bims-ecemfi 2026-03-08 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–03–08
eleven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

The Intersecting Physical Mechanisms That Regulate Cell Viability in 3D Synthetic Hydrogels.
Multiscale mechanisms driving tissue rupture by invading cells.
Adhesion-driven invasion: disentangling the interplay between cell-cell and cell-matrix interactions in cancer cell migration.
Leveraging bond dissociation kinetics to tune shear-thickening behavior in dynamic covalent tetra-PEG hydrogels.
Common Signatures of Altered Gene Regulation and Invasiveness of Different Breast Cancer Cell Lines after Matrix Interface Crossing.
Magneto-mechanics in mechanobiology: enabling remote force transmission to cells and extracellular matrix.
Harnessing Phase Separation for the Development of High-Performance Hydrogels.
Nonlinear elasticity and transition to macroscopic irreversibility in composite hydrogels.
Stress-dependent growth in breast cancer arises from a mechano-osmotic coupling and cell-sizing checkpoint.
Hydrogel-Based Airway-on-Tube With Perfusable Endothelial Lumen and Outward Epithelialization.
Precancerous niche remodelling dictates nascent tumour persistence.

Adv Mater. 2026 Mar 05. e21245

The Intersecting Physical Mechanisms That Regulate Cell Viability in 3D Synthetic Hydrogels.

Nathan R Richbourg, Akaansha Rampal, Adrian Lorenzana, Juan F Flechas-Beltran, Shelly R Peyton.

  Hydrogels restrict protein transport to different extents, with nanoporous synthetic polymer networks providing far less protein permeability compared to microporous biopolymer networks. To evaluate whether reduced permeability was a driving factor in reduced cell viability in synthetic hydrogels, we compared poly(ethylene glycol) vinyl sulfone (PEG-VS) hydrogels with Matrigel to quantify the influences of modulus, transport, and confinement on encapsulated cells. We observed extensive reductions in cell viability when encapsulated in PEG-VS gels compared to Matrigel. In transwell experiments that decouple hydrogel-restricted serum from cell-gel adhesion, serum restriction reduced cell viability, matching the cell viability observed in 3D cultures. Our unique combination of 2D and 3D hydrogel-based cell cultures provides a framework for investigating the intersecting effects of the cell microenvironment's properties on cell viability. This work demonstrates that biomaterial-restricted protein transport is a critical design consideration when using synthetic 3D cell culture hydrogels.

Keywords:  confinement; extracellular matrix; hydrogel design; poly(ethylene glycol); transport

DOI:  https://doi.org/10.1002/adma.202521245
Dev Cell. 2026 Mar 04. pii: S1534-5807(26)00039-0. [Epub ahead of print]

Multiscale mechanisms driving tissue rupture by invading cells.

Selwin K Wu, Fuqiang Sun, Celestine Z Ho, Yuting Lou, Christina Bao-Xian Huang, Mui Hoon Nai, Jingwei Xiao, Murat Shagirov, Jasmine Fei Li Chin, Diana Lim, Suzie Verma, David S P Tan, Philippe Marcq, Alpha S Yap, Chwee Teck Lim, Tetsuya Hiraiwa, Yuan Lin, Boon Chuan Low.

  Cells migrate and invade tissues during development, immune responses, and cancer. Collective invasion is generally understood to be driven by invading cells unjamming and pushing through barriers such as the extracellular matrix and surrounding tissues. Whether these barriers actively contribute to invasion remains unclear. Using ovarian adenocarcinoma spheroids invading mesothelium derived from benign pleural effusions as an experimental model, combined with modeling, we examine invasion across molecular to multicellular scales. We identify intercellular integrin adhesions linking invasive leader cells to the tissue barrier, triggering apical constrictions within the barrier. This constriction shrinks cell-cell contacts, leading to barrier rupture. Thus, the tissue barrier plays a mechanically active role in invasion. Rather than cells pushing through, we find that coordinated subcellular contractility between the invading leader cell and the barrier drives barrier tensile rupture and invasion, independent of a jamming transition. Together, our findings challenge prevailing paradigms of collective cell invasion.

Keywords:  E-cadherin; active wetting; apical constriction; collective cell invasion; integrin adhesion; jamming transition; ovarian cancer metastasis; phase transition; tensile fracture; tissue mechanics

DOI:  https://doi.org/10.1016/j.devcel.2026.01.016
Biophys J. 2026 Feb 27. pii: S0006-3495(26)00146-3. [Epub ahead of print]

Adhesion-driven invasion: disentangling the interplay between cell-cell and cell-matrix interactions in cancer cell migration.

Quirine J S Braat, Klara Beslmüller, Cornelis Storm, Erik H J Danen, Liesbeth M C Janssen.

Metastasis proceeds through the dissemination of cells from the primary tumor into the surrounding extracellular matrix (ECM), initiating further spread throughout the body. The invasion of cancer cells into the ECM is significantly influenced by cell-cell adhesion, cell-matrix adhesion, and the generation of traction forces. However, the complex interplay between these different aspects makes it difficult to disentangle their roles in the invasive process, hampering our mechanistic understanding of collective cell invasion. Here, we combine integrin knockout experiments in Hs578T and 4T1 breast cancer cell lines with a computational cellular Potts model to explore how variations in adhesion and traction may contribute to invasive cell behavior. By tuning the cell-cell and cell-matrix adhesion parameters in our computational model, we identify model parameter regimes consistent with our experimental observations. Our model indicates that strong cell-matrix interactions promote invasion, while strong cell-cell adhesion promotes the formation and dissemination of multicellular clusters. Moreover, our model delineates a threshold for invasion and predicts that tumor morphology - particularly the number of branches from the primary tumor - correlates with its invasive potential, suggesting that morphological tumor features may serve as a proxy for metastasis. Our approach highlights the importance of combining biological experiments with computational and predictive modeling, offering new insights into the mechanisms driving cancer cell migration.

DOI: https://doi.org/10.1016/j.bpj.2026.02.025
Sci Adv. 2026 Mar 06. 12(10): eadz9563

Leveraging bond dissociation kinetics to tune shear-thickening behavior in dynamic covalent tetra-PEG hydrogels.

Anne D Crowell, Jiho Kang, Diana L Conrad, Thomas M FitzSimons, Eric V Anslyn, Delia J Milliron, Adrianne M Rosales.

Dynamic covalent cross-links impart hydrogels with viscoelastic and self-healing properties, motivating applications as biomimetic cell scaffolds and injectable materials. The long bond lifetime results in complex rheological behavior including shear thickening. We hypothesized that this behavior applies broadly across dynamic covalent hydrogels and can be engineered through reaction rate constants. Thus, we synthesized multiarm poly(ethylene glycol) (PEG) hydrogels with conjugate addition, boronate ester, or terpyridine-zinc cross-links, which tune bond dissociation kinetics and hydrogel relaxation times over four orders of magnitude. All formulations exhibited shear thickening, with the onset dictated by the relaxation time. Although multiple mechanisms may underlie this behavior, chain stretching is hypothesized to contribute to shear thickening, as the cross-linking concentration remained constant under shear and networks with more defects correlated with increased shear thickening. These molecular and structural drivers of shear thickening apply across dilute dynamic covalent tetra-PEG hydrogels, clarifying their suitability for applications under shear.

DOI: https://doi.org/10.1126/sciadv.adz9563
Adv Healthc Mater. 2026 Mar 05. e05616

Common Signatures of Altered Gene Regulation and Invasiveness of Different Breast Cancer Cell Lines after Matrix Interface Crossing.

Cornelia Clemens, Hannah Trampert, Nataliia Kotsiuba, Tilo Pompe.

  Interfaces between dense tumor tissue and surrounding more porous healthy tissue have been shown to trigger aggressive phenotypes in transmigrating MDA-MB-231 breast cancer cells, promoting directional migration, proliferation, and chemoresistance. Here, we show that such interface-instructed phenotype switching represents a common feature across triple-negative breast cancer (TNBC) cell lines, highlighting the potential for targeting these matrix interfaces in therapeutic approaches. Using a biomimetic collagen I interface model, we compared the different breast cancer cell lines, namely, MDA-MB-231, SUM159PT, and Hs578T, during the transmigration process. The interface-induced trigger of invasiveness was more pronounced in MDA-MB-231 and SUM159PT cells. RNA sequencing revealed shared transcriptional response in all three cell lines, with 228 commonly regulated genes and enrichment of pathways linked to cell cycle, chromatin organization, and DNA repair. Differences in pathway activation reflected the baseline characteristics of the three cell lines. Together, the results demonstrate that the topological and mechanical stimuli of tissue interfaces in general induce transcriptional reprogramming in TNBC cells with features of higher aggressiveness.

Keywords:  cell migration; extracellular matrix interfaces; invasiveness; phenotype switching; transcriptomic reprogramming; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/adhm.202505616
Biophys Rev. 2025 Dec;17(6): 1837-1862

Magneto-mechanics in mechanobiology: enabling remote force transmission to cells and extracellular matrix.

Daniel Garcia-Gonzalez.

  Mechanobiology explores how cells sense, transmit, and respond to mechanical forces, with the extracellular matrix (ECM) serving as a dynamic interface that governs cellular behavior through stiffness, viscoelasticity, poroelasticity, and topographical cues. Traditional techniques for force application, such as atomic force microscopy, micropipette aspiration, and optical tweezers, have provided foundational insights but are often limited in dimensionality, invasiveness, and capacity to mimic native, time-evolving microenvironments. Magneto-mechanical actuation offers a transformative alternative by enabling remote, reversible, and spatially programmable force delivery to cells and tissues via particle-based, substrate-based, or microrobotic platforms. This review examines ECM structure-function relationships, cellular mechanotransduction via the cytoskeleton and mechanosensitive ion channels, as well as the capabilities and constraints of existing mechanical probing tools. Magneto-mechanical modalities, design considerations, calibration strategies, and integration with real-time biological readouts are then detailed, highlighting their potential to reproduce complex, dynamic mechanical cues relevant to development, disease, and regeneration. Finally, current technical and biological challenges are discussed, proposing bioinspired actuation schemes for temporal mechanical conditioning, and envisioning multiphysics integration as a path toward next-generation mechanomedicine.

Keywords:  Cellular mechanotransduction; Extracellular matrix (ECM); Magnetic actuation; Magneto-active materials; Mechanobiology; Viscoelasticity

DOI:  https://doi.org/10.1007/s12551-025-01379-7
Adv Sci (Weinh). 2026 Mar 02. e00032

Harnessing Phase Separation for the Development of High-Performance Hydrogels.

Yue Shao, Yiming Ma, Baihao Shao, Molly M Stevens.

  Hydrogels are indispensable for the development of next-generation bioelectronics, soft robotics, and biomedical devices, where their mechanical properties determine performance and reliability. Among strategies to enhance hydrogel mechanics, phase separation enables controlled heterogeneity resulting in gel networks that are reinforced by more than just covalent bonds and polymer entanglements. By regulating the demixing of polymer-rich and solvent-rich domains, phase separation leads to architectures that couple strength, elasticity, and dynamic responsiveness. This article reviews the recent advances in designing high-performance phase-separated hydrogels by linking phase separation behavior within polymer networks to emergent properties such as toughness, fatigue resistance, adhesion, and stimuli-responsiveness. We highlight how mesoscale organization governs multifunctional performance and demonstrate how these principles help resolve the key trade-offs in critical applications, such as high-pressure hemostatic sealants, low-impedance bioelectronics, perfusable tissue engineering scaffolds, and adaptive soft robotics. Finally, we discuss critical challenges, including in situ characterization and scalability, and future opportunities like machine-learning-guided design, which are essential to translate phase separation from a materials heuristic into design rules for reliable, high-performance hydrogel materials.

Keywords:  hydrogel; phase separation; polymer; soft robotics; wearable sensors

DOI:  https://doi.org/10.1002/advs.202600032
Soft Matter. 2026 Mar 03.

Nonlinear elasticity and transition to macroscopic irreversibility in composite hydrogels.

Ippolyti Dellatolas, Thibaut Divoux, Emanuela Del Gado, Irmgard Bischofberger.

Filler-hydrogel composites combine enhanced mechanical properties with functionalities conferred by the nanofillers. When the nanofillers interact attractively with the hydrogel matrix, even low nanofiller volume fractions can lead to a strong increase in the linear viscoelastic moduli. Here, we build on our understanding of the microscopic phenomena at play in these systems to explore their nonlinear response, using attractive nanofillers embedded in a gelatin matrix. We identify a critical deformation beyond which the material no longer recovers its macroscopic viscoelastic properties, marking the onset of macroscopic irreversibility. Increasing nanofiller volume fraction leads to nanofiller-induced stiffening of the polymer matrix, yet the overall viscoelastic response of the composites remains qualitatively similar to that of pure hydrogels: under increasing strain amplitude, their elastic and viscous moduli, G' and G″, exhibit a pronounced overshoot followed by a crossover associated with yielding. A transition occurs in the composite at the strain amplitude where G' reaches its maximum, characterized by a marked change in the stress relaxation dynamics. Beyond , the composites no longer recover their initial viscoelastic properties in repeated strain amplitude sweeps, indicating that the material has sustained macroscopically irreversible changes and a permanent loss of elasticity. We thus identify three distinct regimes in the strain-stiffening materials: nonlinear elasticity, macroscopic irreversibility, and yielding. We further suggest that the plasticity underpinning macroscopic irreversibility is due to the breaking of bonds that contribute most to the composite's strain stiffening response in the hydrogel matrix.

DOI: https://doi.org/10.1039/d5sm00990a
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2523159123

Stress-dependent growth in breast cancer arises from a mechano-osmotic coupling and cell-sizing checkpoint.

Irish Senthilkumar, Jef Vangheel, Vatsal Kumar, Laoise McNamara, Bart Smeets, Enda Howley, Eoin McEvoy.

  Mechanoresponsive cell proliferation is a feature of growing tumors, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behavior have not yet been established. In this study, we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodeling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analyzed through a neural-network-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extracellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analyzing growth in a wider range of normal and malignant biological tissues.

Keywords:  cancer mechanobiology; discrete cell modeling; stress-dependent growth

DOI:  https://doi.org/10.1073/pnas.2523159123
Adv Mater. 2026 Mar 02. e23588

Hydrogel-Based Airway-on-Tube With Perfusable Endothelial Lumen and Outward Epithelialization.

Ali Doryab, Jack F Murphy, Michael Bartolf-Kopp, Jenny C-C Hsin, Alice Chernaik, Frank McCaughan, Yan Yan Shery Huang, Tomasz Jungst, Jürgen Groll.

  Chronic lung diseases are a leading cause of mortality worldwide, yet therapeutic options remain limited. A major barrier to pulmonary drug development is the lack of preclinical models that recapitulate lung complexity. While recent airway-on-chip models have advanced by integrating vascular and extracellular matrix (ECM) components, these are largely limited to planar configurations. Only a few tubular designs exist, yet they generally lack a perfusable vascular compartment that supports dynamic endothelial-epithelial interactions. To address this gap, we introduce an airway-on-tube that integrates an engineered ECM (EnECM) hydrogel, tuned to match lung tissue stiffness, with a tubular melt electrowritten (MEW) scaffold. The MEW reinforces the EnECM hydrogel for dynamic culture without affecting cell behavior. The tubular EnECM/MEW construct incorporates patient-derived primary human lung microvascular endothelial cells embedded within the EnECM hydrogel, forming a perfusable endothelial lumen, while primary human bronchial epithelial cells are cultured on the outer (abluminal) surface, establishing an outward-facing epithelium at the air-liquid interface (ALI). Pulsatile perfusion through the endothelial lumen delivers nutrients and mechanical cues (shear stress and cyclic stretch) while maintaining ALI culture. Together, this study establishes a versatile hydrogel-based platform for next-generation airway-on-chip models, opening new opportunities for preclinical lung research and precision therapeutic development.

Keywords:  airway‐on‐chip; air–liquid interface (ALI); engineered extracellular matrix hydrogel; melt electrowriting (MEW); tubular geometry

DOI:  https://doi.org/10.1002/adma.202523588
Nature. 2026 Mar 04.

Precancerous niche remodelling dictates nascent tumour persistence.

G Skrupskelyte, J E Rojo Arias, H Ajith, Y Dang, D Rossetti, S Han, M K S Tang, M T Bejar, B Colom, J C Fowler, K Murai, W Knight, D Aust, M H H Schmidt, J Jászai, S Zeki, A Noorani, P H Jones, S Rulands, B D Simons, M P Alcolea.

Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1-3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.

DOI: https://doi.org/10.1038/s41586-026-10157-8