tissue remodeling, cell homeostasis and migration, and gene expression. Full-field methods to reveal the internal mechanics of extracellular matrix, cells, and nuclei are emerging and can uncover new discoveries in mechanobiology. Here we detail a noninvasive technology to probe the internal mechanics of extracellular matrix, cells, and nuclei using a combination of imaging and deformation-matching computational approaches. Important to this technology is the acquisition of image data showing sufficient spatial and temporal resolution to capture a motion event, which can be readily evaluated using automated assessment of structural features. With careful consideration of image acquisition and processing parameters, micron- to nanometer-scale intracellular and intranuclear mechanics can be reliably measured with small displacement errors (<0.04 µm) using a conventional confocal or wide-field microscope. Further, the technology can be used to spatially correlate a multitude of biological events in complex biological problems. © 2026 Wiley Periodicals LLC. Basic Protocol: Quantifying cellular and nuclear deformation using deformation microscopy.

Keywords:  cell and nuclear mechanics; image‐based biomechanics; strain; tissue mechanics; traction force microscopy

DOI:  https://doi.org/10.1002/cpz1.70421
ACS Appl Polym Mater. 2026 Aug 14. 8(15): 12772-12781

Engineering Multilayer Poly(ethylene glycol) Hydrogels via Off-Stoichiometry Thiol-Ene Chemistry.

Ridhi Pradhan, Ravinun Khamleart, Waqas Saleem, Michael J McShane.

  Multilayer hydrogels with spatially controllable mechanical and functional properties are increasingly valuable, yet their utility is often constrained by fabrication challenges such as weak interfacial adhesion as well as reliance on cytotoxic photoinitiators and UV exposure. This study presents a simple, robust, and photoinitiator-free method to engineer multilayer poly-(ethylene glycol) (PEG) hydrogels using off-stoichiometry thiol-ene (OSTE) Michael addition chemistry. By deliberately utilizing an alternating thiol-rich and vinyl sulfone-rich PEG formulation, residual functional groups are preserved at the layer interfaces and subsequently form covalent bonds between the adjacent layers, enabling strong interfacial adhesion without UV irradiation, photoinitiators, or adhesives. The resulting hydrogels exhibited rapid and tunable gelation (1-5 min), with mechanical properties spanning ∼0.5-6 kPa through varying polymer concentration (5-10 wt %) and thiol-ene ratio (0.6-1.6). Ellman's assay confirmed the presence of stoichiometry-dependent unreacted thiol groups, validating the proposed interfacial bonding mechanism. Peel tests revealed strong interfacial adhesion, with failure occurring within the bulk material rather than at the interface. Nanoindentation further revealed spatially defined stiffness profiles across the multilayer construct, confirming precise mechanical compartmentalization. The hydrogels displayed tunable swelling behavior and degradation profiles depending on the formulations. Additionally, all single- and multilayer hydrogels maintained high cytocompatibility (>90% NIH/3T3 mice fibroblast viability) independent of polymer concentration, thiol-ene ratios, or layering. Incorporation of alginate microparticles provided an additional strategy for modulating hydrogel properties, significantly reducing swelling and enhancing stiffness while preserving structural integrity. Overall, the findings established a platform for engineering heterogeneous hydrogel constructs with spatially controlled properties, biofunctionality, and compatibility features that make them relevant for biomedical applications.

Keywords:  Michael addition; biomaterials; compartmentalization; interfacial adhesion; multilayer hydrogel; off-stoichiometry thiol–ene; spatially controlled mechanics

DOI:  https://doi.org/10.1021/acsapm.6c01912
Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2528342123

Initiation of rotational collective migration in Drosophila through tissue geometry and mechanochemical feedback.

Sierra Schwabach, Sreejith Santhosh, Audrey Miller Williams, Maureen Cetera, Mattia Serra, Sally Horne-Badovinac.

  Collective migration of epithelial cells drives diverse tissue remodeling processes. In many cases, a free tissue edge works alone or in combination with other external cues to align the cells for collective movement, but how edge-free or closed epithelia become polarized for directed migration without these cues is unclear. Here, we use the rotational migration of the follicular epithelial cells in the Drosophila egg chamber to explore how cells in an edgeless epithelium initiate rotational collective migration, and how the rotational axis is specified. By employing methods for long-term live imaging and delaying the onset of rotation, we show that symmetry breaking can occur at multiple developmental stages and that the atypical cadherin Fat2 promotes local motility at the basal epithelial surface before rotation begins. We then combine experiments with theoretical modeling to identify a positive feedback loop in which planar polarization of Fat2 aligns the front-rear axes of the individual cells in a common direction and the resulting tissue motion leads to the planar polarization of Fat2. This mechanosensitive feedback, coupled with rigid-body dynamics of the egg chamber, can break chiral symmetry and produce sustained rotation in silico. We further propose that mechanical constraints arising from intertissue interactions and tissue geometry ensure that rotation occurs around the anterior-posterior axis. Our findings suggest a biophysical mechanism-combining Fat2-mediated velocity-polarity alignment, rigid-body dynamics, and tissue geometry-by which a closed epithelial tissue can self-organize into persistent, large-scale rotational migration in vivo, expanding current flocking theories.

Keywords:  chiral symmetry breaking; collective cell migration; epithelium; mathematical modeling; self-organization

DOI:  https://doi.org/10.1073/pnas.2528342123
Biochem Biophys Res Commun. 2026 Aug 19. pii: S0006-291X(26)01229-5. [Epub ahead of print]834 154465

Tumor microenvironment and its implications for atomic force microscopy-based nanomechanics of cancer cells: a perspective.

Mi Li, Lianqing Liu.

  Forces are crucial for regulating physiological and pathological processes, and in particular, the mechanical phenotype of cancer cells has been appreciated as a promising biomarker that complements traditional biological features. Over the past few decades, atomic force microscopy (AFM)-based force spectroscopy has been widely used as an important method to characterize the nanomechanical properties of cancer cells, remarkably enhancing our understanding of tumorigenesis and metastasis from the biophysical perspective and making significant contributions to the field of cancer mechanobiology. Concurrently, it is increasingly apparent that tumor microenvironment is not a passive bystander but plays a pivotal role in shaping cancer cell functions and promoting tumor development. Nevertheless, the effect of the tumor microenvironment on cancer cell mechanics has long been omitted in experiments utilizing AFM to perform force measurements on cancer cells. The tumor microenvironment differs extensively from the healthy tissue in composition and structure, including altered extracellular matrix (ECM), aberrant blood vessels/lymphatic vessels, and the existence of diverse recruited cells (such as stromal cells and immune cells), which endows the tumor microenvironment with a variety of unique characteristics (e.g., solid stress, interstitial fluid pressure, hypoxia, acidity). Therefore, conducting AFM measurements on cancer cells under conditions resembling the tumor microenvironment is beneficial for exploring the faithful mechanical phenotype of cancer cells. There are emerging studies incorporating tumor microenvironmental cues into AFM detection of cancer cells, yielding additional insights into the mechanical behavior of cancer cells for a comprehensive understanding of tumor pathogenesis. This Perspective highlights the importance of considering tumor microenvironment in AFM-based nanomechanical analysis of cancer cells and discusses the future directions for advancing physical oncology.

Keywords:  Atomic force microscopy; Cancer cell; Mechanobiology; Nanomechanical analysis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrc.2026.154465
ACS Macro Lett. 2026 Aug 18. 15(8): 1093-1100

Effects of Concentration, Cross-Linking, and Compression on Macromolecular Partitioning in Biological Hydrogels.

Dan Wang, Juan Pablo Arango Velasquez, Matthew J Gust, Rishi Dhayananth, Joseph Farroha, Daniel Lee, Nafi Bassoum, Caroline Calodney, Grace Castellano, John Castellano, Saran Diakite, Sena Gebreyesus, Lucas Klingele, Mauricio Lahera-Castillo, Patrick Megahan, Hafsa Musa, Katherine Neviaser, Maxi Ortiz, Priya Rangi, Richard S Nho, Matthew A Reilly, Nicholas Ferrell.

Transport of macromolecules in biological hydrogels is important for understanding delivery, distribution, and movement of growth factors, cytokines, and peptide- or protein-based drugs within and between biological tissues. This is primarily mediated by basement membranes and extracellular matrixes that separate tissue compartments and structurally support the extracellular microenvironment. Changes in the extracellular matrix (ECM) architecture alter molecular transport and have implications for delivery of biologically active agents in both normal and pathological settings. Matrix density and cross-linking are altered in cancer, fibrotic diseases, and diabetes. Under physiological conditions, ECMs may be compressed to varying degrees under normal or pathological stresses. Here we used multiple biological hydrogels including agarose, collagen I, and Matrigel to understand the relative effects of concentration, cross-linking, and compression on nanoscale molecular transport. We hypothesized that increasing concentration, enzymatic cross-linking, and imparting gel compression would all result in reduced molecular partitioning into hydrogels due to reductions in gel porosity. We found that concentration and compression had significant impacts on molecular partitioning into hydrogels. Cross-linking with multiple enzymatic and chemical cross-linkers increased gel stiffness but had minimal impact on diffusion-based molecular transport. These results indicate that changes in matrix architecture due to increased concentration or reductions in porosity induced by mechanical compression, but not cross-linking, significantly alter macromolecular transport in biological hydrogels.

DOI: https://doi.org/10.1021/acsmacrolett.6c00249
Lab Chip. 2026 Aug 19.

EnView: a tunable microphysiological platform with human crypt-scale topography and independent apical-basal flow for long-term culture and imaging of colonic epithelial monolayers.

Duvan Rojas-Garcia, Dimitri Hamel, Julie Foncy, Marie Hut, Christophe Thibault, Dior Sambe, Sandra Pefaure, Muriel Quaranta-Nicaise, Lauriane Onfroy-Roy, Laurent Malaquin, Audrey Ferrand.

Microphysiological systems (MPS) can improve intestinal epithelial modelling by combining 3D topographical cues, extracellular matrix mechanics and controlled apical-basal access. We present the EnView system, an imaging-compatible microphysiological platform configured to integrate human colon-inspired crypt-scale topography, tunable matrix stiffness and independent perfusion of apical/luminal and basal/stromal compartments. Crypt-like structures were molded in an interpenetrating polyacrylamide/collagen type I hydrogel, generating soft and stiff matrices with bulk stiffness values of 3.8 ± 1.8 kPa and 26.2 ± 8.4 kPa. Molecular transport through the hydrogel was characterized using FITC-dextrans of increasing molecular weight, and the experimentally derived diffusion coefficients were implemented in a numerical diffusion model to estimate the time required for soluble mediators to reach defined regions of the epithelial interface. Human colonic epithelial Caco-2 cells were cultured under continuous microfluidic perfusion for up to 21 days. Cells colonized the patterned surface, formed polarized epithelial monolayers and displayed stiffness-dependent morphology, with a more columnar organization on softer matrices highlighting the importance of matrix stiffness on cell morphology. Relative to standard 2D Transwell® conditions, these cultures exhibited increased gene expression of enterocyte markers such as FABP1 (fatty acid binding protein-1), ALPI (intestinal alkaline phosphatase), KRT20 (cytokeratin-20) and VIL1 (villin-1), indicating that the EnView environment supports better epithelial polarization and maturation-associated features compared with conventional Transwell® culture. Basal/stromal TNF-α stimulation induced an apical/luminal measurable epithelial IL8 secretion, demonstrating the capacity of the system for basal stimulation and apical sampling. Our results show the relevance of considering matrix stiffness when modelling the human colon epithelium. This innovative MPS, recapitulating 3D topography, tunable matrix stiffness and continuous microfluidic perfusion, represents a powerful platform for long term culture and in situ imaging of epithelial constructs enabled by active microfluidic control of the apical/luminal and basal/stromal compartments.

DOI: https://doi.org/10.1039/d6lc00192k