bims-ecemfi 2026-03-01 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–03–01
ten papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Ultrafast-relaxing and photopolymerizable PEG hydrogels enable viscoelasticity-mediated cell remodeling in synthetic matrices.
Topology Outweighs Stiffness: Self-Reinforced Cell Mechanotransduction via Multiaxial Curvature Engineering of Ultrasoft Hydrogels.
Collective transitions from orbiting to matrix invasion in three-dimensional multicellular spheroids.
Bioactive and Injectable Granular Hydrogels Incorporating Decellularized Extracellular Matrix.
Conformation-driven mechanical duality: Viscoelastic and poroelastic switching in protein hydrogels.
Cell strain-stiffening drives cell breakout from embedded spheroids.
Geometric confinement reveals scale-free velocity correlations in epithelial cell monolayer.
Photo-click Decellularized Matrix Hydrogels for Generating Pancreatic Ductal Organoids.
Thiol-Methylsulfone Crosslinked Hydrogels for Cell Encapsulation: Molecular Scale Modulation of Physiochemical Properties.
Mechanical force regulates the inhibitory function of PD-1.

Matter. 2026 Feb 04. pii: 102524. [Epub ahead of print]9(2):

Ultrafast-relaxing and photopolymerizable PEG hydrogels enable viscoelasticity-mediated cell remodeling in synthetic matrices.

Bruce E Kirkpatrick, Abhishek P Dhand, Lea Pearl Hibbard, Matthew W Jaeschke, Tvishi Yendamuri, Benjamin R Nelson, Joshua S Lee, Kaustav Bera, Hannah M Zlotnick, Carly A Fox, Bianca Meurer-Zeman, Connor E Miksch, Nathaniel P Skillin, Michael R Blatchley, Timothy J White, Christopher N Bowman, Jason A Burdick, Kristi S Anseth.

  Synthetic hydrogels provide powerful material platforms to engineer cellular microenvironments with control over stiffness, viscoelasticity, porosity, degradability, and biochemical signals. Here, we demonstrate how orthogonal crosslinking reactions allow fabrication of covalent adaptable networks to tailor photopolymerizable bioresin formulations relevant for tissue engineering. Specifically, we synthesize multifunctional poly(ethylene glycol) (PEG) macromers containing dynamic boronate ester bonds and dithiolane and norbornene moieties that allow for photopolymerization and projection-based biofabrication. These materials are used to print human mesenchymal stromal cells (MSCs) in formulations where the ratio of elastic versus adaptable crosslinks is engineered to study and manipulate MSC spreading, actin structure, and macroscopic material-level deformation. We demonstrate how material and print parameters, peptide ligands, actomyosin-modulating drug treatments, and cell types influence cell-material interactions and emergence of morphogenesis that is uniquely enabled by viscoelasticity. The presented materials introduce a versatile strategy for spatiotemporal control over dynamic mechanical properties in cell-laden matrices.

Keywords:  PEG hydrogel; boronate ester; dithiolane; hMSC; photopolymerization; viscoelasticity

DOI:  https://doi.org/10.1016/j.matt.2025.102524
ACS Nano. 2026 Feb 24.

Topology Outweighs Stiffness: Self-Reinforced Cell Mechanotransduction via Multiaxial Curvature Engineering of Ultrasoft Hydrogels.

Yong Hou, Xinhao Hu, Cheng Qian, Wenyan Xie, Linjie Ma, Luyao Zhang, Xiaomei Han, Youhua Tan, Yuan Lin, Chao Fang, Zhiqin Chu.

  Geometric curvature critically regulates cellular behavior in soft tissue microenvironments, yet its role in mechanotransduction is underexplored due to stiffness-centric paradigms and challenges in creating stable curvatures on ultrasoft materials. We developed a solvent-induced buckling strategy to engineer multiaxial curvatures on ultrasoft hydrogels (500-750 Pa), recapitulating the anisotropic topologies of natural tissues such as cerebral gyri and breast lobules. Human mesenchymal stem cells on these surfaces exhibit robust focal adhesion maturation, cytoskeletal reorganization, nuclear mechanosensing (e.g., elevated Lamin A/C), and enhanced osteogenesis─phenotypes typically seen on rigid substrates but markedly attenuated on flat ultrasoft controls. This curvature-dominated mechanosensing persists in 3D injectable microgels, decoupling topological cues from the substrate stiffness. Mechanistic studies and energy minimization modeling reveal that curvature segregates stress fiber functions: basal fibers align circumferentially in high-curvature regions to enhance Rho-mediated contractility and focal adhesions, while apical fibers orient radially in low-curvature zones to minimize the bending energy. These findings establish topology as a primary driver of cellular tension and fate, providing fundamental insights into designing biomaterials and biointerfaces for soft tissue repair and regenerative medicine.

Keywords:  curvature engineering; mechanosensing; multiaxial curvatures; tissue engineering; ultrasoft substrate

DOI:  https://doi.org/10.1021/acsnano.5c19367
Nat Phys. 2026 Feb;22(2): 275-286

Collective transitions from orbiting to matrix invasion in three-dimensional multicellular spheroids.

Jiwon Kim, Hyuntae Jeong, Carles Falcó, Alex M Hruska, W Duncan Martinson, Alejandro Marzoratti, Mauricio Araiza, Haiqian Yang, Vera C Fonseca, Stephen A Adam, Christian Franck, José A Carrillo, Ming Guo, Ian Y Wong.

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bidirectional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. In turn, orbiting along sharper curvature results in locally stronger contractile tractions, which gradually align collagen fibers in the radial direction. Thus, the initially elongated morphology primes the matrix towards subsequent invasion of two to four strands that are roughly aligned with the major axis. We then show that orbiting can be arrested and invasion can be reversed using osmotic pressure. We also investigate coordinated orbiting in mosaic spheroids, showing a small fraction of cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Altogether, this work elucidates how symmetry-breaking in tissue morphogenesis is governed by the interplay of collective migration and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

DOI: https://doi.org/10.1038/s41567-025-03150-x
ACS Biomater Sci Eng. 2026 Feb 23.

Bioactive and Injectable Granular Hydrogels Incorporating Decellularized Extracellular Matrix.

Daniela Trindade, Nikolas Di Caprio, Ana C Maurício, Nuno Alves, Carla Moura, Jason A Burdick.

  Decellularized extracellular matrices (dECMs) provide bioactive cues that may be useful for the repair of fibrocartilaginous tissues, such as the temporomandibular joint disc (TMJd), which lacks a natural regenerative capacity. While potent in bioactivity, dECM hydrogels do not possess the mechanical properties necessary for joint repair, motivating the development of improved materials. Granular hydrogels provide a unique opportunity to repair tissues by mechanically stabilizing the defect with injectable, jammed hydrogel microparticles that exhibit microporosity to support cellular infiltration. Here, we combined the bioactivity of dECM with the stability of norbornene hyaluronic acid (NorHA) granular hydrogels to create a system that promotes cell adhesion and allows for ECM release. Two concentrations of dECM (0.4% and 0.8%, w/v, dry weight) were encapsulated within NorHA microgels and shown to increase microgel stiffness and support ECM release over time. The microgels were formed into granular hydrogels with shear-thinning and self-healing properties that also undergo secondary cross-linking either with photo-cross-linking via visible light or with the addition of an interstitial dECM. The incorporated dECM supported the adhesion of fibrochondrocytes. The addition of dECM to microgels and within the interstitial space resulted in an injectable and bioactive biomaterial.

Keywords:  decellularized extracellular matrix; granular hydrogels; hyaluronic acid; injectable; temporomandibular joint

DOI:  https://doi.org/10.1021/acsbiomaterials.5c02060
Acta Biomater. 2026 Feb 20. pii: S1742-7061(26)00122-4. [Epub ahead of print]

Conformation-driven mechanical duality: Viscoelastic and poroelastic switching in protein hydrogels.

Mattan Ze'ev Becker, Maya Georgia Pelah, Ofek Avrahami, Ionel Popa, Ronen Berkovich.

  Bovine serum albumin (BSA) hydrogels reveal a fundamental mechanical duality in protein-based biomaterials. Using chemically crosslinked BSA networks as a model system, we show that the same hydrogel can dissipate stress through two distinct regimes depending on protein conformation. Native BSA hydrogels exhibit viscoelastic relaxation, governed by unfolding of protein domains, whereas chemically denatured BSA hydrogels display poroelastic dissipation, dominated by solvent migration through the deformed matrix. This denaturation-driven switch between viscoelastic and poroelastic mechanics highlights the direct coupling between protein structure and macroscopic energy dissipation. By disentangling these two dissipative modes within a single material platform, our findings provide a conceptual framework for designing protein-based hydrogels with state-dependent mechanical responses, with potential applications in biomaterials, mechanobiology, and soft matter engineering. STATEMENT OF SIGNIFICANCE: This study reveals how the folding state of proteins controls the way protein-based hydrogels dissipate mechanical energy. We show that native proteins give rise to viscoelastic behavior, while denatured proteins display poroelasticity, and, most notably, that these two regimes can reversibly switch within the same material. This discovery introduces a new concept of dynamically tunable soft materials, advancing biomaterial design beyond static systems. Our work combines mechanical testing, molecular-level insights, and machine learning-based analysis to connect protein structure with hydrogel mechanics across length scales. These findings open new pathways for designing smart biomaterials with applications in tissue engineering and related biomedical technologies.

Keywords:  Bovine serum albumin; Hydrogel; Poroelasticity; Protein unfolding; Protein-based biomaterials; Viscoelasticity

DOI:  https://doi.org/10.1016/j.actbio.2026.02.038
ArXiv. 2026 Feb 09. pii: arXiv:2602.08737v1. [Epub ahead of print]

Cell strain-stiffening drives cell breakout from embedded spheroids.

Shabeeb Ameen, Kyungeun Kim, Ligesh Theeyancheri, Minh Thanh, Mingming Wu, Alison E Patteson, J M Schwarz, Tao Zhang.

Understanding how cells escape from embedded spheroids requires a mechanical framework linking stress generation within cells, across cells, and between cells and the surrounding extracellular matrix (ECM). We develop such a framework by coupling a 3D vertex model of a spheroid to a fibrous ECM network and deriving a 3D Cauchy stress tensor for deformable polyhedral cells, enabling direct cell-level stress quantification in three dimensions. We analyze maximum shear stress in solid-like and fluid-like spheroids: solid-like spheroids exhibit broader stress distributions and radial stress gradients, while fluid-like spheroids show lower stresses with weak spatial organization. Cell shape anisotropy is not generically aligned with principal stress directions, indicating that morphology alone is an unreliable proxy for mechanical state. We further demonstrate strain stiffening at the single-cell level, where elongation produces nonlinear increases in maximum shear stress, allowing boundary cells in otherwise low-stress, fluid-like spheroids to transiently generate forces sufficient to remodel the matrix. To connect strain-induced stress amplification to invasion modes, we introduce an extended 3D vertex model with explicit, tunable cell-cell adhesion springs. In this minimal mechanical framework, single-cell breakout results from strain stiffening combined with reduced adhesion, whereas multi-cell streaming additionally requires anisotropic adhesion strengthened along the elongation axis and weakened orthogonally. Together, these results identify distinct mechanical pathways coupling cell strain, stress amplification, and adhesion organization to spheroid invasion.
Eur Phys J E Soft Matter. 2026 Feb 26. pii: 19. [Epub ahead of print]49(3):

Geometric confinement reveals scale-free velocity correlations in epithelial cell monolayer.

Guillaume Duprez, Mélina Durande, François Graner, Hélène Delanoë-Ayari.

Collective cell flows are a hallmark of tissue dynamics in development, wound healing, and various diseases. Here, we investigate how the size, shape, topology and rigidity of patterned substrate influence the organization of flows and mechanical fields in an epithelial MDCK cell monolayer at several time and space scales. Using micropatterned substrates with and without free front (a strip and a closed racetrack), we show that confinement and obstacles induce spatial heterogeneities in velocity and force fields, leading to the emergence of domains, waves, and long-range correlations. We show that spatial velocity correlations are scale-free, following a power law whose exponent evolves as the monolayer matures. This challenges the notion of a single intrinsic correlation length. We also show that in absence of free front, spontaneous collective motions are stronger on soft than on hard substrate. Our findings provide new insights into the rheology of epithelial tissues and the interplay between mechanics and collective migration.

DOI: https://doi.org/10.1140/epje/s10189-026-00564-0
bioRxiv. 2026 Feb 20. pii: 2026.02.16.706185. [Epub ahead of print]

Photo-click Decellularized Matrix Hydrogels for Generating Pancreatic Ductal Organoids.

Ngoc Ha Luong, Kunming Shao, Van Thuy Duong, Xiaoping Bao, Chien-Chi Lin.

Pancreatic ductal organoids (PDOs) generated from human induced pluripotent stem cells (iPSCs) can be used to model pancreatic diseases and to conduct drug screening/testing. However, current protocols for generating PDOs rely heavily on tumor-derived Matrigel, which has been shown to upregulate oncogenes. Furthermore, Matrigel has undefined composition and weak mechanical properties that hamper mechanistic studies of cell-material interactions. In this study, we explore photo-clickable decellularized small intestine submucosa-norbornene (dSIS-NB) hydrogels as a Matrigel replacement for generating human iPSC-derived PDOs. To achieve this, pancreatic progenitors (PP) were first differentiated in conventional two-dimensional (2D) culture, aggregated into spheroids, then encapsulated and differentiated within dSIS-NB hydrogels with tunable stiffness. The differentiated organoids were analyzed by morphology, expression of key pancreatic ductal markers, and single-cell RNA sequencing (scRNA-seq). Post-differentiation, PDOs generated in stiffer photo-clickable dSIS-NB hydrogels (shear moduli ∼2.5 kPa) maintained ductal epithelial phenotype and exhibited pronounced forskolin-induced swelling. In contrast, differentiation of PP spheroids in softer dSIS-NB gels (shear moduli ∼0.9 kPa) and Matrigel resulted in a persistent mesenchymal phenotype and failed to generate functional PDOs. Finally, scRNA-seq results revealed that stiffer dSIS-NB hydrogels strongly biased ductal cell differentiation, yielding greater than 97% ductal progeny.

DOI: https://doi.org/10.64898/2026.02.16.706185
Macromol Biosci. 2026 Feb;26(2): e00627

Thiol-Methylsulfone Crosslinked Hydrogels for Cell Encapsulation: Molecular Scale Modulation of Physiochemical Properties.

Hafiz Syed Usama Bin Farrukh, Aleeza Farrukh, Syuzanna Hambardzumyan, Therese Steudter, Samuel Pearson, Aránzazu Del Campo.

  Hydrogels mimicking the mechanical and biochemical features of the cellular microenvironment allow cell encapsulation and facilitate in vitro 3D culture. In addition to biocompatibility and reactivity in physiological conditions, a key criterion for crosslinking chemistry is appropriate gelation kinetics to allow mixing and homogeneous distribution of cells with the hydrogel precursors. We have previously presented aryl methylsulfone/thiol (MS/SH) reaction as a thiol-reactive cross-linking system for cell encapsulation in star polyethylene glycol (PEG4) hydrogels with a gelation kinetics in minutes time scale. Remaining experimental challenges for this system are a finer modulation of gelation kinetics and streamlining the synthesis of the prepolymer. Here we present the possibility to tune the gelation kinetics by introducing an electron-withdrawing substituent at p-position of the aryl MS ring. This variant also presents synthetic advantages. We study the influence of the p-substituent on the physicochemical properties of MS/SH crosslinked hydrogels, and their performance for cell encapsulation. We compare these properties with the PEG-MS variant containing an electron-donating linker. The new star poly(ethylene glycol)-4-(5-(methylsulfonyl)-1H-tetrazol-1-yl)benzamide (PEG4-CONH-TzMS) shows superior properties as cell encapsulating hydrogel in terms of ease of mixing polymer precursors, faster gelation, homogenous cell distribution and high enzymatic stability.

Keywords:  3D cell encapsulation; aryl methylsulfone; crosslinking kinetics; thiol crosslinking

DOI:  https://doi.org/10.1002/mabi.202500627
EMBO Rep. 2026 Feb 25.

Mechanical force regulates the inhibitory function of PD-1.

Hui Chen, Yong Zhang, Lei Cui, Juan Fan, Huaying Zhu, Songfang Wu, Hang Zhou, Yanruo Zhang, Guangtao Song, Ning Jiang, Mingzhao Zhu, Changjie Lou, Wei Chen, Jizhong Lou.

  The immune checkpoint molecule, programmed cell death 1 (PD-1), critically regulates T-cell activation upon binding PD-L1 or PD-L2, making it a key target in cancer immunotherapy. Although extensively studied, the molecular mechanism of the inhibitory function of PD-1 remains incompletely understood. Using the biomembrane force probe (BFP), we measure catch-slip bond behavior between PD-1 and PD-L1/PD-L2 under force. Steered molecular dynamics (SMD) simulation reveals a force-induced bound state distinct from the force-free state observed in solved complex structures. Disrupting interactions that stabilize either state weakens the catch bond, and diminishes the inhibitory function of PD-1. Interestingly, soluble forms of PD-L1/PD-L2 compete with their surface-bound counterparts and attenuate PD-1-mediated T-cell inhibition, suggesting that soluble PD-1 ligands could potentially serve as anti-PD-1 drugs. Tumor growth studies using a gain of function mutant based on the catch-bond mechanism confirm the anti-cancer activity of soluble PD-L1. Our findings highlight that mechanical force governs the inhibitory function of PD-1 and suggest that PD-1 acts as a mechanical sensor in T-cell suppression. Thus, mechanical regulation should be considered when designing PD-1 blocking therapies.

Keywords:  Immunological Synapse; Immunotherapy; Mechanical Force; PD-1; T Cells

DOI:  https://doi.org/10.1038/s44319-026-00715-6