bims-ecemfi 2025-08-10 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–08–10
ten papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Interpenetrating Polymer Network Hydrogel Composition Alters Encapsulated MSC Spreading and In Vivo Degradation Behavior.
Digital light processing of photoresponsive and programmable hydrogels.
STRESS, an automated geometrical characterization of deformable particles for in vivo measurements of cell and tissue mechanical stresses.
A sulfonated cartilage interpenetrating polymer network reinforces and protects the extracellular matrix of degraded cartilage.
Structure-reactivity based control of radical-mediated degradation in thiol-Michael hydrogels.
Integrating Deep Learning and Real-Time Imaging to Visualize In Situ Self-Assembly of Self-Healing Interpenetrating Polymer Networks Formed by Protein and Polysaccharide Fibers.
Fatty acid albumin conjugates mechanically weaken and disrupt degradation of fibrin networks.
Vimentin intermediate filaments as structural and mechanical coordinators of mesenchymal cells.
Cell surface crowding is a tunable energetic barrier to cell-cell fusion.
Mechanical strain-regulated hydrogel biodegradation for biological scaffolds with programmable lifetime.

ACS Biomater Sci Eng. 2025 Aug 04.

Interpenetrating Polymer Network Hydrogel Composition Alters Encapsulated MSC Spreading and In Vivo Degradation Behavior.

Liaura Ifergan-Azriel, Orit Bar-Am, Galit Saar, Talia Cohen, Claudia Loebel, Jason A Burdick, Dror Seliktar.

  An interpenetrating polymer network (IPN) hydrogel was developed for the three-dimensional (3D) culture of multipotent mesenchymal stromal cells (MSCs) with the aim of independently controlling cell spreading and material modulus. Based on our previous studies, we formulated a semisynthetic material composed of two networks: a covalent network of poly(ethylene glycol) (PEG)-fibrinogen (PF) and a second guest-host (GH) network of hyaluronic acid (HA) coupled to β-cyclodextrin (CD) and adamantane (Ad). The PF network provided cell attachment, precise control over modulus through the incorporation of additional PEG-diacrylate (PEG-DA) cross-linking, and proteolytic degradability. The GH-HA network contributed to the hydrogel's dynamic properties through enhanced viscoelasticity. This dynamic versatility enabled MSCs to better spread and grow in the IPN, even within highly cross-linked formulations. We also observed that the IPN facilitated significantly faster cell spreading kinetics, independent of the material modulus, when compared to single-network PF hydrogels. Hydrogel biodegradation was also characterized after subcutaneous implantation for up to 8 weeks by using MRI analysis. Increasing the PEG-DA cross-linking of the IPN significantly accelerated the in vivo bioresorption, whereas the biodegradation in single-network PF hydrogels was significantly delayed by the additional PEG-DA. We conclude that the covalent cross-links maintain the bulk structural integrity of the hydrogel, whereas the reversible GH interactions provide more localized adaptability for cell-mediated proteolysis and matrix remodeling, possibly through increased network heterogeneity. This design effectively mimics the ECM by providing a more supportive environment for encapsulated cells that allows them to adhere, spread, and proliferate, which may be useful in various MSC-based tissue engineering and regenerative medicine applications.

Keywords:  biomaterials; hydrogels; interpenetrating polymer network; scaffolds; stem cells; tissue engineering

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00980
Sci Adv. 2025 Aug 08. 11(32): eadw9262

Digital light processing of photoresponsive and programmable hydrogels.

Abhishek P Dhand, Bruce E Kirkpatrick, Manuela Garay-Sarmiento, Benjamin R Nelson, Connor E Miksch, Bianca Meurer-Zeman, Hannah M Zlotnick, Arkodip Mandal, Joshua S Lee, Jaxon Cione, Christopher N Bowman, Kristi S Anseth, Jason A Burdick.

Light-mediated manipulation of hydrogel physicochemical properties is attractive for numerous applications, yet the processing of such hydrogels via vat photopolymerization [e.g., digital light processing (DLP)] is challenging as photoresponsive chemistries may be consumed during printing. Here, we report a facile strategy to DLP print hydrogels that combines short light exposures to set the shape of a printed object and complementary dark polymerization to continue the reaction of macromers without disturbing photoresponsive groups. Postprinting, hydrogels are then programmed using single- or multiphoton light and photoinitiator-free reactions: tetrazole-alkene click reaction (for photofunctionalization), dithiolane ring-opening polymerization (for photostiffening), and o-nitrobenzyl cleavage (for photosoftening). We demonstrate the versatility of this approach through applications that include the patterning of ligands to direct cell-material interactions, four-dimensional shape morphing, and bottom-up construction of multiscale models, including microscale perfusable channels. This approach provides access to highly tunable 3D-printed photoresponsive hydrogels for a range of soft matter applications.

DOI: https://doi.org/10.1126/sciadv.adw9262
Sci Rep. 2025 Aug 05. 15(1): 28599

STRESS, an automated geometrical characterization of deformable particles for in vivo measurements of cell and tissue mechanical stresses.

Ben Jeffrey Gross, Johannes Richard Soltwedel, Elijah Shelton, Carlos Gomez, Otger Campàs.

From cellular mechanotransduction to the formation of embryonic tissues and organs, mechanics has been shown to play an important role in the control of cell behavior and embryonic development. Most of our existing knowledge of how mechanics affects cell behavior comes from in vitro studies, mainly because measuring cell and tissue mechanics in 3D multicellular systems, and especially in vivo, remains challenging. Oil microdroplet sensors, and more recently gel microbeads, use surface deformations to directly quantify mechanical stresses within developing tissues, in vivo and in situ, as well as in 3D in vitro systems like organoids or multicellular spheroids. However, an automated analysis software able to quantify the spatiotemporal evolution of stresses and their characteristics from particle deformations is lacking. Here we develop STRESS (Surface Topography Reconstruction for Evaluation of Spatiotemporal Stresses), an analysis software to quantify the geometry of deformable particles of spherical topology, such as microdroplets or gel microbeads, that enables the automatic quantification of the temporal evolution of stresses in the system and the spatiotemporal features of stress inhomogeneities in the tissue. As a test case, we apply these new code to measure the temporal evolution of mechanical stresses using oil microdroplets in developing zebrafish tissues. Starting from a 3D timelapse of a droplet, the software automatically calculates the statistics of local anisotropic stresses, decouples the deformation modes associated with tissue- and cell-scale stresses, obtains their spatial features on the droplet surface and analyzes their spatiotemporal variations using spatial and temporal stress autocorrelations. We provide fully automated software in Matlab/Python and also in Napari (napari-STRESS), which allows the visualization of mechanical stresses on the droplet surface together with the microscopy images of the biological systems. The automated nature of the analysis will help users obtain quantitative information about mechanical stresses in a wide range of 3D multicellular systems, from developing embryos or tissue explants to organoids.

DOI: https://doi.org/10.1038/s41598-025-13419-z
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667232. [Epub ahead of print]

A sulfonated cartilage interpenetrating polymer network reinforces and protects the extracellular matrix of degraded cartilage.

Christian D DeMoya, Pierson Husted, Dev R Mehrotra, Michael B Albro, Brian D Snyder, Mark W Grinstaff.

Cartilage extracellular matrix (ECM) comprises a type-II collagen fibril network that affords structure and tensile strength, complemented by a negatively charged, sulfated glycosaminoglycan (GAG) matrix that retains interstitial water. These components act synergistically, bestowing the rheological and tribological material properties essential to cartilage function. At the onset of osteoarthritis, a disease characterized by cartilage degeneration, GAGs diminish from the ECM reducing interstitial fluid load support ( IFLS ) and transferring load to the collagen fibril network, which subsequently breaks down, culminating in increased hydraulic permeability, and decreased cartilage stiffness. We restore the material properties of damaged cartilage critical to diarthrodial joint function by forming an interpenetrating polymer network (IPN) with the native collagen using a synthetic, hydrophilic, and biocompatible GAG-mimetic polymer. Upon visible light activation, the monomer, 3-sulfopropylmethacrylate (SPM), and the crosslinker, polyethylene glycol diacrylate (PEGDA), form a sulfonated and anionic IPN that entangles and fills the existing porous degraded collagen matrix. Mechanistically, the highly sulfated, anionic SPM IPN retards water transport, reestablishes collagen fibril network integrity, and restores tissue IFLS , thereby returning the stiffness and viscoelastic properties of degraded cartilage to healthy levels. Additionally, the SPM IPN protects cartilage from further degradation by reducing the infiltration of inflammatory cytokines that upregulate catabolic matrix metalloproteinases and downregulate GAG production.
Statement of significance: Amelioration of OA requires a comprehensive approach: neutralize or impede catabolic enzymes that degrade cartilage and reconstitute damaged cartilage by augmenting tissue ECM constituents. Currently, there are no clinical treatments that restore the viscoelastic material properties of hyaline cartilage tissue critical to its mechanical function and impart chondroprotection after OA induction. This work suggests that reconstituting GAG-depleted cartilage using a synthetic sulfonated interpenetrating polymer to reestablish IFLS that can be instilled into the joint and polymerized with white light during conventional arthroscopy represents a novel, minimally invasive, clinical treatment for early OA.

DOI: https://doi.org/10.1101/2025.07.28.667232
J Mater Chem B. 2025 Aug 05.

Structure-reactivity based control of radical-mediated degradation in thiol-Michael hydrogels.

Bruce E Kirkpatrick, Miranda T Rubio, Tvishi Yendamuri, Naomi V Elmer, Danielle S W Benoit, C Allan Guymon, Kristi S Anseth, Tayler S Hebner.

Thiol-Michael addition reactions are widely used for forming cytocompatible and well-defined hydrogels. Numerous types of Michael acceptors have been implemented in these reactions; while maleimides enable rapid crosslinking under physiological conditions and are commonly used for their simplicity, slower-reacting electrophiles such as vinyl sulfones and acrylates offer distinct advantages including improved network homogeneity and ease of handling because of the slower reaction rates. Additionally, thiol-acrylate adducts are hydrolytically labile, whereas thiol-vinyl sulfone adducts are comparably more stable in aqueous environments. Building on our previous work demonstrating radical-mediated degradation of thiol-maleimide hydrogels, we sought to determine whether other thiol-Michael adducts are similarly susceptible to cleavage by radical species. Using both linear and network-forming polymer systems, we found that both Michael-adduct types undergo radical-mediated degradation to varying extents. Furthermore, acrylates are far more prone to radical homopolymerization, enabling semi-orthogonal degradation modes in hydrogels, wherein hydrolytic and radical responses are independently programmed according to the chemical structure and stoichiometric excess of the Michael acceptor. Extending the results of these findings in networks synthesized via thiol-Michael addition, we also observed similar radical-mediated degradation behavior in thiol-norbornene networks formed via thiol-ene photopolymerization, suggesting that even electron-rich thioethers are degradable under sufficiently aggressive initiation conditions where the concentration of radicals exceeds that of the crosslinks. Together, these results extend the chemical space for engineering hydrogels with variable degradation profiles and illustrate design principles for tuning material responses to multiple chemical stimuli.

DOI: https://doi.org/10.1039/d5tb01237f
ACS Appl Mater Interfaces. 2025 Aug 05.

Integrating Deep Learning and Real-Time Imaging to Visualize In Situ Self-Assembly of Self-Healing Interpenetrating Polymer Networks Formed by Protein and Polysaccharide Fibers.

Gloria Pelayo-Punzano, Rafael Cuesta, José J Calvino, José M Domínguez-Vera, Miguel López-Haro, Juan de Vicente, Natividad Gálvez.

  Fibrillar protein hydrogels are promising sustainable biomaterials for biomedical applications, but their practical use is often limited by insufficient mechanical strength and stability. To address these challenges, we transformed native proteins into amyloid fibrils (AFs) and incorporated a fibrillar polysaccharide, phytagel (PHY), to engineer interpenetrating polymer network (IPN) hydrogels. Notably, we report for the first time the formation of an amyloid-based hydrogel from apoferritin (APO), with PHY reinforcing the network's mechanical integrity. In situ self-assembly of APO within the PHY matrix yields fully natural, biopolymer-based IPNs. Rheological analyses confirm synergistic interactions between AF and PHY fibers, with the composite hydrogels exhibiting significantly enhanced viscoelastic moduli compared with individual components. The AF-PHY hydrogels also demonstrate excellent self-healing behavior, rapidly restoring their storage modulus after high-strain deformation. A major advancement of this study is the application of deep learning (DL)-based image analysis, using convolutional neural networks, to automate the identification, segmentation, and quantification of fibrillar components in high-resolution scanning electron microscopy images. This AI-driven method enables precise differentiation between AF and PHY fibers and reveals the three-dimensional microarchitecture of the IPN, overcoming key limitations of traditional image analysis. Complementary real-time confocal laser scanning microscopy, with selective fluorescent labeling of protein and polysaccharide components, further validates the IPN structure of the hybrid hydrogels. Our results demonstrate that DL significantly enhances structural characterization and provides insights into gelation processes. This approach sets a new guide for the analysis of complex soft materials and underlines the potential of AF-PHY hydrogels as mechanically robust, self-healing, and fully sustainable biomaterials for biomedical engineering applications.

Keywords:  IPN networks; deep learning; fibrillar polysaccharide; hydrogels; protein fibers; real-time CLSM imaging

DOI:  https://doi.org/10.1021/acsami.5c11459
Acta Biomater. 2025 Aug 06. pii: S1742-7061(25)00590-2. [Epub ahead of print]

Fatty acid albumin conjugates mechanically weaken and disrupt degradation of fibrin networks.

Yujen Wang, Sajjad Norouzi, Arsalan Nisar, Justin Houser, Sachin Kumar, Mohammadhasan Hedayati, H Samet Varol, Paula Delgado, Naomi Calhoun, Leah Gutzwiller, Jeanne C Stachowiak, Manuel K Rausch, Sapun H Parekh.

  Cardiovascular diseases and stroke together account for the largest causes of death in Western countries. These pathologies are directly linked to the formation of blood clots that block blood flow to vital organs. Common risk factors for such clots are obesity, high blood pressure, diabetes, and high LDL cholesterol. Immediate thrombolytic treatment to dissolve fibrin-rich clots can save lives, but recent research has shown that pure fatty acids (FA) can inhibit thrombolysis via interaction with plasmin. However, since FAs are often complexed to serum albumin in the blood, it is unclear how FAs in blood interact with plasmin, or perhaps with clots, to modulate thrombolysis. Here, we studied how elevated levels of two abundant FAs (oleic and palmitic acid) complexed to bovine serum albumin (BSA) affect fibrin hydrogels and their degradation. We observed the binding of fatty acid-BSA (FABSA) conjugates to fibrin via Förster resonance energy transfer microscopy and noted the effects of FABSA on fibrin gels mechanics and fibrinolysis compared to pure fibrin networks. Specifically, with FABSA in the fibrin network, fibrin hydrogels were mechanically weakened and showed a significant decrease in fibrinolysis speed. These studies show that elevated fatty acid content modifies clot properties, making them mechanically weaker and more resistant to degradation. STATEMENT OF SIGNIFICANCE: Fibrin networks are the primary load-bearing element in blood clots, which are subject to various cyclic forces in the body and have excellent mechanical properties resulting from fibrin's hierarchical structure. These networks are formed in the presence fatty acids, lipoproteins, and albumin in the blood; however, little is known about how these additional constituents modify fibrin network properties. By imaging protein fiber orientation, molecular structure, and degradation in situ, we find that fibrin formation in the presence of elevated fatty acids conjugated to albumin modifies network structure, mechanically weakens fibrin networks, and slows fibrin network degradation considerably. Based on our findings, we suspect that increased fat in blood may lead impeded fibrin degradation and increased clot persistence.

Keywords:  ECM; ECM mechanics; degradation; fatty acids; fibrin clots

DOI:  https://doi.org/10.1016/j.actbio.2025.08.008
Nat Cell Biol. 2025 Aug 05.

Vimentin intermediate filaments as structural and mechanical coordinators of mesenchymal cells.

Ming Guo, Ian Y Wong, Andrew S Moore, Ohad Medalia, Jennifer Lippincott-Schwartz, David A Weitz, Robert D Goldman.

Vimentin is a cytoskeletal intermediate filament protein that governs the form and function of mesenchymal cells, although the mechanistic details have been poorly understood. Here we highlight recent findings that reveal the diverse role of vimentin in dynamically organizing intracellular architecture and enhancing mechanical resilience. The exceptional deformability of vimentin can now be understood from its high-resolution three-dimensional structure resolved using cryo-electron microscopy. Vimentin also organizes the motion and positioning of numerous organelles, including mitochondria and the nucleus. Furthermore, it synergizes with the actin cytoskeleton to protect cells from extreme mechanical deformations. Finally, vimentin expression in epithelial-mesenchymal transitions has a functional role in tumour invasion analogous to embryonic development and wound healing. These recent developments emphasize the importance of understanding the multifaceted roles of vimentin intermediate filaments in human health and disease.

DOI: https://doi.org/10.1038/s41556-025-01713-x
Nat Commun. 2025 Aug 04. 16(1): 7158

Cell surface crowding is a tunable energetic barrier to cell-cell fusion.

Daniel S W Lee, Liya F Oster, Sungmin Son, Daniel A Fletcher.

Cell-cell fusion is fundamental to processes such as muscle formation and viral infection. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding reduces fusogenicity independent of how fusion is driven. We estimate that crowding presents an energetic barrier to membrane apposition on the scale of ~ 100kBT , greater than that of bare membrane fusion alone. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease their surface crowding prior to fusion. In this work, we show that cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.

DOI: https://doi.org/10.1038/s41467-025-62330-8
J Mater Chem B. 2025 Aug 08.

Mechanical strain-regulated hydrogel biodegradation for biological scaffolds with programmable lifetime.

Akhiri Zannat, Adolfo Lopez, Yijie Cheng, Jie Ma, Mitchell Delemeester, Shaoting Lin, Krishnamurthy Jayaraman, Xinyue Liu.

Precise control over hydrogel biodegradation kinetics is of importance for drug delivery and tissue engineering. However, existing strategies usually rely on fixed material chemistries and offer limited tunability once implanted. Here, we introduce mechanical strain as a programmable cue to regulate hydrogel degradation in situ. Using peptide-crosslinked tetra-PEG hydrogels and proteinase K as a model system, we developed a real-time stress-monitoring platform to quantitatively study strain-dependent enzymatic degradation. Time-resolved measurements reveal that mechanical strain significantly accelerates degradation by simultaneously enhancing diffusion and reaction rates. For thick hydrogel samples, uniaxial stretching significantly reduces the degradation time by four-fold from 7.6 hours (undeformed) to 1.9 hours (stretched), shifting the process from slow, surface-limited to rapid, volumetric degradation. A multiscale theoretical model that we developed identifies three synergistic effects of mechanical strain: reduced diffusion path due to geometric thinning, increased network mesh size for enhanced enzyme penetration, and elevated chain tension that promotes bond cleavage. These findings establish mechanical loading as a universal tool in biological systems to dynamically modulate hydrogel lifetimes, offering new opportunities for programmable drug release and scaffold-guided tissue remodeling.

DOI: https://doi.org/10.1039/d5tb01056j