bims-ecemfi 2025-11-23 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–11–23
twenty-two papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Deep learning reveals how cells pull, buckle, and navigate fibrous environments.
Independent Tuning of Stiffness and Pore Size in 3D Rat Tail Collagen I Matrices.
Rotational migration in human pancreatic ductal organoids depends on actin and myosin activity.
Hydrogels with Hierarchical Hydrogen Bonds Enable Tunable Stress Relaxation to Direct Macrophage-Driven Immunoregulation.
T Cells Tear Apart Confining Extracellular Matrix Via a Breaststroke-like Motion to Generate Migration Paths.
Inter-Spheroid Proximity and Matrix Remodeling Determine Cancer Associated Fibroblast Mediated Cancer Cell Invasion.
Matrix viscoelasticity regulates dendritic cell migration and immune priming.
Collagen nanofiber alignment attenuates leader-follower energetic and metabolic differences during collective migration in pancreatic cancer.
Collagen-Based Tumor Spheroid Model for Investigating Tumor-Macrophage Interactions through Extracellular Matrix Remodeling.
Dynamic cell patterning and photopolymerization with electric field modulation for constructing hierarchical tumor microenvironments.
Matrix composition and glucose availability cooperatively determine cancer spheroid bioenergetics in 3D hydrogels.
Enhanced Spreading of Viscous Macromolecular Fluids on Phase-Separated Aqueous Interfaces.
Macrophages Mediate Mesoscale Brain Mechanical Homeostasis.
Intermediate filaments promote glioblastoma cell invasion by controlling nuclear deformations and mechanosensitive expression of MMP14.
A microfluidic rheometer for tumor mechanics and invasion studies.
Bicontinuous Interconnected Porous Biomaterials for Tissue Engineering and Regeneration.
Hydrostatic pressure from basal side promotes cancer proliferation, enhances migration and alters cell polarity: a model of the effects of interstitial fluid pressure in tumor microenvironment.
Chemical signaling in reaction networks generates corresponding mechanical impulses.
3D pore shape is predictable in randomly packed particle systems.
Fiber-Tip Shear Force Probe for Single-Cell Adhesion Force Measurements.
Increasing the dimensionality of transistors with hydrogels.
Polyrotaxanes Send Shuttling Signals.

Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2424047122

Deep learning reveals how cells pull, buckle, and navigate fibrous environments.

Abinash Padhi, Arka Daw, Atharva Agashe, Medha Sawhney, Maahi M Talukder, Mehran M H Pour, Mohammad Jafari, Guy M Genin, Farid Alisafaei, Sohan Kale, Anuj Karpatne, Amrinder S Nain.

  Cells in tissues navigate fibrous environments fundamentally differently than they do on flat substrates, but the establishment of cell forces in physiological fibrous settings remains poorly understood. Although factors such as the stiffness of the extracellular matrix (ECM) are known to drive behaviors, including cell motility on flat nonfibrous substrates, the interplay between fiber architecture and stiffness in fibrous ECM is not known. Here, we find that in fibrous environments, the directionality of mechanical forces overrides ECM stiffness as the primary regulator of contractility in migrating cells. Using an approach combining phase microscopy with deep learning to map forces in real time, termed deep learning-enabled live-cell fiber-force microscopy (DLFM), we reveal that when cells transition between anisotropic and isotropic stress fields, their contractility significantly drops despite encountering stiffer ECM, contrary to the behavior of cells on flat nonfibrous substrates. Unlike the peripheral adhesions observed on flat nonfibrous substrates, cells in fibrous matrices form force-generating adhesions throughout their body, stabilized by out-of-plane mechanical components unique to fiber geometry. Cells exhibit distinct force signatures during migration, division, and differentiation, with temporal signatures that predict stem cell fate. These findings, enabled by combining deep learning and the mechanics of cells and fibers, explain long-standing paradoxical behavior of cells navigating deformable fibrous environments, how they can pull and tug at them, and identify tension anisotropy as a master regulator of cell behavior, with implications for cancer invasion, tissue engineering, and regenerative medicine.

Keywords:  cell-fiber interactions; focal adhesions; machine learning; mechanobiology; traction force microscopy

DOI:  https://doi.org/10.1073/pnas.2424047122
bioRxiv. 2025 Oct 04. pii: 2025.10.02.680089. [Epub ahead of print]

Independent Tuning of Stiffness and Pore Size in 3D Rat Tail Collagen I Matrices.

Theadora Vessella, Qi Wen, Hong Susan Zhou.

The interplay between the extracellular matrix (ECM) mechanical properties and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression. Three-dimensional (3D) culture systems have emerged as essential platforms for in-vitro cell-based applications, offering microenvironments that are more physiologically relevant compared to traditional two-dimensional (2D) cultures. However, independently controlling the topological and mechanical features of 3D matrices remains challenging due to the interdependence of these parameters. In this study, we demonstrate a method for independently tuning pore size and stiffness in collagen I (Coll I) networks and examine their effects on breast cancer and epithelial cell morphology and cluster formation. Collagen concentration was used to modulate bulk stiffness, while polymerization temperature was adjusted to control pore size. Using this approach, we developed a 3D Coll I matrix with tuned stiffnesses from 80, 228 and 360 Pa while simultaneously holding pore size constant (2.5 µm). Similarly, we developed a low- (1.5 mg/mL) and high- (3.5 mg/mL) concentration collagen hydrogel with varying pore sizes from 2.5 µm to 3.1 µm and 2.0 µm to 2.4 µm, respectively, without altering stiffness (80 Pa and 350 Pa). Integrating a breast epithelial cell line, MCF-10A, and metastatic breast cancer cell line, MDA-MB-231, we demonstrate matrix stiffness and pore size independently and differentially regulate cell morphology and cluster formation. Our results establish a robust method for decoupling stiffness and pore size in Coll I matrices enabling more precise investigations into how ECM mechanical properties influence metastatic and epithelial cell behavior.
Statement of Significance: This study presents a robust method to independently tune stiffness and pore size in 3D collagen I matrices, overcoming a key challenge in extracellular matrix modeling. By decoupling these parameters through collagen concentration and polymerization temperature, the platform enables more accurate investigation of how ECM mechanical properties influence metastatic and epithelial cell behavior. Our finding reveals that matrix stiffness and pore size independently and differentially regulate cell morphology and cluster formation, demonstrating the distinct cellular responses to specific ECM properties and underscoring the importance of the tumor microenvironment in cancer biology and tissue engineering.

DOI: https://doi.org/10.1101/2025.10.02.680089
ArXiv. 2025 Sep 30. pii: arXiv:2509.25680v1. [Epub ahead of print]

Rotational migration in human pancreatic ductal organoids depends on actin and myosin activity.

Gengqiang Xie, Chaity Modak, Olalekan H Usman, Raphael Wf Tan, Nicole Coca, Gabriela De Jesus, Yue Julia Wang, D Thirumalai, Xin Li, Jerome Irianto.

Rotational migration is one specific form of collective cell migration when epithelial cells are confined in a spherical geometry, such as in the epithelial acini. This tissue-level rotation motion is crucial for the morphogenesis of multiple epithelial systems. Here, we introduce a new primary human model for the study of rotational migration, pancreatic ductal organoids. Live imaging revealed the persistent rotation of the organoids over time. By tracking the nuclei, the three-dimensional trajectory of the cellular movement was reconstructed and the velocity of the rotation was quantified. The presence of focal adhesion clusters and prominent actin stress fibers were observed at the basal side of the organoids, suggesting the interactions between the cells and the surrounding extracellular matrix. Finally, our inhibition study showed the dependence of pancreatic ductal organoid rotational migration on myosin activity, actin polymerization, and actin branching. We hope that this model will enable future studies with human primary cells, which are more faithful to normal epithelial cells.
Acta Biomater. 2025 Nov 18. pii: S1742-7061(25)00848-7. [Epub ahead of print]

Hydrogels with Hierarchical Hydrogen Bonds Enable Tunable Stress Relaxation to Direct Macrophage-Driven Immunoregulation.

Xiaoman Han, Xueying Yang, Reifeng Zhang, Kaiwen Chen, Chuanfeng An, Dawei Li, Shuang Guo, Fei Shao, Chengze Li, Yi Shen, Yue Zhang, Qiwei Ying, Huanan Wang.

  Matrix viscoelasticity as the typical mechanical feature of the extracellular matrix (ECM) of living tissues has been recently identified to impose profound impact on cellular behavior and functionalities. However, their effect on macrophages and the related inflammatory responses have been rarely explored, in which a major hurdle is the lack of candidate ECM-mimicking biomaterials with independently fine-tunable viscoelasticity. Herein, we developed a class of photopolymerizable hydrogels based on hierarchical hydrogen bond (H-bond) design to enable controllable stress relaxation behavior. Specifically, acrylamide (AM) and N-acryloyl glycinamide (NAGA) monomers were polymerized to form hydrogel networks consisting of varying ratio of single H-bond by AM and dual H-bond by NAGA, thus hydrogels with tunable stress relaxation rate but constant matrix elasticity can be developed via mediating monomer mixing ratios and polymerization degree. We further revealed that slower stress relaxation induced macrophage towards pro-inflammatory M1 polarization, while faster stress relaxation stimulated macrophage to polarize towards anti-inflammatory M2 phenotype. In vivo subcutaneous implantation of different hydrogel matrices using a mice model showed similar impact on host immune responses, as evidenced by severer inflammation characterized by thicker fibrosis encapsulation for matrix with slower stress relaxation than the faster ones. In general, we demonstrate that matrix viscoelasticity can significantly affect macrophage-mediated inflammatory responses, which provides new insights for the design and applications of implantable biomaterials. STATEMENT OF SIGNIFICANCE: This work revealed how extracellular matrix viscoelasticity characterized by stress relaxation rate can significantly impact macrophage polarization and inflammatory responses, which has rarely been explored previously. We proposed an innovative and ease-of-preparation class of copolymer hydrogels based on tailoring the mixing ratio of acrylamide (AM) and N-acryloyl glycinamide (NAGA) monomers, wherein matrix with fine-tunable stress relaxation rates can be achieved via controlling the combination of singular or dual hydrogen bonds. We further demonstrated that slower stress relaxation induced macrophage towards pro-inflammatory M1 polarization, while faster stress relaxation stimulated macrophage to polarize towards anti-inflammatory M2 phenotype. Our study suggests matrix viscoelasticity can significantly affect macrophage-mediated inflammatory responses, and provides new insights for the design and applications of implantable biomaterials.

Keywords:  hierarchical hydrogen bonds; inflammation; macrophage polarization; stress relaxation; viscoelasticity

DOI:  https://doi.org/10.1016/j.actbio.2025.11.024
bioRxiv. 2025 Oct 05. pii: 2025.10.03.680352. [Epub ahead of print]

T Cells Tear Apart Confining Extracellular Matrix Via a Breaststroke-like Motion to Generate Migration Paths.

Byunghang Ha, Peter Xie, Benjamin Johns, Cole Allan, Maria Korah, Daniel Delitto, Paul Bollyky, Natalie Torok, Ovijit Chaudhuri.

T cells migrate through soft tissues to target infected and abnormal cells and regulate immunity. T cell migration is typically studied in microfluidic devices or other contexts where there is a pre-existing migration path; how they create paths in confining nanoporous extracellular matrices (ECM), such as can occur during fibrosis and around tumors, remains unclear. Here, we studied T cell migration in confining collagen-rich matrices with a range of stiffness, viscoelasticity, mechanical plasticity, and shear strength, or the stress at which the material fails. Strikingly, only shear strength, the stress at which a material fails, not stiffness or viscoelasticity, correlates with migration. During migration, T-cells extend thin actin-rich, finger-like protrusions into the ECM, which then undergo a divergent breaststroke-like motion. Thus, T cells tear apart confining matrices using a breaststroke-like motion to generate migration paths.

DOI: https://doi.org/10.1101/2025.10.03.680352
Acta Biomater. 2025 Nov 19. pii: S1742-7061(25)00850-5. [Epub ahead of print]

Inter-Spheroid Proximity and Matrix Remodeling Determine Cancer Associated Fibroblast Mediated Cancer Cell Invasion.

Pranav Mehta, Ankur Deep Bordoloi, Cor Ravensbergen, Ma Kristen H David, Wilma Mesker, Gerrit Jan Liefers, Peter Ten Dijke, Pouyan E Boukany.

  Breast cancer is the most commonly diagnosed malignancy worldwide, with molecular subtypes following distinct clinical trajectories. While Luminal A breast cancers are typically indolent, a subset enriched in α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) exhibits aggressive behavior, facilitating tumor invasion. However, the biophysical mechanisms by which CAFs drive invasion and extracellular matrix (ECM) remodeling remain unclear. In addition, the temporal and spatial dynamics of CAF interactions with the collagen matrix and cancer cell spheroids remain unknown, raising the question of whether these processes follow a deterministic sequence or occur stochastically. To address this, we conducted histological analysis of Luminal A tumors, which revealed variation in CAF, cancer cell, and ECM organization at tumor boundaries. To assess the impact of CAF on cancer cell invasion, we use a 3D in-vitro model co-embedding 19TT breast CAF and MCF7 luminal breast cancer spheroids within a three-dimensional (3D) collagen-I hydrogel and performed time-lapse imaging. We demonstrate that inter-spheroid distance critically determines 19TT CAF-induced MCF7 spheroid behavior. Moreover, we showed that CAF-mediated collagen matrix remodeling and degradation precedes observed MCF7 spheroid disruption and is critical in promoting cancer cell spheroid expansion and cell dissemination. While broad-spectrum matrix metalloproteinase inhibition suppressed CAF-driven collagen degradation and MCF7 spheroid expansion, it did not prevent ECM remodeling, CAF migration, or single-cell dissemination of cancer cell spheroids. Furthermore, a complementary heterospheroid model revealed similar ECM remodeling and invasion dynamics despite altered cellular arrangement of cancer cells and CAFs. Our findings enhance our understanding of the relationship between CAF activity and collagen matrix remodeling processes that promote cancer cell invasion, providing insights into the potential therapeutic benefits of targeting CAFs in breast cancer treatment. STATEMENT OF SIGNIFICANCE: This research provides key insights into breast cancer-associated fibroblasts (CAFs) mediated remodeling of the extracellular matrix (ECM) and subsequent breast cancer cell dissemination and invasion. Herein, we demonstrated that CAFs remodel collagen fibres before migration and matrix metalloproteinase (MMP)-mediated degradation. Using a 3D in-vitro model, we showed that cancer cell spheroid expansion and single-cell dissemination are governed by distinct mechanisms: while expansion depends on collagen matrix integrity, dissemination relies on CAF-driven collagen remodeling. These findings advance our understanding of the relationship between CAF activity and collagen matrix remodeling processes that promote cancer cell invasion, providing insights into the potential therapeutic benefits of targeting CAFs in breast cancer treatment.

Keywords:  Cancer-Associated Fibroblasts (CAFs); breast cancer; cancer cell invasion; collagen; extracellular matrix (ECM); heterogeneous spheroids; matrix remodeling

DOI:  https://doi.org/10.1016/j.actbio.2025.11.027
bioRxiv. 2025 Sep 30. pii: 2025.09.28.678961. [Epub ahead of print]

Matrix viscoelasticity regulates dendritic cell migration and immune priming.

Wei-Hung Jung, Emie Humann, Joshua M Price, Yoav Binenbaum, Azra Haseki, Sanjana Iyer, Daivd J Mooney.

The tumor microenvironment shapes immune surveillance through its mechanical properties, yet the role of matrix viscoelasticity remains unclear. Here, we used a collagen system with tunable viscoelasticity to define how matrix relaxation directs dendritic cell (DC) behavior. Elastic matrices impaired DC migration by limiting actomyosin-driven collagen remodeling, thereby reducing DC-T cell encounters and weakening T cell priming, activation, proliferation, and tumor killing. Blocking DC migration in fast-relaxing gels recapitulated key aspects of the impaired T cell priming seen in elastic matrices. Prolonged confinement in elastic extracellular matrix induced a mechanomemory state, locking DCs into reduced motility even after transfer to viscoelastic environments, corresponding to altered chromatin accessibility. Finally, studies with patient-derived ependymoma samples confirmed these findings, identifying viscoelasticity as a barrier to antitumor immunity with implications for therapeutic intervention.

DOI: https://doi.org/10.1101/2025.09.28.678961
Acta Biomater. 2025 Nov 19. pii: S1742-7061(25)00853-0. [Epub ahead of print]

Collagen nanofiber alignment attenuates leader-follower energetic and metabolic differences during collective migration in pancreatic cancer.

Madison R Pickett, Mohini Kamra, David A Castilla-Casadiego, Sepehr Noori, William Matsui, Adrianne M Rosales, Janet Zoldan, Sapun H Parekh.

  The extracellular matrix (ECM) is a dynamic microenvironment that influences cell behavior and fate, with changes in its architecture linked to processes such as differentiation and disease progression in cancer. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer associated with a dense ECM composed of collagen I fibers. While considerable research on PDAC metastasis has focused on single-cell migration, recent studies suggest PDAC cells undergo a process called "collective migration" as groups. This study investigates PDAC migration and metabolism on electrospun collagen I nanofiber meshes. A 3D-printed, removable insert is used to create a gap-like a scratch-that allows for analysis of cell migration on intact fibers. By tuning nanofiber orientation, this study replicates the PDAC ECM during stromal remodeling to assess cellular metabolism and the energetic state of leader and follower cells during migration. Interestingly, the data suggests that nanofiber architecture strongly modulates differences between PDAC leader and follower cells during collective migration. While leader cells require more ATP and rely more on oxidative phosphorylation in both conditions, this reliance is particularly pronounced in the random condition. These findings underscore the interplay between collective migration, ECM architecture, and metabolism in PDAC migration. STATEMENT OF SIGNIFICANCE: The role of the stromal extracellular matrix (ECM) in metastasis and migration is well studied, yet its impact on metabolic processes underlying metastasis, especially in pancreatic ductal adenocarcinoma (PDAC), remains unclear. PDAC is marked by high metastasis rates and a densely fibrotic ECM, with increased collagen alignment correlating to poor prognosis. In this study, we explore how ECM architecture, represented by near-native electrospun collagen nanofibers, influences collective migration and metabolism in PDAC. Our findings show that increased collagen alignment reduces metabolic differences, including ATP/ADP ratio, gene expression, and mitochondrial membrane potential, between leader and follower cells during migration. This is the first study to investigate leader-follower dynamics in PDAC collective migration using tunable, stromal-mimicking, fibrous substrates.

Keywords:  cancer metabolism; extracellular matrix (ECM); migration; nanofibers; pancreatic ductal adenocarcinoma (PDAC)

DOI:  https://doi.org/10.1016/j.actbio.2025.11.031
bioRxiv. 2025 Oct 03. pii: 2025.10.01.679587. [Epub ahead of print]

Collagen-Based Tumor Spheroid Model for Investigating Tumor-Macrophage Interactions through Extracellular Matrix Remodeling.

Luna Zhang, Sanab Abdi, Hannah M Szafraniec, Paolo P Provenzano, Kathryn L Schwertfeger, David K Wood.

  Macrophages in the tumor microenvironment (TME) can constitute up to 50% of tumor mass and play a critical role in cancer cell proliferation, invasion, and metastasis. While their contribution to extracellular matrix (ECM) degradation through matrix metalloproteinases (MMPs) has been explored, the role of other macrophage-derived factors in ECM remodeling and their impacts beyond degradation remain poorly understood. Here, we describe the development of a 3D collagen-based tumor spheroid model to investigate the impact of peripheral blood mononuclear cell (PBMC)-derived macrophages on cancer cell-ECM and cancer cell-macrophage interactions within the TME. We observed that cancer cells stimulated PBMC-derived macrophages into an M2-like phenotype and that tumor spheroid conditioned macrophages (TSCMs) shifted cancer cell populations toward phenotypes with greater invasion distances and reduced circularity, indicative of increased malignancy. Such observations can be explained by macrophage-mediated ECM remodeling. Specifically, we demonstrate that TSCMs secreted a variety of soluble factors that are known to contribute to ECM remodeling, including ECM degradation and fiber realignment. These processes collectively create a tumor-favoring environment by loosening the collagen matrix and aligning fibers that serve as invasion tracks for migrating tumor cells that facilitate cancer cell migration and invasion. This model provides a robust platform to study the interactions between cellular and non-cellular components in the TME and to identify the molecular mechanisms underlying cancer progression. These insights may aid in the development of novel therapeutic strategies targeting macrophage-mediated processes in cancer.

Keywords:  ECM remodeling; Macrophages; Tumor microenvironment; Tumor spheroid model

DOI:  https://doi.org/10.1101/2025.10.01.679587
Acta Biomater. 2025 Nov 13. pii: S1742-7061(25)00843-8. [Epub ahead of print]

Dynamic cell patterning and photopolymerization with electric field modulation for constructing hierarchical tumor microenvironments.

Anping Wu, Yanfeng Zhao, Xinyi Dong, Jiaxin Liu, Zhiqiang Zheng, Qing Shi, Toshio Fukuda, Huaping Wang.

  Engineered tumor models that replicate the hierarchical, heterogeneous microenvironment of in vivo tumors have shown huge potential in biomedical and clinical research. Tumor spheroids are widely used as in vitro models to investigate tumor pathophysiology. However, due to the complex cell-cell and cell-extracellular matrix (ECM) interactions in native tumor tissues, tumor spheroids alone often fail to replicate the intricate architecture and functionality of the tumor microenvironment (TME). Here, we propose a versatile strategy that assembles tumor spheroids while simultaneously constructing individualized ECM-mimicking environments, thereby more accurately replicating the native hierarchical TME. By applying a uniform electric field, the wettability of cell-laden hydrogel droplets is modulated, enabling their transport to predefined locations. Once positioned, a non-uniform electric field induces dielectrophoresis (DEP), guiding the cells to aggregate into tumor spheroids following predefined patterns. A digital micromirror device (DMD) then dynamically controls the shape and position of ultraviolet (UV) patterns, triggering photopolymerization of the hydrogel and precisely encapsulating the cell spheroids, thereby forming tumor models. In our experiment, breast cancer and liver cancer cells were aggregated to form tumor spheroids that maintained high cell viability, proliferative capacity, and morphological regularity, with the spheroid circularity reaching 0.84. Furthermore, when liver cancer spheroids were encapsulated in hydrogels containing endothelial cells, their invasiveness increased by approximately 77 %. We anticipate that our method will be capable of regenerating more complex tumor models with unprecedented possibilities for future drug discovery. STATEMENT OF SIGNIFICANCE: Reconstructing a hierarchical tumor microenvironment (TME) requires not only the formation of cell aggregates with natural intercellular connections but also the precise spatial organization of stromal cells and extracellular matrix components (ECM). However, achieving such dynamic cellular assembly and controllable heterogeneity during bioprinting remains challenging. Here, we present a multifunctional strategy that integrates dielectrophoretic droplet manipulation into a 3D bioprinting system to induce the in situ formation of compact, viable, and uniform tumor spheroids. Bioinks containing ECM components and stromal cells are then spatially patterned and photopolymerized with high precision to build customizable, biomimetic TMEs. This approach provides a versatile and controllable platform for drug screening, cancer research, and personalized medicine.

Keywords:  Bioprinting; Cellular microassembly; Photopolymerization; Tumor microenvironment reconstruction; Tumor spheroids

DOI:  https://doi.org/10.1016/j.actbio.2025.11.020
Cancer Metab. 2025 Nov 19. 13(1): 45

Matrix composition and glucose availability cooperatively determine cancer spheroid bioenergetics in 3D hydrogels.

Paula Guerrero-López, Gorana Drobac, Eduardo A Silva, Hanne R Hagland, José Manuel García-Aznar.



Keywords:  3D cell culture; Biomechanical properties; Cancer spheroid; Collagen hydrogels; Extracellular matrix; Fibrin hydrogels; Glucose; Metabolism

DOI:  https://doi.org/10.1186/s40170-025-00413-2
ACS Macro Lett. 2025 Nov 19. 1808-1812

Enhanced Spreading of Viscous Macromolecular Fluids on Phase-Separated Aqueous Interfaces.

Feipeng Chen, Huiyanchen Li, Ho Cheung Shum.

The spreading and wetting of liquids on surfaces are ubiquitous in nature and industrial applications. Conventionally, highly viscous macromolecular fluids (e.g., honey and silicone oils) are hard to spread on various surfaces compared to low viscous fluids, such as water, due to strong viscous resistance at the interface. In this study, we report an opposite phenomenon that highly viscous fluids enriched in poly(ethylene glycol) (PEG) spread over substantially larger areas on immiscible, phase-separated aqueous interfaces than their low-viscosity counterparts. These aqueous interfaces are formed through the liquid-liquid phase separation between PEG of different molecular weights and sodium citrate salts or dextran. Experiments and scaling analysis reveal that this enhanced spreading arises from interfacial tension gradients between the two immiscible aqueous phases, with the spreading capability of fluids quantitatively characterized by the spreading coefficient. Furthermore, we demonstrate that these interfacial gradients arise from the asymmetric partitioning of PEG and its surfactant-like effect in reducing liquid-air interfacial tensions. Together, our work illustrates how macromolecular phase separation could facilitate the spreading of highly viscous fluids, with crucial implications for intracellular liquid-liquid phase separation and various industrial applications.

DOI: https://doi.org/10.1021/acsmacrolett.5c00557
Adv Mater. 2025 Nov 18. e17493

Macrophages Mediate Mesoscale Brain Mechanical Homeostasis.

Woong Young So, Bailey Johnson, Patricia B Gordon, Kevin S Bishop, Hyeyeon Gong, Hannah A Burr, Jack Rory Staunton, Chenchen Handler, Khanh Loan Ly, Raman Sood, Giuliano Scarcelli, Kandice Tanner.

  Mechanical cues orchestrate cellular behavior in the brain, yet how they interface with immune regulation remains unresolved. Here, gigahertz-frequency Brillouin microscopy with optical trap-based active microrheology is integrated to map the mechanical impact of macrophage activity across timescales. It is revealed that microglia, brain's resident macrophages, actively sustain tissue viscoelasticity, rather than quiescently residing within the tissues under normal conditions. Moreover, macrophage colony-stimulating factor 1 receptor (csf1r)-driven stromal remodeling alters brain mechanical properties in vivo. These findings establish a direct link between immune activity, viscoelastic integrity, and structural plasticity of neural tissue. By bridging high-frequency material responses with immune-driven remodeling, the approach provides a framework for decoding how biophysical properties regulate slower-timescale signaling and offers mechanistic insights for increasing the efficacy of csf1r-targeted therapies in cancer and neurodegeneration.

Keywords:  Brillouin microscopy; CSF1R; macrophages; optical tweezer; tissue mechanics

DOI:  https://doi.org/10.1002/adma.202517493
Cell Rep. 2025 Nov 14. pii: S2211-1247(25)01324-5. [Epub ahead of print]44(11): 116553

Intermediate filaments promote glioblastoma cell invasion by controlling nuclear deformations and mechanosensitive expression of MMP14.

Emma J van Bodegraven, Elvira Infante, Florent Peglion, David Pereira, Yekta Kesenci, Vanessa Roca, Isabelle Perfettini, Emmanuel Terriac, Juliana Geay, Laura Soto, Jacqueline Sluijs, Reinier Rietveld, Shailaja Seetharaman, Batiste Boëda, Jean-Christophe Olivo-Marin, Atef Asnacios, Aleix Boquet-Pujadas, Jean-Baptiste Manneville, Sandrine Etienne-Manneville.

  Glioblastoma (GBM), the most aggressive primary brain tumor, is marked by high invasiveness that enables resistance to current therapies. Single-cell RNA sequencing analysis reveals that elevated expression of glial intermediate filament (IF) genes correlates with pro-invasive markers in GBM samples. Notably, vimentin expression correlates with a lower survival rate. Functional assays demonstrate that cytoplasmic IFs, despite reducing GBM cell deformability, enhance 3D invasion both in vitro and in vivo. Mechanistically, IFs support leader cell invasion through mechanosensitive matrix degradation by buffering nuclear deformations under compressive stress. Moreover, IFs correlate with high matrix metalloproteinase (MMP)14 levels in patients and activate MMP14 production in vitro. These findings reveal the crucial role of IFs in promoting GBM cell invasion and suggest that IF expression can serve as a molecular marker of invading GBM cells.

Keywords:  CP: cancer; Vimentin; cellular mechanics; cytoskeleton; glioma; matrix metalloprotease; mechanotransduction; microrheology; spheroids

DOI:  https://doi.org/10.1016/j.celrep.2025.116553
bioRxiv. 2025 Oct 01. pii: 2025.09.29.679368. [Epub ahead of print]

A microfluidic rheometer for tumor mechanics and invasion studies.

Young Joon Suh, Manli Liu, Bangguo Zhu, Mrinal Pandey, Brian Cheung, Jaemin Kim, Nikolaos Bouklas, Chris Roh, Jeffrey E Segall, Chung-Yuen Hui, Mingming Wu.

Clinically, the feel, touch, and shape of a solid tumor are important diagnostic methods for determining the malignant state of the disease. However, there are limited tools for quantifying the mechanics and the malignancy of the tumor in a physiologically realistic setting. Here, we developed a microfluidic rheometer - termed the microrheometer - that enables simultaneous measurements of tumor spheroid mechanics and their invasiveness into a 3D extracellular matrix (ECM). The microrheometer consists of a pneumatic pressure control unit for applying controlled static or cyclic compression to tumor spheroids, and a sample chamber for containing spheroid embedded ECM. The innovation here lies in the integration of a polyacrylamide membrane force sensor within the sample chamber, enabling a direct force measurement in a physiologically relevant setting. We found that both tumor stiffness and the viscoelastic properties of the tumor are closely correlated with tumor invasiveness. The microrheometer allowed us to measure tumor mechanics in a short time (less than a minute) and has the potential to be used clinically in the future. We note that the microrheometer here can be easily extended to studies of mechanics of single cell, nucleus, as well as other cell/tissue types.

DOI: https://doi.org/10.1101/2025.09.29.679368
Small Sci. 2025 Nov;5(11): 2500207

Bicontinuous Interconnected Porous Biomaterials for Tissue Engineering and Regeneration.

Aihik Banerjee, Anjana Khanal, Prince D Okoro, Shankar P Kharal, Kevin Dalsania, Baishali Kanjilal, Shiril B Iragavarapu, Yiqing Chen, Janitha M Unagolla, Huinan H Liu, Joshua T Morgan, Robert P Hesketh, Arash Pezhouman, Reza Ardehali, Bahman Anvari, Martin F Haase, Iman Noshadi.

  Biomaterials mimicking natural extracellular matrix are necessary to create an optimal microenvironment for cell adhesion, migration, proliferation, and differentiation. These scaffolds must possess bicontinuous interconnected porosity to ensure the effective exchange of oxygen, nutrients, and metabolic waste, which are crucial for developing functional tissues. Here, a novel bicontinuous interfacially jammed emulsion (BIJEL)-Integrated PORous Engineered System (BIPORES) is developed to confer bioinert synthetic polyethylene glycol diacrylate (PEGDA) with unique bicontinuous interconnected porosity and surface topography. This platform is fabricated through controlled phase separation and interfacial stabilization of two continuous phases by nanoparticles. Functional validation using human mesenchymal stem cells, and human induced pluripotent stem cells-derived cardiomyocytes and cardiac fibroblasts, reveals outstanding cell attachment, growth, proliferation, and/or differentiation within tissue-scale BIPORES scaffolds. These findings indicate that bicontinuous interconnected porosity with negative Gaussian curvature in the BIPORES scaffolds plays a key role in organ-scale tissue engineering and regeneration.

Keywords:  bicontinuous materials; human induced pluripotent stem cells; interconnected porosity; polyethylene glycol diacrylate; solvent transfer‐induced phase separation

DOI:  https://doi.org/10.1002/smsc.202500207
Mol Biol Cell. 2025 Nov 19. mbcE25050261

Hydrostatic pressure from basal side promotes cancer proliferation, enhances migration and alters cell polarity: a model of the effects of interstitial fluid pressure in tumor microenvironment.

Keisuke Onoi, Aosa Nakamura-Sasada, Shinsaku Tokuda, Mototaka Fukui, Yuki Katayama, Hayato Kawachi, Naoya Nishioka, Masahiro Iwasaku, Toshiyuki Sakai, Tatsuo Furuya, Shunta Ishihara, Satoru Okada, Masayoshi Inoue, Tadaaki Yamada, Koichi Takayama.

The tumor microenvironment contributes to tumorigenesis and tumor progression. Interstitial fluid pressure is elevated in almost all solid malignant tumors, and physical pressure in the tumor microenvironment influences various cancer cell functions, including cell proliferation. However, the direction of the pressure applied to cancer cells has not been considered in previous studies, and the role of physical pressure in the tumor microenvironment in tumor progression remains unclear. Therefore, we investigated the effects of hydrostatic pressure applied to the basal side on lung cancer cells cultured on Transwell filters. Our data show that hydrostatic pressure from the basal side alters various phenotypes of cancer cells, including cell migration, polarity, proliferation, and cell death, all of which are presumed to contribute to tumor progression. These results suggest that physical pressure in the tumor microenvironment provides cancer cells with an advantage in various phenotypes and plays an important role in cancer cell biology. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-05-0261
PNAS Nexus. 2025 Nov;4(11): pgaf330

Chemical signaling in reaction networks generates corresponding mechanical impulses.

Oleg E Shklyaev, Anna C Balazs.

  Chemical reaction networks (CRNs) in the body are directed pathways that transmit reagents to reactive sites and trigger chemical processes, which ultimately instigate the appropriate physical activity. Typically, models for CRNs do not describe the coupling among chemistry, hydrodynamics and fluid-structure interactions that inherently arise in fluids. Herein, we develop a model that describes the above interrelated physicochemical behavior and show that chemical transport in a CRN spontaneously gives rise to transduction of chemistry into mechanical work, to form a complementary chemo-mechanical network (CMN). To simulate CRNs, we use the repressilator model, a reaction pathway involving biomimetic feedback loops. The encompassing material system is formed from an ordered array of enzyme-coated beads that are interlinked to form a flexible network. Coupling of chemistry and hydrodynamics occurs through the solutal buoyancy mechanism where variations in chemical concentration drive the fluid motion that deforms the flexible network of beads. Consequently, this system displays chemo-mechanical transduction as chemical signals in the CRN are converted to mechanical action. Using this model, we design materials systems encompassing CRNs that spontaneously generate CMNs, which perform the mechanical work of transporting particles or morphing the structure of the elastic network. The propagation of chemical signals along CMN that lead to mechanical actions mimic a nervous system, which transmits signals that instruct a responsive musculature.

Keywords:  biomimetic behavior; chemical reaction networks; chemo-mechanical transduction; synchronization of mobile oscillators; synthetic biology

DOI:  https://doi.org/10.1093/pnasnexus/pgaf330
Matter. 2025 Oct 20. pii: 102493. [Epub ahead of print]

3D pore shape is predictable in randomly packed particle systems.

Yasha Saxena, Lindsay Riley, Runxin Wu, Mohammed Shihab Kabir, Amanda Randles, Tatiana Segura.

  Geometric classifications of 3D pores are useful for studying relationships between pore geometry and function in granular materials. Pores are typically characterized by size, but size alone cannot explain 3D phenomena like transport. Here, we implement a KNN-based pore classification approach emphasizing shape-related properties. We find pore types produced in randomly packed systems resemble those of ideal, hexagonally packed systems. In both random and perfect systems, pores tend to configure as octahedrons (O's) and icosahedrons (I's). We demonstrate the physical implications of this by running flow simulations through a granular system and observe differences in fluid dynamic behaviors between pore types. We finally show the O/I pore distribution can be tuned by modifying particle properties (shape, stiffness, size). Overall, this work enables analysis of granular system behaviors by 3D pore shape and informs system design for desired distributions of pore geometries.

Keywords:  Random packing; complex systems; dimensionality reduction; flow; granular materials; material characterization; microstructure; pore classification; pore structure; shape classification

DOI:  https://doi.org/10.1016/j.matt.2025.102493
ACS Sens. 2025 Nov 18.

Fiber-Tip Shear Force Probe for Single-Cell Adhesion Force Measurements.

Mengqiang Zou, Yanping Chen, Yu Liu, Yiping Wang, Changrui Liao.

  Single-cell adhesion studies play a crucial role in cell biology. Cell adhesion measurement methods, such as atomic force microscopy (AFM) technology, can be used to measure the single-cell adhesion force. However, these methods have many limitations, such as complex operations or the need for labeling. In this study, we proposed a miniature fiber-tip shear force probe (FSFP) that can achieve accurate measurement of the single-cell adhesion force under physiological conditions. A shear force probe structure that facilitates lateral manipulation was designed based on the principles of structural mechanics and fabricated integrally at the end face of a single-mode fiber using femtosecond laser two-photon polymerization technology. The relationship between the FSFP spectral output and the applied force was established, and its microforce sensitivity was obtained to be 2.81 nm/μN, a minimal detectable force is 7.1 nN. The achieved overall measurement range of the device is 69 μN. The adhesion force of MCF-7 breast cancer cells was measured under physiological conditions by using the FSFP. Compared to polymer substrates, the average adhesion force of cells was greater on glass substrates with greater stiffness. The average cell adhesion force value decreased by more than two times after trypsin stimulation. In addition, experiments have shown that cells tend to spread into shuttle shapes on glass substrates with greater stiffness and have a denser actin filaments distribution. To the best of our knowledge, this is the first report on the accurate measurement of the single-cell adhesion force using a miniature all-fiber microforce sensor, which is flexible, fast, and label-free, opening new avenues for single-cell analysis.

Keywords:  biosensor; cell adhesion; optical fiber sensor; single-cell analysis; two-photon polymerization

DOI:  https://doi.org/10.1021/acssensors.5c02849
Science. 2025 Nov 20. 390(6775): 824-830

Increasing the dimensionality of transistors with hydrogels.

Dingyao Liu, Jing Bai, Xinyu Tian, Yan Wang, Binbin Cui, Shilei Dai, Wensheng Lin, Zhuowen Shen, Chun Kit Lai, George G Malliaras, Shiming Zhang.

Transistors, fundamental to modern electronics, are traditionally rigid, planar, and two-dimensional (2D), limiting their integration with the soft, irregular, and three-dimensional (3D) nature of biological systems. Here, we report 3D semiconductors, integrating organic electronics, soft matter, and electrochemistry. These 3D semiconductors, in the form of hydrogels, realize millimeter-scale modulation thickness while achieving tissue-like softness and biocompatibility. This breakthrough in modulation thickness is enabled by a templated double-network hydrogel system, where a secondary porous hydrogel guides the 3D assembly of a primary redox-active conducting hydrogel. We demonstrate that these 3D semiconductors enable the exclusive fabrication of 3D spatially interpenetrated transistors that mimic real neuronal connections. This work bridges the gap between 2D electronics and 3D living systems, paving the way for advanced bioelectronics systems such as biohybrid sensing and neuromorphic computing.

DOI: https://doi.org/10.1126/science.adx4514
J Am Chem Soc. 2025 Nov 19.

Polyrotaxanes Send Shuttling Signals.

Xinlin Jiang, Yuting Tan, Guangsong Xie, Yichen Lin, Wenjie Fu, Junyan Zhang, Zehuan Li, Xin Cui, Lin Xiao, Chao Zhang, Baohua Ji, Junjie Deng, Dong Ma, Qianming Lin.

Mimicking intercellular communication by dynamically presenting signaling molecules to cells is central to understanding biological processes and building artificial life systems. However, precise replication and control of such communication at the molecular level in synthetic environments remain largely unexplored. Here, we present a polyrotaxane-based, molecular machine-like platform that regulates shuttling motions of signaling ligands within a mechanically interlocked network. This molecularly dynamic presentation of topological constrained signals directs T cell differentiation and significantly enhances therapeutic efficacy in vivo. Mechanistic studies reveal how T cells sense and transduce dynamic molecular motions into distinct intracellular responses, demonstrating that identical ligands can produce divergent outcomes depending on their molecular dynamics. These findings establish molecular motion as a critical determinant of intercellular signaling and provide a framework for engineering artificial dynamic systems that precisely control cell fate, opening new avenues for therapeutic applications based on molecular machine principles.

DOI: https://doi.org/10.1021/jacs.5c15927