bims-ecemfi 2025-08-17 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–08–17
nineteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Hydrogel Viscoelasticity Modulates Cell Nascent Extracellular Matrix Deposition.
Tissue-dependent mechanosensing by cells derived from human tumors.
Fully Synthetic Hydrogels Promote Robust Crypt Formation in Intestinal Organoids.
Norbornene Homopolymerization Limits Cell Spreading in Thiol-Ene Photoclick Hydrogels.
Aligned Collagen Fibers Drive Distinct Traction Force Signatures to Regulate Contact Guidance.
Bio-orthogonally double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity for cardiac tissue engineering.
Compressed Cells Facilitate Adhesion Through Glycocalyx.
Complementary cytoskeletal feedback loops control signal transduction excitability and cell polarity.
Differential PaxillinB dynamics at Dictyostelium cell-substrate adhesions.
Targeting Cholesterol-Dependent Piezo1 Activation Impairs Amoeboid Migration in Melanoma Cells.
Functionalized Annealed Microgels for Spatial Control of Osteogenic and Chondrogenic Differentiation.
Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.
Hydrogels with Tethered Transcription Circuit Elements for Chemical Communication and Collective Computation.
Tuning of task-relevant stiffness in multiple directions.
Glucose-Responsive Self-Rolling Antioxidant Hydrogel Actuators for a Cell Culture Platform.
A Synthetic Hydrogel with Tunable Stiffness for Engineering Pancreatic Cancer Organoids and Drug Testing.
Development of Photocurable NorHA-dECM Hybrid Hydrogels to Study Cell-Matrix Interactions.
Magnetic-Driven Viscous Mechanisms in Ultra-Soft Magnetorheological Elastomers Offer History-Dependent Actuation with Reprogrammability Options.
Size-dependent invasion and therapeutic phenotype of 42MGBA glioblastoma spheroids.

Macromol Rapid Commun. 2025 Aug 14. e00435

Hydrogel Viscoelasticity Modulates Cell Nascent Extracellular Matrix Deposition.

Matthew L Tan, Avinava Roy, Eleanor M Plaster, Haguy Wolfenson, Adam Abraham, Claudia Loebel.

  Polymeric hydrogels are valuable platforms for determining how specific mechanical properties of native tissue extracellular matrix (ECM) regulate cell function. Recent research has focused on incorporating viscous and elastic properties into hydrogels to investigate cellular responses to time-dependent mechanical properties of the ECM. However, a critical aspect is that cells continuously remodel their microenvironment in hydrogels, such as by the deposition of newly secreted (nascent) ECM. While this nascent ECM has been demonstrated to play a vital role in transmitting mechanical signals across various biological contexts, the mechanisms by which it regulates cellular function in response to time-dependent mechanical properties remain poorly understood. In this study, we developed an interpenetrating polymer network that enables independent control of viscous and elastic hydrogel properties. We show that cells cultured on high-viscosity hydrogels deposit increased nascent ECM, which also correlates with enhanced hydrogel remodeling. Interestingly, higher nascent ECM deposition on high-viscosity hydrogels was decoupled from intracellular contractility. These results establish a relationship between hydrogel viscosity and nascent ECM deposition that may extend to diverse cell types and offer new insights into cell-hydrogel interactions.

Keywords:  extracellular matrix deposition; hydrogels; mechanotransduction; viscoelasticity

DOI:  https://doi.org/10.1002/marc.202500435
NPJ Biol Phys Mech. 2025 ;2(1): 19

Tissue-dependent mechanosensing by cells derived from human tumors.

Kshitiz Parihar, Jonathan Nukpezah, Daniel V Iwamoto, Katrina Cruz, Fitzroy J Byfield, LiKang Chin, Maria E Murray, Melissa G Mendez, Anne S van Oosten, Anne Herrmann, Elisabeth E Charrier, Peter A Galie, Megan Donlick, Tongkeun Lee, Paul A Janmey, Ravi Radhakrishnan.

  Alterations of the extracellular matrix (ECM), including both mechanical (such as stiffening of the ECM) and chemical (such as variation of adhesion proteins and deposition of hyaluronic acid (HA)) changes, in malignant tissues have been shown to mediate tumor progression. To survey how cells from different tissue types respond to various changes in ECM mechanics and composition, we measured physical characteristics (adherent area, shape, cell stiffness, and cell speed) of 25 cancer and 5 non-tumorigenic cell lines on 7 different substrate conditions. Our results indicate substantial heterogeneity in how cell mechanics changes within and across tissue types in response to mechanosensitive and chemosensitive changes in ECM. The analysis also underscores the role of HA in ECM with some cell lines showing changes in cell mechanics in response to presence of HA in soft substrate that are similar to those observed on stiff substrates. This pan-cancer investigation also highlights the importance of tissue-type and cell line specificity for inferences made based on comparison between physical properties of cancer and normal cells. Lastly, using unsupervised machine learning, we identify phenotypic classes that characterize the physical plasticity, i.e., the distribution of physical feature values attainable, of a particular cell type in response to different ECM-based conditions.

Keywords:  Atomic force microscopy; Computational biophysics; Diseases

DOI:  https://doi.org/10.1038/s44341-025-00023-5
Adv Mater. 2025 Aug 15. e09672

Fully Synthetic Hydrogels Promote Robust Crypt Formation in Intestinal Organoids.

Ella A Hushka, Michael R Blatchley, Laura J Macdougall, F Max Yavitt, Bruce E Kirkpatrick, Kaustav Bera, Peter J Dempsey, Kristi S Anseth.

  Initial landmark studies in the design of synthetic hydrogels for intestinal organoid culture identify precise matrix requirements for differentiation, namely decompression of matrix-imposed forces and supplementation of laminin. But beyond stating the necessity of laminin, organoid-laminin interactions have gone largely unstudied, as this ubiquitous requirement of exogenous laminin hinders investigation. In this work, a fast stress relaxing, boronate ester-based synthetic hydrogel is used for the culture of intestinal organoids, and it is fortuitously discovered that unlike all other synthetic hydrogels to date, laminin does not need to be supplemented for crypt formation. This highly defined material provides a unique opportunity to investigate laminin-organoid interactions and how it influences crypt evolution and organoid function. Via fluorescent labeling of non-canonical amino acids, it is further shown that adaptable boronate ester bonds increase deposition of nascent proteins, including laminin. Collectively, these results advance the understanding of how mechanical and matricellular signaling influence intestinal organoid development.

Keywords:  biomaterials; extracellular matrix; intestinal organoids; laminin; stress relaxing hydrogels

DOI:  https://doi.org/10.1002/adma.202509672
Adv Healthc Mater. 2025 Aug 15. e02172

Norbornene Homopolymerization Limits Cell Spreading in Thiol-Ene Photoclick Hydrogels.

James L Gentry, Steven R Caliari.

  Thiol-ene click chemistry is a powerful tool for engineering tissue-mimicking hydrogels permissive to 3D cell spreading. Thiol-norbornene chemistry allows precise control over crosslinking while seemingly avoiding alkene homopolymerization that can restrict 3D cell spreading. However, limited stress relaxation of a guest-host crosslinked norbornene-modified hyaluronic acid (NorHA) hydrogel employing a thiol-norbornene photoclick reaction prompts investigation into unintended norbornene homopolymerization. Norbornene conversion exceeds 1:1 thiol-ene expectations across various formulations, implicating homopolymerization. Reducing the number of norbornenes per NorHA chain (f) mitigates network formation via norbornene homopolymerization. Guest-host hydrogels fabricated with Nor8HA (f = 8) exhibit 93.0 ± 1.6% relaxation, while those fabricated with Nor40HA (f = 40) achieve only 42.3 ± 0.1% relaxation. As early as day 3 of culture, Nor8HA hydrogels facilitate spreading of encapsulated human mesenchymal stromal cells (hMSCs) into a spindle-like morphology (aspect ratio: 2.95 ± 0.38), while Nor40HA hydrogels appear to constrain cells into a spherical or compact star morphology (aspect ratio: 1.22 ± 0.01). Inference of a single-cell morphological space validates the two distinct hMSC morphological phenotypes primarily associated with polymer f. These results demonstrate that thiol-norbornene crosslinking is not fully stoichiometric in dilute aqueous systems and that network topology, modulated by f, is critical for restoring hydrogel permissivity and enabling cell spreading.

Keywords:  cell spreading; hydrogels; norbornene homopolymerization; stress relaxation

DOI:  https://doi.org/10.1002/adhm.202502172
ACS Nano. 2025 Aug 14.

Aligned Collagen Fibers Drive Distinct Traction Force Signatures to Regulate Contact Guidance.

Gopal Niraula, Azarnoosh Foroozandehfar, Fred Rogers Namanda, Ian Christopher Schneider.

  Cellular forces on deposited nonfibrillar extracellular matrix (ECM) have been measured extensively. However, in vivo, cells exert traction forces on collagen fibers within the ECM. Oftentimes, collagen fibers are aligned, as seen in cancer, fibrosis, and during wound healing. How forces are transmitted on aligned collagen fibers and how the cytoskeleton regulates this is unknown. Here, we develop a fiber-traction force microscopy (f-TFM) approach that uses collagen fibers transferred to flexible substrates with fiducial markers on the collagen fibers and in the underlying flexible substrates. We find that the elastic modulus of the substrate determines the steady-state traction stress exerted by cells on aligned collagen fibers but does not affect traction force kinetics. Collagen fiber networks result in higher traction stresses than adsorbed collagen, particularly for randomly oriented fibers. In cells that weakly contact guide, formins and Arp2/3 modulate traction stress differently, with formins increasing traction stress magnitude, while Arp2/3 increases traction stress kinetics. However, both are important in driving traction force increases during cell turning on aligned collagen fibers. In cells that strongly contact guide, Arp2/3 and formins are less important than myosin II. In addition, there is a positive correlation between traction force and directionality on aligned collagen fibers for modest cell alignment. Further increases in traction stress are not required for high cell alignment. These findings underscore the complex interplay between the mechanics of collagen fiber networks, cytoskeletal regulators, and cellular traction forces, providing insights into how cells navigate complex fiber networks during migration.

Keywords:  collagen fibril and directionality; contact guidance; mechanobiology; traction force microscopy

DOI:  https://doi.org/10.1021/acsnano.5c06736
Mater Today Bio. 2025 Oct;34 102121

Bio-orthogonally double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity for cardiac tissue engineering.

Daniele Testore, Alice Zoso, Camilla Paoletti, Sara Groppo, Elena Marcello, Valeria Chiono.

  Growing evidence has shown that cells respond to the viscoelastic properties of the extracellular matrix (ECM), particularly its stress-relaxation, which influences their spreading, proliferation, and remodeling. Since cardiac tissue viscoelasticity plays a key role in modulating cellular mechanosensing, the development of biomimetic viscoelastic hydrogels is highly needed in cardiac tissue engineering (CTE). This work presents bio-orthogonal double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity, designed to replicate the dynamic mechanical properties of cardiac ECM. Alginate and gelatin were functionalized with azide groups and cross-linked by a 4-arm-dibenzocyclooctyne (DBCO) crosslinker using strain-promoted azide-alkyne cycloaddition (SPAAC) with 0.5:1 (AG_Click(R0.5)) and 1:1 (AG_Click(R1)) DBCO:azide molar ratios. Calcium ions were also introduced to obtain double cross-linked hydrogels (AG_DC(R0.5) and AG_DC(R1)). Rheology showed that hydrogels exhibited tunable stiffness and stress relaxation, closely mimicking the properties of native cardiac tissue. The behavior of human cardiac fibroblasts (HCFs), seeded on hydrogels, was analyzed. When compared to purely elastic polyacrylamide (pAAm) hydrogels with comparable stiffness, soft stress-relaxing hydrogels (AG_Click(R0.5) and AG_DC(R0.5)) were found to promote cell spreading area, while stiffer stress-relaxing hydrogels (AG_Click(R1) and AG_DC(R1)) enhanced asymmetric cell elongation, reflecting substrate-mediated mechanosensing. Additionally, HCFs showed high viability when cultured in 3D hydrogels over 7 days. Overall, rapid gelation, biocompatibility, and tunable viscoelastic properties of bio-orthogonal double cross-linked alginate-gelatin hydrogels support their use as injectable formulations or engineered cardiac tissues for CTE.

Keywords:  Bio-orthogonal; Cardiac tissue engineering; Click chemistry; Hydrogels; Viscoelasticity

DOI:  https://doi.org/10.1016/j.mtbio.2025.102121
Adv Sci (Weinh). 2025 Aug 15. e13586

Compressed Cells Facilitate Adhesion Through Glycocalyx.

Xiaole Wang, Jonne Helenius, Daniel J Müller, Nico Strohmeyer.

  Exposed to mechanical confinement, mammalian cells can establish remarkable unspecific adhesion, which is independent of integrins. How cells facilitate such adhesion remains unclear. Here, it is investigated how mammalian cells exposed to compression initiate unspecific and integrin-mediated adhesion. It is observed that with increasing compression, cells increase adhesion to collagen I or fibronectin and strengthen adhesion faster. Under low and medium compression, cells minimally increase unspecific adhesion to substrates that lack specific binding sites for cell surface receptors, such as integrins. However, under high compression, mammalian cells switch to a strong unspecific adhesion state, which significantly contributes to cell-extracellular matrix (ECM) adhesion. Thereby cells use the glycocalyx to directly facilitate strong unspecific adhesion and to enhance early integrin-mediated adhesion. The mechanistic insight of how cells unspecifically adhere to substrates under confinement opens avenues to better understand cell adhesion in development, homeostasis, disease, and in a wide range of biotechnological and medical applications in which cells are exposed to mechanical confinement.

Keywords:  cell adhesion initiation; collagen; compression; fibronectin; glycocalyx; integrin; single‐cell force spectroscopy

DOI:  https://doi.org/10.1002/advs.202413586
Nat Commun. 2025 Aug 12. 16(1): 7482

Complementary cytoskeletal feedback loops control signal transduction excitability and cell polarity.

Jonathan Kuhn, Parijat Banerjee, Andrew Haye, Douglas N Robinson, Pablo A Iglesias, Peter N Devreotes.

To navigate complex environments, cells integrate chemical and mechanical cues through dynamic feedback between signaling networks and the cytoskeleton. Using synthetic tools to manipulate cytoskeletal components in Dictyostelium and human neutrophils, we uncover feedback mechanisms that regulate Ras/PI3K signaling and control front- and back-states of the cell. Increased branched actin and actin polymerization enhance Ras/PI3K activity. Similarly, decreased myosin II assembly also elevates signaling and chemotactic sensitivity. Conversely, inhibiting branched actin increases cortical actin and blocks Ras/PI3K activation-an effect lessened by decreasing filamentous actin or in myosin II-null cells. Activating RacE to increase actin crosslinking suppresses Ras activity without triggering branched actin nucleators, yet promotes spreading and protrusion. These results informed a computational model incorporating positive cytoskeletal feedback loops, which predicts shifts in polarity and migration with cytoskeletal changes. We propose that such feedback locally tunes signal network excitability, enabling cells to navigate tissues, extracellular matrix, and fluid environments.

DOI: https://doi.org/10.1038/s41467-025-62799-3
bioRxiv. 2025 Aug 06. pii: 2025.08.04.668536. [Epub ahead of print]

Differential PaxillinB dynamics at Dictyostelium cell-substrate adhesions.

Julio C Fierro Morales, Minna Roh-Johnson.

Adhesion-based migration is regulated by focal adhesions, multi-protein nanostructures linking the intracellular cytoskeleton to the extracellular substrate. Efficient adhesion-based migration has been shown to be regulated by focal adhesion dynamics such as lifetime, size and turnover, which in turn are influenced by the molecular composition of focal adhesions. We recently identified the formation of cell-substrate adhesion populations in Dictyostelium discoideum with differing molecular compositions, but it is unclear how these distinct compositions influence Dictyostelium adhesion dynamics and cell migration. Here, we further investigate the role of molecular composition on Dictyostelium adhesion lifetime and protein turnover during cell migration. We show that co-localization of VinculinB to PaxillinB-positive cell-substrate adhesions increases adhesion lifetime without changing PaxillinB turnover. We further show that perturbing cell-substrate adhesion composition with a PaxillinB N-terminal truncation increases adhesion lifetime and decreases PaxillinB turnover at adhesions. These findings suggest that similar to mammalian focal adhesions, molecular composition of Dictyostelium cell-substrate adhesion regulates their adhesion lifetimes and protein turnover, providing insight into how cell-substate adhesions function during Dictyostelium cell migration.
SUMMARY STATEMENT: Fierro Morales and Roh-Johnson demonstrate that Dictyostelium PaxillinB, a homolog of the core focal adhesion protein Paxillin, exhibits differential dynamics in distinct populations of cell-substrate adhesions.

DOI: https://doi.org/10.1101/2025.08.04.668536
bioRxiv. 2025 Jul 17. pii: 2025.07.11.664494. [Epub ahead of print]

Targeting Cholesterol-Dependent Piezo1 Activation Impairs Amoeboid Migration in Melanoma Cells.

Sylvia Kuang, Alleah Abrenica, Neelakshi Kar, Jeremy S Logue.

Bleb-based migration enables cancer cells to navigate the heterogeneous tumor microenvironment. Here, we report a phenotypic screen identifying drugs that inhibit bleb formation, a driver of amoeboid migration. Statins, including Fluvastatin and Pitavastatin, suppress amoeboid migration of melanoma cells in confined environments by reducing intracellular cholesterol. This disrupts plasma membrane tension sensing by Piezo1, lowering intracellular Ca 2 + levels. Both cholesterol supplementation and Piezo1 activation rescue migration in confined environments, confirming their functional link. Notably, high cholesterol biosynthesis enzyme levels correlate with reduced patient survival in melanoma. These findings reveal that cholesterol is essential for confinement sensing through Piezo1, identifying cholesterol biosynthesis or uptake as rational therapeutic targets against metastasis.
Significance Statement: This study builds on a phenotypic drug screen that identified statins as inhibitors of bleb-based migration, a key mode of cancer cell movement through confined spaces. We show that statins reduce membrane cholesterol, disrupting the function of the mechanosensitive channel Piezo1 and impairing melanoma cell migration. Restoring cholesterol or activating Piezo1 rescues this effect, revealing a functional link between cholesterol and confinement sensing. Our findings highlight cholesterol biosynthesis as essential for invasive cell behavior and identify it as a therapeutic vulnerability. Importantly, elevated cholesterol pathway activity correlates with reduced survival in melanoma patients, underscoring the clinical relevance of targeting this pathway to limit metastasis.

DOI: https://doi.org/10.1101/2025.07.11.664494
Adv Funct Mater. 2024 Jul 24. pii: 2311017. [Epub ahead of print]34(30):

Functionalized Annealed Microgels for Spatial Control of Osteogenic and Chondrogenic Differentiation.

Jeremy M Lowen, Erika E Wheeler, Nathan K Shimamoto, David H Ramos-Rodriguez, Katherine H Griffin, Gabriella C Bond, J Kent Leach.

  The biophysical heterogeneity of the bone-cartilage interface requires complex materials to mimic differences in bone density, extracellular matrix composition, and mineralization. Biomaterial approaches to repair osteochondral tissue typically use multilayer scaffolds, which require multi-step fabrication and may undergo delamination at the construct interface. This work describes the development of functionalized microgels for the repair of osteochondral tissues using an N-cadherin peptide, BMP-2 peptide, and changes in stiffness to create pro-osteogenic and pro-chondrogenic microgels. Microgels, when annealed into a scaffold, outperformed bulk hydrogel controls evidenced by upregulation of osteogenic and chondrogenic markers in mesenchymal stromal cells (MSCs). The macroporous void space present in microgel annealed scaffolds enabled robust cell proliferation and ECM deposition throughout the entire scaffold. We then created a bilayer functionalized annealed microgel scaffold and assessed the ability to spatially control the differentiation of MSCs. Osteochondral bilayer scaffolds exhibited distinct regions of osteogenic and chondrogenic protein expression as a function of microgel population upon immunostaining for osteocalcin and aggrecan, respectively. Spatial transcriptomics confirmed osteogenic and chondrogenic genes were upregulated in their respective microgel regions. These studies highlight the tunable and functionalizable nature of microgels and the importance of macroporous void space.

Keywords:  chondrogenesis; microgel; osteochondral; osteogenesis; spatial transcriptomics

DOI:  https://doi.org/10.1002/adfm.202311017
Nat Commun. 2025 Aug 14. 16(1): 7566

Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.

Yuan-Hung Lo, Hudson T Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C Bassik, Dung-Fang Lee, Lei S Qi, Jonathan S Weissman, Jin Chen, Calvin J Kuo.

Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.

DOI: https://doi.org/10.1038/s41467-025-62818-3
ACS Nano. 2025 Aug 12.

Hydrogels with Tethered Transcription Circuit Elements for Chemical Communication and Collective Computation.

Kuan-Lin Chen, Joshua Cole, Cheng-Hung Chou, Chloe W Lindeman, Samuel W Schaffter, Pepijn Moerman, Moshe Rubanov, Keren Sneh, Rebecca Schulman.

  Tissues, robots, and other distributed systems must communicate to make decisions about information originating from different physical locations and then orchestrate the responses. In tissues, for example, cell-cell communication is essential for morphogenesis, immune response, and wound healing. However, devising methods for programming distributed communication in synthetic materials to program behaviors such as multiscale pattern formation, motion, and self-assembly remains a challenge. Here, we devise a design principle for reliable distributed chemical computation and communication and then construct a library of transcription circuit elements, termed tethered genelets (TGs), that implement this design principle within networks of 50 μm hydrogel nodes (HNs). TGs exhibit digital behavior in the form of a "distance-response curve"─they switch off in response to signals emanating from HNs within a specific distance, but are unaffected by faraway signals. In experiments, we verify that TGs send and receive signals as designed and validate the function and modularity of a library of 15 TG circuit elements. The principle of "digital distance-response" and the library of circuit elements we construct together will allow a diverse range of distributed chemical behaviors, communication, and dynamics to be programmed into materials such as soft robots and responsive surfaces.

Keywords:  DNA computing; DNA nanotechnology; digital abstraction; in vitro transcription; programmable matter

DOI:  https://doi.org/10.1021/acsnano.4c14232
Sci Rep. 2025 Aug 15. 15(1): 29916

Tuning of task-relevant stiffness in multiple directions.

Chenguang Zhang, Federico Tessari, James Hermus, Himanshu Akolkar, Neville Hogan, Andrew B Schwartz.

In contrast to robots, humans can rapidly and elegantly modulate the impedance of their arms and hands during initial contact with objects. Anticipating collisions by setting mechanical impedance to counter near-instantaneous changes in force and displacement is one reason we excel at manipulating objects. We investigated the ability to set impedance in an object interaction task with rapid changes in force and displacement, like those encountered during manipulation in different directions. Subjects (n = 20) predictively co-activated antagonist muscles to adjust one component of the impedance - stiffness - to match the task demands before the movement began, irrespective of movement direction. Subjects adopted the minimal stiffness needed to complete the task, but when pushed to the most difficult condition, they were limited by their ability to produce high stiffness rather than large force. This robust and simple strategy ensured task success at the expense of energy efficiency. Our results confirm the ability of humans to predictively set and control mechanical impedance in task-relevant directions in anticipation of breaking contact. This offers the prospect that future investigations will find neural correlates of impedance, which in turn, could improve the ability of neuro-prosthetic limbs to interact with objects.

DOI: https://doi.org/10.1038/s41598-025-14989-8
ACS Appl Mater Interfaces. 2025 Aug 14.

Glucose-Responsive Self-Rolling Antioxidant Hydrogel Actuators for a Cell Culture Platform.

Zhiyu Zheng, Ruxin Xiao, Xiaochen Ma, Ziqian Yu, Jiaxin Zeng, Liqiong Liao.

  Three-dimensional (3D) cell culture technology can mimic the physiological characteristics of tissues and organs, making it highly suitable for cell therapy, organ chips, and tissue engineering applications. However, achieving a uniform cell distribution within the 3D matrix while mitigating the effects of reactive oxygen species (ROS) accumulation generated during the 3D cell culture remains a critical challenge. Hydrogel actuators, with their excellent bioactivity and controllable self-rolling behavior, provide an optimal microenvironment for the 3D cell culture. To support normal cellular function, hydrogel actuators must be triggered by external stimuli that are biocompatible with the cell culture process. Glucose, a key intermediate in energy metabolism and biological processes, is ubiquitous in cell culture media and physiological systems. In this work, a glucose-responsive hydrogel actuator (AP@Que/gelatin) with controllable self-rolling behaviors and ROS scavenging capability was constructed for 3D cell culture, which consists of an active layer composed of phenylboronic acid (PBA)-quercetin (Que) complexes and a passive layer of a biocompatible gelatin hydrogel. The hydrogel actuator exhibited excellent glucose response performance, characterized by notable reswelling behavior, favorable ductility, and cytocompatibility. Its self-rolling behavior in high-glucose culture media was synchronized with cell adhesion timelines, enabling its application as a 2D-to-3D dynamic substrate for cell culture and expansion. Meanwhile, Que was released from the hydrogel actuator through the competitive reaction of PBA with glucose and Que. The formation of the 3D tubular architecture during cell culture facilitated cell growth, while the sustained release of Que effectively eliminated ROS generated during cell passaging. These findings highlight the potential of AP@Que/gelatin hydrogel actuators as an advanced platform for a 3D cell culture.

Keywords:  ROS; cell culture; glucose; hydrogel actuator; quercetin

DOI:  https://doi.org/10.1021/acsami.5c11328
ACS Biomater Sci Eng. 2025 Aug 11. 11(8): 5000-5011

A Synthetic Hydrogel with Tunable Stiffness for Engineering Pancreatic Cancer Organoids and Drug Testing.

Tingting Tao, Haitao Liu, Zhongqiao Gan, Jia He, Xu Zhang, Xianliang Li, Jianhua Qin.

  Pancreatic cancer organoids (PCOs) have gained extensive attention as promising in vitro models that can advance our understanding of translational cancer biology and biomedical research. To date, PCOs are mostly cultured in animal-derived matrices, which are limited by their low similarity with native tumors due to batch-to-batch variations, stringent operating conditions, and uncontrollable physicochemical properties. Here, we developed a more controllable hydrogel matrix comprising sodium alginate (NaA) and hyaluronic acid (HA) that can mimic the mechanical properties of native tumor tissue, such as extracellular matrix (ECM) components and stiffness. The PCOs cultured in the hydrogel matrix exhibited similar viability and growth rate with that in commercial Matrigel. Furthermore, we observed improvements of PCOs in 1% NaA-HA hydrogel matrices over tumor-specific features observed previously in animal-derived matrices. Transcriptional analysis revealed the activation of signaling pathways associated with ECM organization in the PCOs generated in hydrogel. Moreover, we noted that the biomimetic stiffness of hydrogel enhanced the drug resistance of PCOs of conventional chemotherapy agents but improved the sensitivity to targeted antitumor drugs (Erlotinib) of the PCOs with EGFR mutation. This work represents foundation for the customizing hydrogel stiffness that can be utilized to mimic the native tumor tissue, as well as a new platform for performing pancreatic cancer research and antitumor drug screening in the future.

Keywords:  defined hydrogels; drug testing; pancreatic cancer; tunable stiffness

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00705
ACS Macro Lett. 2025 Aug 13. 1241-1247

Development of Photocurable NorHA-dECM Hybrid Hydrogels to Study Cell-Matrix Interactions.

Tuba Marjan, Alyson R Owen, Taimoor H Qazi.

Biomimetic culture platforms aid in understanding cell behavior in vitro and are useful for studying mechanisms of disease progression and tissue regeneration. Synthetic hydrogels are widely used for this purpose, but while they offer advantages such as tunability and mechanical stability, they lack the range of biochemical signals present in the native microenvironment. On the other hand, decellularized extracellular matrices (dECMs) retain native biochemical signals but their adoption as stable in vitro culture platforms is limited due to batch variability, poor mechanical stability, and limited tunability. Here we report the development of hybrid hydrogels comprising dECM and a photocurable norbornene-modified hyaluronic acid (NorHA) polymer. To overcome structural heterogeneity of dECM that inhibits its solubility, uniform gelation, and spatial uniformity during cell culture, we physically process dECM by grinding, shearing, or both, prior to incorporation within NorHA. Both processing methods reduce microscale dECM aggregation and improve physical gelation at 37 °C. The addition of dECM up to 10 mg/mL within NorHA hydrogels neither affects rapid UV cross-linking nor compromises mechanical properties, as evaluated using oscillatory shear rheology and uniaxial compression testing. Both processes significantly improve the uniform distribution of dECM within 3D hybrid hydrogels, as evaluated by staining hydrogel cryosections. Fibroblasts show significantly higher spreading area and proliferation on hybrid hydrogels compared with control NorHA hydrogels. Taken together, photocurable hybrid hydrogels having uniformly distributed dECM combine the biochemical complexity of native dECM with the tunability of a synthetic polymer and represent an advance in the engineering of biomimetic platforms to investigate cell-matrix interactions.

DOI: https://doi.org/10.1021/acsmacrolett.5c00339
Adv Sci (Weinh). 2025 Aug 13. e06790

Magnetic-Driven Viscous Mechanisms in Ultra-Soft Magnetorheological Elastomers Offer History-Dependent Actuation with Reprogrammability Options.

Ernesto Gonzalez-Saiz, Maria Luisa Lopez-Donaire, Lucía Gutiérrez, Kostas Danas, Daniel Garcia-Gonzalez.

  This work elucidates an important open question in the field of mechanically soft magnetorheological elastomers (MREs): how microstructural rearrangements during magnetic actuation modulate their viscoelastic behavior. Experimental assays are provided on mechanically confined and very soft MREs that, under magnetic actuation, show an order of magnitude increase in relaxation times compared to purely mechanical cases. It is demonstrated that such a modulation in the viscous response can be tuned by the amplitude and actuation rate of the magnetic stimuli, and is intrinsically linked to microstructural rearrangements of the magnetic particles. Motivated by these experimental observations, magnetic actuation protocols are conceived to enable mechanical responses in soft materials with force-memory. Specifically, due to the magnetically induced long-term viscous relaxation, one can induce magnetic-driven yielding by introducing material hardening during cycling loading. This mechanical memory of the MRE can be subsequently removed by releasing the magnetic stimuli for 1$\hskip.001pt 1$ h, resetting the material performance and its microstructural state. These mechanisms are deeply understood by a combination of different experimental approaches and a new theoretical magneto-mechanical continuum model. The results reported herein respond to unraveled fundamental questions in soft MREs, and provide a game-changing concept for designing a new branch of soft sensor-actuator and reservoir computing systems.

Keywords:  constitutive model; magnetorheological elastomer; mechanical memory; resevoir computing; viscoelasticity

DOI:  https://doi.org/10.1002/advs.202506790
bioRxiv. 2025 Aug 06. pii: 2025.07.09.663980. [Epub ahead of print]

Size-dependent invasion and therapeutic phenotype of 42MGBA glioblastoma spheroids.

Sheridan Fok, Anagha Shreesha, Angela Appiah-Kubi, Rebecca B Riggins, Brendan A C Harley.

Glioblastoma (GBM) is one of the most common malignant brain tumors, with patient mortality driven by invasion into the surround brain microenvironment and drug resistance. Multicellular spheroids are increasingly a common model to study GBM invasion and drug response in engineered biomaterials. However, a key design feature of tumor spheroid studies is the size of each spheroid (number of cells, diameter). Given the heterogenous growth of GBM cells at the surgical margin, spheroids of different sizes may also have clinical relevance. Here, we define shifts in behavior and drug response of wild type and temozolomide (TMZ) resistant GBM spheroids as a function of initial spheroid size. GBM spheroids ranging from 100 to 12,000 cells in size were embedded into a methacrylamide-functionalized gelatin (GelMA) hydrogel. GBM spheroid size had an inverse relationship with the number of apoptotic cells. We observed significant spheroid size dependent effects on TMZ efficacy for both TMZ resistant and wild type cells. Interestingly, high single doses of TMZ were more effective in reducing three-dimensional migration from smaller spheroids than metronomic dosing while high single dose and metronomic dosing were equally effective in reducing invasion for large TMZ-resistant spheroids. Our study highlights the importance of considering and reporting spheroid size for cancer tissue engineering studies considering invasion and drug resistance. It also informs future studies of residual GBM at the tumor margins most responsible for patient relapse and mortality.

DOI: https://doi.org/10.1101/2025.07.09.663980