bims-ecemfi 2026-02-08 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–02–08
eighteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Nascent extracellular matrix converts biomaterial cues into cell fate decisions.
Tunable viscoelastic collagen/polyethylene glycol composite hydrogels modulate neural and tumor cell behavior in 3D microenvironments.
Hyaluronic Acid-Based, Double Network Hydrogels With Tunable Viscoelasticity for Neural Cell Culture.
Hydrogel Design to Understand and Guide 3D Cell Migration.
Periodic confined cell migration drives partially reversible chromatin reorganization in cancer cell lines.
From confinement to remodeling: modeling topotaxis-driven cell migration in obstacles networks.
Engineering the microstructure and spatial bioactivity of MAP scaffolds instructs vasculogenesis in vitro and modifies vessel formation in vivo.
Mechanically heterogeneous hydrogel with cell-programmed network restructuring promotes tissue regeneration by mechano-epigenetic modulation.
Recapitulating the Native Tendon Environment in a Synthetic 3D Anisotropic Hydrogel as an Engineered Extracellular Matrix.
Targeting the D93 cryptic collagen epitope alters integrin α2β1-dependent cellular migration and collagen remodeling in metastatic breast cancer.
Dynamic Gelatin Hydrogels Crosslinked by Dithiolane-Norbornene Click Chemistry.
Engineering bioinspired, high-density collagen microgels with tunable intrafibrillar mineralization for accelerated osteogenesis in vitro and bone regeneration in vivo.
Fiber-integrated hydrogels: a versatile platform to improve structural and biological performance in 3D biofabrication.
Bioprinting of Microtissues Within Mechanically Tunable Support Baths to Engineer Anisotropic Musculoskeletal Tissues.
The Notch1 intracellular domain orchestrates mechanotransduction of fluid shear stress.
Granular aerogel scaffolds with engineered pore microarchitecture for rapid cell infiltration, tissue integration, and vascularization.
Integrin αv contributes to the regulation of vascular smooth muscle cell stiffness.
Stochastic Nanoscale Biophysical Cues as a Basis for the Induction of Glioblastoma-Like Transcriptional Programs in Astrocytes.

bioRxiv. 2026 Jan 12. pii: 2026.01.10.698826. [Epub ahead of print]

Nascent extracellular matrix converts biomaterial cues into cell fate decisions.

J Y Liu, E M Plaster, M Fan, D W Ahmed, A Roy, P Duran, P Panovich, A S Piotrowski-Daspit, C A Aguilar, M L Killian, C Loebel.

Hydrogels serve as powerful models for investigating cell-extracellular matrix (ECM) interactions. While chemical modifications are routinely used to tune hydrogel properties, it remains unclear whether these modifications mediate cell fate. Previous work has shown that cells deposit newly synthesized (nascent) ECM at the cell-hydrogel interface. Here, we demonstrate that this nascent ECM interface regulates how cells interpret chemical modifications. Using hydrogels with varied chemical modifications, we isolated the effects of chemical modification on nascent ECM and cell fate. Nascent ECM deposition increased as a function of hydrogel modification and with distinct matrisome compositions. While low modification hydrogels promoted cell differentiation, high modifications increased cell proliferation. Perturbing cell-nascent ECM interactions reversed this cell fate. Our findings reveal that nascent ECM regulates cell fate by converting hydrogel cues into signals that control cell fate. This tri-directional interplay among hydrogel chemical modifications, nascent ECM, and cell fate reframes how we interpret cell-hydrogel interactions.

DOI: https://doi.org/10.64898/2026.01.10.698826
Biomater Transl. 2025 ;6(4): 437-449

Tunable viscoelastic collagen/polyethylene glycol composite hydrogels modulate neural and tumor cell behavior in 3D microenvironments.

Hexu Zhang, Ziyan Chen, Runxiang Yao, Yuyun Liang, Chaoyong He, Jing Yang, Houzhi Kang, Liyang Shi.

  Three-dimensional (3D) cell culture systems provide a more physiological environment than traditional two-dimensional cultures by better mimicking the complex interactions within the extracellular matrix (ECM). Among the key properties of the ECM, viscoelasticity is essential for regulating cell behaviors, such as proliferation, differentiation, and migration. However, many present 3D culture systems are complex and technically demanding, which limits their broad application. In this study, we developed two hydrogel systems with identical stiffness but distinct viscoelastic properties, designed to serve as ECM-based 3D culture platforms. These hydrogels were constructed through the cross-linking reaction between type I collagen and functionalized polyethylene glycol derivatives, resulting in either reversible (dynamic) or stable (static) network structures. This platform effectively simulated ECM-like mechanical cues, enabling the investigation of viscoelastic effects on both neural and cancer cell responses. Our results demonstrated that dynamic hydrogels, characterized by rapid stress relaxation, enhanced PC12 cell elongation, promoted neural stem cell differentiation, and significantly facilitated the invasiveness and tumorigenic capacity of DU145 cells in vitro and in vivo. These findings highlight the critical importance of matrix viscoelasticity in modulating cell behavior and underscore the potential of this hydrogel-based system as a versatile and accessible tool for applications in neural tissue engineering, cancer research, and mechanobiology.

Keywords:  3D cell culture; Cell behavior; Collagen; Hydrogel; Viscoelasticity

DOI:  https://doi.org/10.12336/bmt.25.00096
J Biomed Mater Res A. 2026 Feb;114(2): e70042

Hyaluronic Acid-Based, Double Network Hydrogels With Tunable Viscoelasticity for Neural Cell Culture.

Talia Sanazzaro, Sabrina Pietrosemoli Salazar, Neha Arvinth, Arushi Nath, Talon Blottin, Ze Zhong Wang, Stephanie K Seidlits.

  Brain tissue is the softest, most viscoelastic tissue in mammals and these mechanical properties strongly influence cell phenotypes. However, conventional hydrogels for 3D cultures rarely provide the ability to tune the elasticity (G') independently of the viscosity (G″), making it impossible to decouple the effects of each mechanical component on cell behavior. To address this deficiency, we have developed a hyaluronic acid (HA)-based, double network hydrogel platform, in which G' and G″ can be tuned independently, keeping G' within the range observed in native brain tissue. The double network hydrogel includes a covalently photocrosslinked HA network (thiolene) to control the elasticity and a dynamically crosslinked HA (hydrazone) network to regulate the viscosity. Addition of the dynamic network to the static single networks increased viscoelasticity, as assessed by the stress-relaxation time and dissipation factor (tan(δ)), of the biomaterial fourfold over that of the covalent network alone, without affecting the storage modulus (G'). The proliferation and spreading of two neural cell types, patient-derived glioblastoma (GBM) tumor cells and mouse neural stem cells (mNSCs), were evaluated in single and double network hydrogels with varying elasticities. An increase in viscoelasticity increased cell proliferation in one patient-derived GBM line, independently of elasticity, while the converse was found in mNSCs. In both GBM and mNSCs cultures, increased cell spreading was observed in stiff double network, compared to stiff single network, gels. This double network hydrogel model allows for the orthogonal tuning of elasticity and viscosity to better represent the mechanics of CNS tissue.

Keywords:  hyaluronic acid; hydrogel; neural tissue engineering; viscoelasticity

DOI:  https://doi.org/10.1002/jbma.70042
Regen Eng Transl Med. 2025 ;11(4): 802-813

Hydrogel Design to Understand and Guide 3D Cell Migration.

Karen L Xu, Robert L Mauck, Jason A Burdick.

   Purpose: The extracellular environment is critical for cell migration in three-dimensions (3D), which has been understudied when compared to cell migration on two-dimensional (2D) substrates. In 3D, cells must degrade or remodel their surroundings to overcome barriers to migration or find paths that act as migration routes.
Methods: We performed a literature search for studies related to the engineering of hydrogels to understand and control cell migration.
Results: This review highlights the cell-intrinsic machinery that is required for migration, describes how cell migration can be modeled in vitro, and provides examples where hydrogels have been designed with permissive extracellular cues that enhance cell migration for biomedical applications.
Conclusions: Hydrogels can be engineered to mimic many features of the extracellular space to help us better understand the interplay between cells and their environment and interpret how these complex processes support or limit cell migration. With this understanding, hydrogels can be designed to guide cellular migration, particularly in the context of tissue repair and regenerative medicine.
Lay Summary: Cell movement is important in both healthy and diseased tissues. An understanding of how cells migrate and the development of methods to control their migration can be utilized to improve patient therapies in the future in applications such as tissue repair and regeneration. Hydrogels are water-swollen materials that mimic many features of tissues. This allows their use to understand how cells respond to various features in their environment, as well as for therapeutic materials in tissue repair. This review highlights advances on these topics.

Keywords:  Cell migration; Cell-material interfaces; Engineered matrices; Microinterfaces

DOI:  https://doi.org/10.1007/s40883-025-00395-z
Commun Biol. 2026 Feb 06.

Periodic confined cell migration drives partially reversible chromatin reorganization in cancer cell lines.

Maria Del Valle Blazquez-Romero, Marco Mendivil-Carboni, Maria Sarasquete-Martinez, Alejandro Sainz-Agost, Fernando Falo, Marco De Corato, Maria Jose Gomez-Benito.

Cells throughout physiological and pathological contexts are exposed to a broad spectrum of mechanical stimuli, triggering extensive nuclear deformation and chromatin remodeling. These mechanical cues drive the cell to dynamically adapt through coordinated structural, epigenetic, and biochemical mechanisms to withstand mechanical stress while protecting genomic integrity. However, whether such cellular adaptations are reversible or result in persistent alterations remains unresolved. In cancer metastasis, addressing this issue is critical: confined migration through narrow pores prompts chromatin condensation with heterochromatin enrichment, yet cancer cells must preserve their oncogenic potential while preparing for future deformations. Therefore, the ability of these cells to reconcile reversible chromatin remodeling and mechanical memory could be key to metastatic resilience. Here, using a custom-designed microfluidic device to monitor single-cell chromatin reorganization, we show confined migration induces partially-reversible chromatin condensation: total highly-condensed chromatin content is recovered after deformation, but the distribution of condensed chromatin clusters remains altered. Our findings highlight this duality of chromatin condensation as both a short-term adaptive response and a mechanical memory strategy, which could potentially contribute to address cancer invasiveness.

DOI: https://doi.org/10.1038/s42003-026-09637-4
J Math Biol. 2026 Feb 03. 92(2): 30

From confinement to remodeling: modeling topotaxis-driven cell migration in obstacles networks.

Rachele Allena.

  Several physiological and pathological processes, such as development, wound healing, and cancer invasion, depend on cell migration through fibrous extracellular matrix (ECM). In such contexts, topographical features of the ECM, including fiber alignment and pore size, strongly bias migration, a phenomenon known as topotaxis. To explore this guidance mechanism in a controlled theoretical setting, we present a minimal particle-based model of single-cell motility in two-dimensional environments abstracted as networks of elongated obstacles. This abstraction captures key geometric and topographical constraints of fibrous microenvironments while remaining computationally tractable. Our framework integrates chemotactic bias, stochastic polarity dynamics, steric repulsion from obstacles, escape strategies from mechanical trapping, and minimal remodeling of the obstacles network. Adaptive polarity perturbations mimic active cellular responses such as invadopodial protrusion or random reorientation, while a displacement-based criterion detects trapping events. Heterogeneity is incorporated by assigning variable repulsion strengths to obstacles, and remodeling is implemented by allowing local displacements induced by cell-obstacle contact. Simulation results show that active remodeling of obstacles consistently enhances migration efficiency and target acquisition, whereas escape strategies alone provide only partial improvement, and heterogeneity introduces directional variability. At long timescales, trajectories converge toward effective diffusion, but intermediate dynamics display nontrivial deviations due to confinement and obstacle interactions, highlighting a topotaxis-driven component of motility. Overall, this work positions cell migration within the theoretical context of obstacles networks, providing mechanistic insight into how confinement, anomalous transport, and remodeling interact to shape directional migration. While simplified to two dimensions and lacking entanglement effects characteristic of real three-dimensional ECMs, the model offers a tractable and extensible framework for future studies, including the incorporation of cell deformations or more realistic ECM architectures.

Keywords:  Cell migration; Cell polarity; Extracellular Matrix; Particle-based model; Remodelling

DOI:  https://doi.org/10.1007/s00285-026-02345-x
Adv Funct Mater. 2025 Jan 15. pii: 2400567. [Epub ahead of print]35(3):

Engineering the microstructure and spatial bioactivity of MAP scaffolds instructs vasculogenesis in vitro and modifies vessel formation in vivo.

Alexa R Anderson, Eleanor L P Caston, Lindsay Riley, Long Nguyen, Dimitris Ntekoumes, Sharon Gerecht, Tatiana Segura.

  In tissues where the vasculature is either lacking or abnormal, biomaterials can be designed to promote vessel formation and enhance tissue repair. In this work, we independently tune the microstructure and bioactivity of microporous annealed particle (MAP) scaffolds to guide cell growth in 3D and promote de novo assembly of endothelial progenitor-like cells into vessels. We implement both in silico characterization and in vitro experimentation to elucidate an optimal scaffold formulation for vasculogenesis. We determine that MAP scaffolds with pore volumes on the same order of magnitude as cells facilitate cell growth and vacuole formation. We achieve spatial control over cell spreading by incorporating adhesive microgels in well-mixed, heterogeneous MAP scaffolds. While we demonstrate that integrin engagement is the primary driver of network formation in these materials, introducing adhesive microgels loaded with heparin nanoparticles leads to the formation of vascular tubes after 3 days in culture. We then show in vivo that this unique scaffold formulation enhances vessel maturation in a wound healing model and instructs differential vascular development in the tumor microenvironment. Taken together, this work determines the optimal microstructure and ligand presentation within MAP scaffolds that leads to vascular constructs in vitro and facilitates vessel formation in vivo.

Keywords:  granular; hydrogel; microgel; microstructure; neovascularization; vasculogenesis

DOI:  https://doi.org/10.1002/adfm.202400567
Nat Commun. 2026 Jan 30.

Mechanically heterogeneous hydrogel with cell-programmed network restructuring promotes tissue regeneration by mechano-epigenetic modulation.

Qiangjun Ling, Hao Li, Jianyang Zhao, Weitang Guo, Hong Yu, Zhuo Li, Yuan Hu, Shuzhen Wei, Yiben Fu, Yu Zhang, Kunyu Zhang, Liming Bian.

Stem cell differentiation dynamically remodels and stiffens the extracellular matrix (ECM), generating stage-specific biomechanical cues that guide tissue development. However, conventional biomaterials, designed to mimic mature ECM stiffness, neglect its spatiotemporal heterogeneity due to their static, non-evolvable nature. Herein, we develop a cell-programmed adaptative contraction (CPAC) hydrogel that enables mesenchymal stem cells (MSCs) to actively remodel their microenvironment through alkaline phosphatase (an early osteogenic marker)-mediated hydrophilic-to-hydrophobic transition and contraction of microgels. This cell-programmed remodeling establishes local mechanical heterogeneity and promotes osteogenesis through a positive feedback loop. Mechanistically, the evolving matrix enhances mechanotransduction-related microRNA expression, suppresses EZH2, and reduces H3K27 trimethylation to active osteogenic transcription. In vivo, MSC-laden CPAC hydrogels significantly enhance the repair of rat cranial defects. These findings introduce a paradigm of cell-instructed, dynamically evolvable biomaterials that recapitulate the adaptive nature of native ECM to orchestrate stem cell fate and tissue morphogenesis.

DOI: https://doi.org/10.1038/s41467-026-69004-z
ACS Appl Bio Mater. 2026 Feb 04.

Recapitulating the Native Tendon Environment in a Synthetic 3D Anisotropic Hydrogel as an Engineered Extracellular Matrix.

Tayler S Hebner, Destina E Genc, Danielle S W Benoit.

  The ability of tendons to transmit forces from muscle to bone is fundamentally attributed to the hierarchical anisotropy of the tissue. After injury, disorganized fibrotic scar tissue forms during the natural healing process, resulting in inferior mechanical properties that often lead to reinjury and limited restoration of function. Therefore, intervention is necessary to facilitate regenerative healing of the tendon. Polymeric biomaterials have historically been used to guide cell behavior, showing promise for the use of topological guidance and cell-mediated matrix remodeling as mechanisms for promoting regeneration. Here, we fabricated 3D scaffolds for tenocytes using anisotropic poly(ethylene glycol)-based hydrogels that recapitulate both the biophysical and biochemical properties of the native tendon. These materials were synthesized using a two-stage polymerization strategy that includes an initial cross-linking step facilitated by thiol-Michael addition, an intermediate mechanical stretching step to align the polymer network, and a second-stage crosslinking step facilitated by a thiol-ene reaction. The application of 300% strain during the mechanical alignment of the network resulted in highly oriented materials (S = 0.38). Furthermore, a matrix metalloproteinase (MMP)-degradable peptide was incorporated into the network to facilitate cell-mediated remodeling of the scaffold. After 14 days of exposure to exogenous MMP2, a sufficient number of cross-links were degraded for alignment to be lost (S = 0.03). When tenocytes were encapsulated in the 3D anisotropic hydrogels, they adopted the anisotropic morphology of the polymer network and deposited an extracellular matrix mainly comprised of type I collagen, indicating a pro-regenerative environment. Comparatively, isotropic materials of the same composition induced a random orientation of encapsulated tenocytes, and a matrix primarily comprised of collagen III was deposited, indicating a fibrotic environment. Collectively, these results demonstrate the successful use of a synthetic scaffold with tunable biophysical and biochemical properties for recapitulating the native tendon environment and promoting regenerative cell behavior.

Keywords:  anisotropic materials; extracellular matrix; hydrogels; polymer synthesis; tendon

DOI:  https://doi.org/10.1021/acsabm.5c02408
Res Sq. 2026 Jan 16. pii: rs.3.rs-8406370. [Epub ahead of print]

Targeting the D93 cryptic collagen epitope alters integrin α2β1-dependent cellular migration and collagen remodeling in metastatic breast cancer.

Jordan N Miner, Christopher L Emmerling, Joshua D Hamilton, Joseph Raite, Zoe Vittum, Peter C Brooks, Andre Khalil, Karissa Tilbury.

Targeting the tumor-associated extracellular matrix (ECM) offers a promising strategy for breast cancer therapy. During cancer progression, collagen remodeling within the ECM exposes cryptic collagen epitope sites that antibodies can selectively recognize. Here, we investigate the therapeutic potential of targeting the D93 cryptic collagen epitope in 3D human metastatic breast cancer spheroids derived from MDA-MB-231 and MCF10CA1a (M4) cell lines embedded in collagen type I hydrogels. Treatment with monoclonal antibody (mAb) D93 reduced cellular migration into collagen type I hydrogels, an effect likely mediated by integrin α2β1. Two-photon microscopy further revealed that breast cancer cells drive the exposure of D93 sites and alter collagen architecture at both the fiber and fibril levels. Interestingly, collagen remodeling was altered more in the MDA-MB-231 spheroid models whereas the reduction in cellular migration was more pronounced in the M4 spheroid models, indicating a cell-line specific response to mAb D93. Together, these findings suggest that mAb D93 may inhibit integrin α2β1-dependent metastatic migration in breast cancer.

DOI: https://doi.org/10.21203/rs.3.rs-8406370/v1
Macromol Biosci. 2026 Feb;26(2): e00400

Dynamic Gelatin Hydrogels Crosslinked by Dithiolane-Norbornene Click Chemistry.

Favour O Afolabi, Lydia Yang He, Chien-Chi Lin.

  Hydrogels prepared from gelatin are ideal for mimicking the extracellular matrix (ECM) owing to their inherent cell-adhesive and protease-labile peptide sequences. While gelatin is highly water-soluble, it does not form the triple-helical structure. As a result, physically crosslinked gelatin-based hydrogels are only stable at low temperatures, precluding their use in 3D cell culture. Gelatin-methacryloyl (GelMA) and gelatin-norbornene (GelNB) have been developed to enable the stable crosslinking of gelatin-based hydrogels via chain-growth or step-growth photopolymerization. However, most gelatin-based hydrogels lack dynamically tunable properties unless macromers with dynamically crosslinkable motifs are used. Here, we integrate GelNB with dithiolane-containing crosslinker poly(ethylene glycol)-tetra-lipoic acid (PEG4LA)-for modular photo-crosslinking of GelNB into hydrogels under cytocompatible light exposure (365 nm, 5 mW/cm2) with a low photoinitiator concentration (1 mm LAP). Even under these mild reaction conditions, the stiffness of GelNB/PEG4LA hydrogels could be dynamically tuned by inducing dithiolane ring-opening via secondary light exposure, thereby creating dynamic and cytocompatible hydrogels suitable for in situ encapsulation, culture, and differentiation of human induced pluripotent stem cells (hiPSCs).

Keywords:  3D/4D cell culture; dithiolanes; dynamic hydrogels; gelatin‐norbornene; induced pluripotent stem cells; lipoic acid

DOI:  https://doi.org/10.1002/mabi.202500400
Acta Biomater. 2026 Feb 04. pii: S1742-7061(26)00076-0. [Epub ahead of print]

Engineering bioinspired, high-density collagen microgels with tunable intrafibrillar mineralization for accelerated osteogenesis in vitro and bone regeneration in vivo.

Sofia M Vignolo, Daniela M Roth, May A A Fraga, Lillian Wu, Jameson A Cosgrove, Avathamsa Athirasala, Angela S P Lin, Robert E Guldberg, Luiz E Bertassoni.

  The development of biomaterials that mimic native bone remains a major challenge in regenerative medicine. Here, we present a bioinspired platform using high-density collagen hydrogels with tunable mineral content. These engineered microenvironments promote rapid osteogenesis in vitro without osteogenic supplements and accelerate bone regeneration in vivo in critical-sized defects. By modulating mineralization, we demonstrate that early mechanosensitive signaling in human mesenchymal stem cells is linked to matrix stiffness and biochemical composition. Within two hours, focal adhesion formation decreased with increasing mineral content, and fully mineralized scaffolds significantly increased nuclear YAP1 localization. By 24 hours, RUNX2 expression was markedly increased in fully mineralized scaffolds, with 40.7 ± 3.9% RUNX2+ nuclei (p < 0.0001), and this trend persisted at the gene expression level at 3 days. In a rat calvarial defect model, fully mineralized microgels significantly increased bone volume in males at 12 weeks (18.99 ± 2.66 mm3) compared to empty defects (11.60 ± 2.12 mm3, p = 0.0242), whereas females showed no added benefit of full mineralization. Two-way ANOVA confirmed significant effects of sex (p = 0.0006), treatment (p < 0.0001), and their interaction (p = 0.0158). Histological analyses confirmed osteoinductive behavior across all microgel groups and highlighted reduced scaffold degradation and limited cellular infiltration in mineralized conditions. Together, these results demonstrate that tunable intrafibrillar mineralization modulates early stem cell mechanosensing and osteogenic priming in vitro and drives sex-dependent regenerative outcomes in vivo, emphasizing the need to balance scaffold mechanics and degradation to suit the biological context and improve clinical outcomes. STATEMENT OF SIGNIFICANCE: This study introduces a strategy to fine-tune the properties of implantable materials for bone repair using microscale scaffolds with controlled mineral content. By adjusting composition at the nanoscale, our work identifies how early cellular responses can be directed to influence long-term healing. Importantly, the findings reveal that regenerative outcomes vary by sex, emphasizing the need to consider biological differences in biomaterial design. This work offers new insight into how tailored physical environments can guide tissue repair and highlights the potential for precision approaches in bone graft development.

Keywords:  Bone regeneration; bone tissue engineering; microgels; mineralization; stem cell

DOI:  https://doi.org/10.1016/j.actbio.2026.02.003
Mater Today Bio. 2026 Apr;37 102799

Fiber-integrated hydrogels: a versatile platform to improve structural and biological performance in 3D biofabrication.

Annabelle Neuhäusler, Nils Lindner, Andreas Blaeser.

  Hydrogels emerged as versatile biomaterials for tissue engineering due to their extra cellular matrix similarity and mechanical and biochemical properties. Still, hydrogels expose limited stiffness, anisotropy and nutrient diffusion. By reinforcing hydrogels with synthetic and natural fibers, these drawbacks can be effectively addressed, thereby enabling the modeling of advanced biomimetic tissue. This review discusses recent progress in the fabrication of fiber-integrated hydrogels and brings together developments from biomaterials, biofabrication, mechanobiology, and organ-model engineering. Fiber-addition impact on viscoelastic, time-dependent und nonlinear material properties, on multiscale and hierarchical constructs and on mechanical and biological readouts are analyzed. Specifically, the integration of both synthetic and natural fibers into hydrogel matrices is highlighted which significantly broaden their structural and biochemical versatility. These fiber-added hydrogels display improved properties including enhanced stiffness (up to 10-fold increase), anisotropy (>80 % alignment) and nutrient diffusion (4-fold increase). Moreover, the incorporation of fibers directly impacts cellular behavior by promoting adhesion, migration, proliferation and differentiation. Finally, bone, muscle and nerve tissue are exemplary presented in more detail to highlight the broad potential of these composite materials. In conclusion, fiber-embedded hydrogels represent a decisive step toward enhanced 4D-metamaterials.

Keywords:  4D-metamaterials; Bone; Fibers; Hydrogels; Muscle; Nerve; Tissue engineering

DOI:  https://doi.org/10.1016/j.mtbio.2026.102799
Adv Sci (Weinh). 2026 Feb 06. e09313

Bioprinting of Microtissues Within Mechanically Tunable Support Baths to Engineer Anisotropic Musculoskeletal Tissues.

Francesca D Spagnuolo, Gabriela S Kronemberger, Daniel J Kelly.

  Bioprinting is a powerful tool for engineering living grafts, however replicating the composition, structure and function of native tissues remains a major challenge. During morphogenesis, cellular self-organization and matrix development are strongly influenced by the mechanical constraints provided by surrounding tissues, suggesting that such biophysical cues should be integrated into bioprinting strategies to engineer more biomimetic grafts. Here, we introduce a novel bioprinting platform that spatially patterns mesenchymal stem/stromal cell (MSC)-derived microtissues into mechanically tunable support baths. By modulating the bath's mechanical properties, we can precisely control the physical constraints applied post-printing, directing both filament geometry and cellular behavior. Support bath stiffness regulated mechano-sensitive gene expression and microtissue phenotype, with softer matrices favoring chondrogenesis and stiffer environments promoting (myo)fibrogenic differentiation. In addition, the physical properties of the non-degradable support bath modulated microtissue fusion and extracellular matrix organization, with increased collagen fiber alignment in stiffer baths. Leveraging these findings, it was possible to engineer either articular cartilage, meniscus, or ligament grafts with user-defined collagen architectures by simply varying the physical properties of the support bath. This platform establishes a foundation for bioprinting structurally anisotropic and phenotypically distinct constructs, thereby enabling the scalable engineering of a range of different musculoskeletal tissues.

Keywords:  anisotropy; bioprinting; microtissues; stiffness; support bath

DOI:  https://doi.org/10.1002/advs.202509313
Life Sci Alliance. 2026 Apr;pii: e202503599. [Epub ahead of print]9(4):

The Notch1 intracellular domain orchestrates mechanotransduction of fluid shear stress.

Tania Singh, Kyle A Jacobs, William J Polacheck, Matthew L Kutys.

Hemodynamic shear stress regulates endothelial phenotype through activation of Notch1 signaling, yet the mechanistic basis for this activation is unclear. Here, we establish a fluid shear stress-dependent mechanism of Notch1 activation that is distinct from canonical ligand trans-endocytosis. Application of unidirectional laminar flow triggers the rapid spatial polarization of full-length Notch1 heterodimers into downstream membrane microdomains. Unlike canonical transactivation, Notch1 receptors are cis-endocytosed into the receptor-bearing cell within polarized microdomains. We discover that the Notch1 intracellular domain critically orchestrates receptor polarization and proteolytic cleavage in response to flow, but is dispensable for canonical ligand transactivation. Shear stress increases intracellular domain interaction with annexin A2 and caveolar proteins, which control Notch1 cis-endocytosis and proteolytic activation. These findings define a flow-specific Notch1 mechanotransduction mechanism linking receptor polarization and endocytosis with proteolytic activation and illuminate a new pathway by which mechanical forces integrate with Notch receptor activation.

DOI: https://doi.org/10.26508/lsa.202503599
Biomaterials. 2026 Jan 27. pii: S0142-9612(26)00045-1. [Epub ahead of print]330 124021

Granular aerogel scaffolds with engineered pore microarchitecture for rapid cell infiltration, tissue integration, and vascularization.

Saman Zavari, Sina Kheirabadi, Ji Ho Park, Mohammad Hossein Asgardoon, Alexander Kedzierski, Arian Jaberi, Anton M Hjaltason, Yuanhui Xiang, Dino J Ravnic, Amir Sheikhi.

  Porous biomaterials that integrate tunable biophysical and biochemical cues have been extensively studied for guiding cell behavior and harnessing the body's intrinsic regenerative potential. Aerogels, characterized by their ultralight structure, high porosity, and large surface area, have emerged as promising porous scaffolds for tissue engineering; however, their limited pore tunability may hinder efficient cell infiltration and functional tissue integration. To address this persistent limitation, we develop a new class of porous biomaterials called granular aerogel scaffolds (GAS), assembled from size-tunable gelatin methacryloyl (GelMA) microparticles, enabling the precise control of pore geometry and interconnected micron-scale void networks within the aerogels. GelMA hydrogel microparticles are jammed and photocrosslinked to yield granular hydrogel scaffolds (GHS), followed by supercritical carbon dioxide drying, yielding GAS with tunable pore microarchitecture and preserved structural integrity. Importantly, rehydrated GAS have comparable mechanical, rheological, and pore characteristics to GHS. In vitro analyses and in vivo subcutaneous implantation show that GAS are non-toxic and support progressively greater cell infiltration as the size of their microparticle building blocks increases. Further in vivo analyses using a hindlimb micropuncture surgery model show an increase in scaffold vascularization and vessel maturation with an increase in microparticle size. This work establishes a platform for engineering aerogels with precisely tuned cell-scale interconnected pores, enabling rapid cell infiltration, tissue integration, and vascularization. GAS may serve as versatile, shelf-ready biomaterials for tissue engineering and regenerative medicine.

Keywords:  Aerogel; Cell infiltration; Granular biomaterial; Microgel; Porous; Regenerative medicine; Vascularization

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124021
Sci Rep. 2026 Feb 07.

Integrin αv contributes to the regulation of vascular smooth muscle cell stiffness.

Rümeyza Bascetin, Ekaterina Belozertseva, Véronique Regnault, Alexandre Raoul, Xiao Liu, Caterina Maria Tone, Ali-Akbar Karkhaneh-Yousefi, Huguette Louis, Zhor Ramdane-Cherif, Cindy Lerognon, Stéphane Avril, Adam Lacy-Hulbert, Daniel Henrion, Emmanuelle Lacaze, Pascal Challande, Zhenlin Li, Patrick Lacolley.

  Arterial stiffening is influenced by the organization of focal adhesions in vascular smooth muscle cells (VSMCs). We investigated the contribution of αv integrins to both arterial wall stiffness (Young's modulus measured by echography) and VSMC stiffness (assessed by atomic force microscopy). Mice with VSMC-specific deletion of αv integrins (αvSMKO) were compared with controls at baseline and following angiotensin II infusion. Unstimulated cultured αv-deficient (αv-KD) VSMCs exhibited higher stiffness than controls, with a further increase after angiotensin II. To interpret AFM measurements performed at shallow indentation depths, we developed a computational model of VSMC nanoindentation. Simulations showed that higher apparent Young's moduli at shallow indentation fall within the experimental range of αv-KD cells. These cells also displayed enhanced actin polymerization, further amplified by angiotensin II through the formation of cortical F-actin. In vivo, arterial pressure and wall elastic modulus were similar between αvSMKO and control mice at baseline and after angiotensin II, despite αvSMKO mice exhibiting lower elastin and higher collagen content under angiotensin II. Together, these findings indicate that the comparable increase in arterial stiffness observed in αvSMKO mice under angiotensin II is driven primarily by elevated VSMC stiffness resulting from cortical actin redistribution, which outweighs extracellular matrix changes.

Keywords:  Atomic force microscopy; Cell stiffness; Finite element method; Focal adhesion; Integrins; Vascular smooth muscle cells

DOI:  https://doi.org/10.1038/s41598-026-38948-z
Adv Sci (Weinh). 2026 Feb 03. e09362

Stochastic Nanoscale Biophysical Cues as a Basis for the Induction of Glioblastoma-Like Transcriptional Programs in Astrocytes.

Laurent Starck, Tobias Butelmann, Sabrina Hogan, Melika Sarem, Bernd Heimrich, Ritwick Sawarkar, Marie-Françoise Ritz, Gregor Hutter, V Prasad Shastri.

  Although direct biological factors underlying the progression of Glioblastoma (GBM), an aggressive form of brain cancer, have been extensively studied, emerging evidence suggests that indirect biological triggers, such as traumatic brain injury (TBI), may also have a role. Since proteoglycans, secreted by reactive astrocytes and astroglial cells contribute to biophysical characteristics (stochastic topography, stiffness) of the brain, we postulated a role for stochastic nanoroughness in the induction of glioma following brain trauma. Using a model system to emulate such physical cues that manifest following traumatic injury, we demonstrate that human cortical astrocytes undergo spontaneous organization into spheroids in response to nanoroughness and retain the spheroid phenotype even upon withdrawal of the physical cues. Furthermore, spheroids serve as aggregation foci for naïve astrocytes, express activated MMP2, and disseminate upon implantation in the mouse brain. RNA-seq analysis revealed that astrocytes within spheroids differentially express genes, including p53, ADAMTS proteases, and NOTCH3, and adopt a transcriptional program enriched for GBM proneural signatures, with reactome analysis pointing toward astrocytes with GBM-associated transcriptional traits. Moreover, nanoroughness mediates a cross-talk between cancer cells and astrocytes through induced senescence. These findings implicate a role for stochastic biophysical cues in driving a potential malignant transformation of astrocytes.

Keywords:  MMP‐2; activated astrocytes; cancer phenotype; mechanobiology; p53; senescence; spheroids

DOI:  https://doi.org/10.1002/advs.202509362