bims-ecemfi 2025-03-09 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–03–09
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Measurement and Comparison of Hyaluronic Acid Hydrogel Mechanics Across Length Scales.
3D Mechanical Confinement Directs Muscle Stem Cell Fate and Function.
Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages.
Contractility-Driven Cell Motility against a Viscoelastic Resistance.
ROS-triggered biomimetic hydrogel soft scaffold for ischemic stroke repair.
Alginate-Dialdehyde-Based Reporter Ink Enabling Online Detection of Matrix Metalloproteinase Activity of Encapsulated Cells.
Nanoscale distribution of bioactive ligands on biomaterials regulates cell mechanosensing through translocation of actin into the nucleus.

J Biomed Mater Res A. 2025 Mar;113(3): e37889

Measurement and Comparison of Hyaluronic Acid Hydrogel Mechanics Across Length Scales.

Aina Solsona-Pujol, Nikolas Di Caprio, Hannah M Zlotnick, Matthew D Davidson, Morgan B Riffe, Jason A Burdick.

  Hydrogels are an important class of biomaterials that are being developed for use in medicine, such as in drug delivery and tissue engineering applications. To improve properties (e.g., injectability, nutrient transport, cell invasion), hydrogels are often processed as hydrogel microparticles (microgels) that can be used as suspensions or jammed into granular hydrogels. The mechanical properties of microgels are important across length scales, from macroscale bulk properties of granular assemblies to microscale interactions with cells; however, microgel mechanics are rarely reported due to challenges in their measurement. To address this, we report here a cost-effective, easy-to-use do-it-yourself (DIY) active feedback micropipette aspiration device to quantify the mechanics of individual microgels. Using norbornene-modified hyaluronic acid (NorHA) synthesized via an environmentally friendly, aqueous reaction as an exemplary hydrogel, we compare hydrogel mechanics across scales at various macromer concentrations. Hydrogels tested via uniaxial compression exhibit similar moduli values, trends of increasing modulus with increasing macromer concentration, and mechanical stability over time to the same formulations processed as microgels via batch emulsions (~170 μm) and tested via micropipette aspiration. Moduli range from ~50 to ~100 kPa as the NorHA macromer concentration increases from 3 wt% to 5 wt%. These findings are validated by testing with spherical nanoindentation, with similar moduli measured. Collectively, this work provides an accessible device that allows for the rapid testing of microgel mechanical properties, while also improving our understanding of hydrogel mechanics across scales for use in the design of microgels for biomedical applications.

Keywords:  hydrogel; microgel; microgel mechanics; micropipette aspiration; nanoindentation

DOI:  https://doi.org/10.1002/jbm.a.37889
Adv Biol (Weinh). 2025 Mar 04. e2400717

3D Mechanical Confinement Directs Muscle Stem Cell Fate and Function.

GaYoung Park, Josh A Grey, Foteini Mourkioti, Woojin M Han.

  Muscle stem cells (MuSCs) play a crucial role in skeletal muscle regeneration, residing in a niche that undergoes dimensional and mechanical changes throughout the regeneration process. This study investigates how 3D confinement and stiffness encountered by MuSCs during the later stages of regeneration regulate their function, including stemness, activation, proliferation, and differentiation. An asymmetric 3D hydrogel bilayer platform is engineered with tunable physical constraints to mimic the regenerating MuSC niche. These results demonstrate that increased 3D confinement maintains Pax7 expression, reduces MuSC activation and proliferation, inhibits differentiation, and is associated with smaller nuclear size and decreased H4K16ac levels, suggesting that mechanical confinement modulates both nuclear architecture and epigenetic regulation. MuSCs in unconfined 2D environments exhibit larger nuclei and higher H4K16ac expression compared to those in more confined 3D conditions, leading to progressive activation, expansion, and myogenic commitment. This study highlights the importance of 3D mechanical cues in MuSC fate regulation, with 3D confinement acting as a mechanical brake on myogenic commitment, offering novel insights into the mechano-epigenetic mechanisms that govern MuSC behavior during muscle regeneration.

Keywords:  3D confinement; hydrogels; mechanobiology; mechano‐epigenetics; muscle stem cells; skeletal muscle

DOI:  https://doi.org/10.1002/adbi.202400717
Adv Healthc Mater. 2025 Mar 05. e2405097

Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages.

Dihao Tao, Hanzhe Wang, Shiping Chang, Jiayu Cheng, Ningning Da, Li Zhang, Jianhua Yang, Wenzhe Wang, Feng Xu, Bei Li.

  Understanding the interplay between extracellular matrix (ECM) mechanics and macrophage cellular processes is crucial for bone regeneration. While ECM stiffness has been extensively studied, the role of ECM viscoelasticity (e.g., stress relaxation) in the bone marrow niche and its effects on macrophage function remain unclear. Here, this study reveals how matrix viscoelasticity orchestrates osteogenesis by modulating macrophage metabolism through vasodilator-stimulated phosphoprotein (VASP) / hypoxia-inducible factor 1 alpha (HIF1α) signaling. In the rapid maxillary expansion (RME) model, significant stress relaxation occurs in regenerated bone marrow during the initial 17 days, coinciding with increased transforming growth factor-beta 1 (TGF-β1+) F4/80+ macrophages. Fast stress relaxation enhances macrophage recruitment of mesenchymal stem cells (MSCs) by upregulating TGF-β1. Using a hydrogel-macrophage system mimicking bone marrow viscoelasticity, cranial defect regeneration is significantly improved. Moreover, fast stress relaxation shifts macrophage metabolism from glycolysis to oxidative phosphorylation (OXPHOS) via VASP/HIF1α signaling, facilitating a reparative phenotype. These findings elucidate the relationship between ECM viscoelasticity and macrophage metabolism, suggesting new therapeutic avenues for bone regeneration through mechanomedicine.

Keywords:  OXPHOS; bone regeneration; glycolysis; macrophages; mechanical microenvironment; mechanomedicine

DOI:  https://doi.org/10.1002/adhm.202405097
Phys Rev Lett. 2025 Feb 14. 134(6): 068401

Contractility-Driven Cell Motility against a Viscoelastic Resistance.

Tapas Singha, Pierre Sens.

We study a model of contraction-based cell motility inside a microchannel to investigate the regulation of cell polarization and motion by the mechanical resistance of the environment. A positive feedback between the asymmetry of the acto-myosin cortex density and cell motion gives rise to spontaneous symmetry breaking and motility beyond a threshold contractility that depends on the resistance of extracellular medium. In highly viscous environments, we predict bistability under moderate contractility, so that symmetry breaking needs to be activated. In viscoelastic environments, we find the possibility for periodic oscillations in cortex density polarization and velocity. At the boundary between viscous and viscoelastic environments, the cell may cross, bounce back, or become trapped, depending on the viscoelastic relaxation time. These results are summarized in phase diagrams obtained by combining linear stability analysis and numerical simulations.

DOI: https://doi.org/10.1103/PhysRevLett.134.068401
Biomaterials. 2025 Feb 25. pii: S0142-9612(25)00136-X. [Epub ahead of print]319 123217

ROS-triggered biomimetic hydrogel soft scaffold for ischemic stroke repair.

Wen Zhang, Yang Liu, Yu Wu, Zhicun Wang, Xiyu Liu, Qinsheng Hu, Li Yang, Cheng Hu, Yunbing Wang.

  Millions of individuals worldwide suffer from ischemic stroke (IS). The focal hypo-perfused brain brings about hostile pathological environment, which further restricts endogenous neurogenesis post-stroke. In this work, we report an ROS-triggered hyaluronic acid (HA) and platelet lysates (pls) composite biomimetic hydrogel soft scaffold (pls gel) encapsulating matrix metalloproteinase (MMPs)-responsive triglycerol monostearate nanoparticles loaded with docosahexaenoic acid (TGMS@DHA, TD). Pls gel was chosen to be the hydrogel matrix to mimic brain extracellular matrix (ECM) to provide physical support for cell infiltration and accelerate angiogenesis as a growth factors (GFs) box. The borate ester bonded hydrogel could respond to reactive oxygen species and relieve oxidative stress. The loaded TD nanoparticles could be enzymatically cleaved by overexpressed MMPs in cerebral infarcted site, which could improve the adverse effects triggered by overexpressed MMPs. DHA with rich unsaturated bonds was proven that not only inhibit neuroinflammatory and oxidative stress, but also take part in promote neurogenesis. In brief, the ROS-triggered hydrogel scaffold pls gel@TD created an optimized microenvironment to manipulate the survival and differentiation of neural stem cells and promote endogenous regenerative repair processes. The in vitro results exhibited the biomimetic soft scaffold eliminated oxygen-glucose deprivation-derived free radical, saved mitochondrial dysfunction, reduced neuronal apoptosis, and promoted neovascularization. In the mice focal IS model, the biomimetic hydrogel scaffold regulated pathological environment in the ischemic site and induced migration and differentiation of endogenous neural stem cells, consequently relieved neuron ischemia injury. During the long-term observation, the hydrogel improved mice neurobehavioral functions. In conclusion, the hydrogel soft scaffold pls gel@TD was demonstrated to have promising therapeutic effects on remodeling pathological environment by transforming the hostile state into a pro-regenerative one in the infarct site, consequently promoting endogenous regenerative repair processes.

Keywords:  Hydrogel; Ischemic stroke; Nanoparticles; Platelet lysate

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123217
ACS Biomater Sci Eng. 2025 Mar 07.

Alginate-Dialdehyde-Based Reporter Ink Enabling Online Detection of Matrix Metalloproteinase Activity of Encapsulated Cells.

Benedikt Gantert, Emine Karakaya, Florian Hofmann, Tomasz Jungst, Lorenz Meinel, Anja K Bosserhoff, Rainer Detsch, Tessa Lühmann.

  Biofabrication and three-dimensional (3D) bioprinting enable precise spatial arrangement of cells within biomaterial scaffolds. We developed an alginate-based and Förster resonance energy transfer (FRET)-responsive "turn-on" reporter ink platform to enable real-time monitoring of matrix metalloproteinase (MMP) activity. Three distinct MMP-cleavable turn-on peptide reporters were synthesized and characterized for their cell-specific cleavage profiles using recombinant MMPs, cell-derived media, and different cell cultures (NIH3T3, HEK293, and MelHo). All turn-on reporters were covalently and site-specifically incorporated into alginate dialdehyde (ADA) to yield an MMP reporter ink. The ADA reporter ink with an MMP 13 turn-on reporter was responsive to all tested cell types over time within the cast bulk constructs. The ADA reporter ink material blended with gelatin had comparable print resolution and structural fidelity as observed for ADA. The extrusion-based bioprinted MelHo cell grids, measuring 2 × 2 cm2 and containing 1 × 106 cells/mL, exhibited MMP activity responses comparable to those of the casted reporter ink system, with a 3-fold increase observed at 24 h. This study introduces a versatile, FRET-based alginate bioink platform for the real-time monitoring of MMP activities, expanding the toolkit to understand cellular performance in bioprinted 3D constructs.

Keywords:  FRET peptide sensor; MMP; biofabrication; bioprinting; hydrogel; turn-on reporter

DOI:  https://doi.org/10.1021/acsbiomaterials.4c02399
Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2501264122

Nanoscale distribution of bioactive ligands on biomaterials regulates cell mechanosensing through translocation of actin into the nucleus.

Xiaojing Liu, Man Zhang, Peng Wang, Kaikai Zheng, Xinlei Wang, Wenyan Xie, Xiaokai Pan, Runjia Shen, Ruili Liu, Jiandong Ding, Qiang Wei.

  Cells respond to adhesive ligands such as arginine-glycine-aspartate (RGD) through integrins, which regulates cellular activities via influencing cytoskeleton assembly. Herein, we report that the nanoscale distribution of active ligands on biomaterials regulates cells through not only cytoplasmic tension but also nuclear tension. This is particularly related to translocation of actin into nucleus and highlighted in our interpretation of an "abnormal" phenomenon that large RGD nanospacing (>70 nm) disassembles integrin clusters, inhibits cell adhesion, but promotes osteogenic differentiation of mesenchymal stem cells. Our studies reveal that the unstable adhesion at the 150 nm RGD distance increases actin dynamics, resulting in the nuclear translocation of globular (G) actin. The compartment polymerization of more G-actins to filamentous actins in nucleus increases nuclear tension, facilitating transcription activity and releasing calcium ions from the endoplasmic reticulum. This noncanonical mechanotransduction process sheds insight into mechanotransduction pertinent to cell-material interactions.

Keywords:  RGD nanopattern; biomaterials; mechanotransduction; nuclear actin; stem cell differentiation

DOI:  https://doi.org/10.1073/pnas.2501264122