bims-ecemfi 2026-07-26 papers

Biomaterials. 2026 Jul 15. pii: S0142-9612(26)00484-9. [Epub ahead of print]336 124460

Dynamic stiffening to improve vasculogenesis of hiPSC-Derived endothelial progenitors.

Brett Stern, Jiwan Han, Kathleen Halwachs, Bryce Larsen, Kristie Cheng, Davina Tran, Patrik Parker, Nima Momtahan, Aaron Baker, Nicholas Peppas, Adrianne Rosales, Janet Zoldan.

Multiple groups have reported on the impact of hydrogel stiffness on vascular network formation in vitro, with overall findings indicating that hydrogels with lower stiffness better support vasculogenesis. However, most of this research utilizes hydrogels with static stiffness, even though vasculogenesis occurs in tandem with changes in extracellular matrix stiffness. To that end, we hypothesized that dynamic modulation of hydrogel stiffness during vasculogenesis would improve vascular network formation. Using a Collagen I/Norbornene-modified hyaluronic acid hydrogel system, we diffused additional crosslinker and photoinitiator into the hydrogel and initiated further UV crosslinking at predetermined time points, while maintaining high cell viability (>90%). We observed that in situ stiffening at early time points, prior to the completion of cell elongation, increased vascular network connectivity and volume fraction relative to unstiffened controls, while stiffening at later time points was associated with reduced network formation. Consistent with these findings, cell-laden hydrogels stiffened at early time points implanted subcutaneously in nude mice showed increased blood perfusion, while late-stiffened hydrogels did not improve perfusion relative to controls. Mechanistically, we found that these time-dependent differences were associated with changes in vinculin volume fraction, suggesting differential mechanotransductive signaling. Consistent with this, Rho kinase inhibition suppressed vinculin volume fraction in stiffened hydrogels and partially rescued vascular network formation following in situ stiffening. These findings indicate that the timing of stiffness modulation is a critical factor in determining vasculogenic outcome, and that early-stage stiffening can enhance vascular network formation beyond what is achieved in static hydrogel systems.

Keywords: Dynamic stiffening; Endothelial progenitor; Hydrogel; Matrix stiffness; Mechanotransduction; Vasculogenesis

DOI: https://doi.org/10.1016/j.biomaterials.2026.124460

iScience. 2026 Jul 17. 29(7): 116556

Location matters: Spatial-dependent effects of myofibroblasts modulate survival in breast cancer.

Hannah Si Hui Lau, Veronique Kiak Mien Tan, Ines Poljak, Anita Grigoriadis, Giulia Adriani, Kanaga Sabapathy.

While cancer-associated fibroblasts (CAFs) have been historically considered pro-tumorigenic, several studies found that myofibroblast-like CAFs (myCAFs) may have tumor-restraining properties. Here, we show that myofibroblasts exhibit location-dependent effects in breast cancer progression. Deconvolution of bulk RNA sequencing data from The Cancer Genome Atlas showed that high intratumoral myCAF abundance in ER+/PR+/HER2- breast tumors is associated with poor patient overall survival, whereas an inverse association was observed for peritumoral myCAFs in tumor-adjacent normal tissues. Single-nucleus RNA sequencing of 2 ER+/PR+/HER2- invasive breast carcinomas and their matched peritumoral tissues identified high abundance of myCAFs in the larger tumor, whereas a distinct myofibroblast-like sub-population was found in the peritumoral tissues of the smaller tumor. Three-dimensional co-culture experiments demonstrated that myofibroblasts positioned outside the tumor spheroid reduced breast cancer cell invasion. These data highlight that the spatial location of myofibroblasts determines their effects and provides an explanation for their dual role in cancer biology.

Keywords: breast cancer; cancer-associated fibroblasts; myofibroblasts; tumor microenvironment

DOI: https://doi.org/10.1016/j.isci.2026.116556

ACS Appl Mater Interfaces. 2026 Jul 21.

Model-Assisted Prioritization of Gelatin Methacryloyl (GelMA) Hydrogel Formulations for Three-Dimensional Cell Culture.

Peisong Yin, Xin Wang, Suqing Liu, Yujun Huang, Meiyi Huang, Yu Zhang, Ruijun Peng, Jingwen Sun, Yaobin Wu, Ling Wang.

Owing to highly tunable mechanics, gelatin methacryloyl (GelMA) hydrogels are widely exploited for three-dimensional (3D) cell culture, whereas limited experimental sampling restricts efficient formulation screening. In this work, we developed a BNN-based modeling pipeline to map GelMA hydrogels with various cross-linking parameters toward linear viscoelastic moduli and nonlinear critical stress, thereby categorizing all tested formulations into low/intermediate/high stable mechanical windows. Calibration on C2C12 myoblast morphologies confirmed that nonlinear critical stress complements linear rheological parameters to refine the screening priority of cell-compatible hydrogel recipes. Subsequent validation with primary cardiomyocytes demonstrated consistent morphological trends matching the predefined mechanical windows, alongside ambiguous boundary formulations. Our findings construct a bounded prioritization strategy to rapidly select GelMA compositions under sparse experimental conditions, with further prospective validations demanded before generalized predictive use for diverse tissue engineering scenarios.

Keywords: Gelatin methacryloyl (GelMA); Hydrogels; Mechanical windows; Rheology; Three-dimensional cell culture

DOI: https://doi.org/10.1021/acsami.6c11606

Nat Commun. 2026 Jul 21.

Quiescent tumor cells shape the immunosuppressive microenvironment in pancreatic cancer.

B McClellan, Q Wang, K Aung, W Matsui.

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, has limited activity in pancreatic ductal adenocarcinoma (PDAC). Using orthotopic PDAC mouse models, we identified a rare population of quiescent PDAC cells that increases after CAR-T cell therapy and exhibits relatively higher clonogenic growth and self-renewal potential than bulk tumor cells. These quiescent cells express high levels of Epiregulin (EREG), a secreted ligand for EGFR and ErbB4, and induce an immunosuppressive tumor microenvironment by increasing the frequency of ErbB4-expressing tumor-associated macrophages. Using complementary genetic and pharmacologic approaches, we demonstrate that targeting EREG enhances the sensitivity of quiescent tumor cells and PDAC tumors to CAR T-cell therapy, resulting in reduced relapse and improved overall survival. These findings support a model in which rare quiescent tumor cells contribute to remodeling of the PDAC tumor microenvironment through EREG-associated signaling and suggest that EREG inhibition may enhance the efficacy of adoptive cellular immunotherapy in this disease.

DOI: https://doi.org/10.1038/s41467-026-75883-z

Adv Mater. 2026 Jul 21. e74038

Boolean Logic-Based Control Over Recombinant Protein Biomaterial Degradability and Therapeutic Delivery.

Murial L Ross, Ryan Gharios, Shivani Kottantharayil, Cole A DeForest.

Recombinant protein-based biomaterials offer exciting opportunities in materials design and controlled therapeutic delivery. Though their precursors can be readily synthesized with near-perfect monodispersity and sequence specificity through scalable fermentation processes, recombinant protein materials have yet to achieve the same level of multi-stimuli-responsiveness as their synthetic counterparts. Integrating cutting-edge tools from chemical biology, we autonomously compile topologically specified protein crosslinkers that can be degraded following user-programmable Boolean logic. Covalent step polymerization of these linkers into protein hydrogels yields smart materials whose cargo (e.g., bioactive proteins, cellular therapeutics) can be liberated following bulk degradation in response to user-specified input combinations. Demonstrating the versatility of this approach, we release fluorescent protein mGreenLantern following all 17 possible YES/OR/AND logic outputs in response to a 3-input protease operator set, deliver epidermal growth factor following advanced biocomputation while maintaining native bioactivity, and showcase multiplexed delivery of living cells, all from fully recombinant protein-based hydrogels. Incorporating advanced intelligence into protein biomaterial responsiveness, we anticipate these methods will dramatically expand potential applications in tissue engineering and precision medicine.

Keywords: biomaterials; boolean logic; controlled release; drugamer; recombinant proteins; stimuli‐responsive

DOI: https://doi.org/10.1002/adma.74038

Adv Mater. 2026 Jul 22. e73765

Highly Entangled Bottlebrush Polymer Networks.

Myoeum Kim, Baiqiang Huang, Shiwang Cheng, Li-Heng Cai.

Entanglements are topological constraints that govern the dynamic mechanical behavior of polymer networks. Linear polymers inevitably entangle at relatively low molecular weights, whereas bottlebrush polymers-consisting of a long backbone densely grafted with many relatively short side chains-suppress entanglements, enabling solvent-free networks with tissue-like softness. Yet, the same steric crowding pre-strains the backbone and renders such networks brittle. Here, we report highly entangled bottlebrush elastomers that combine extreme softness and toughness. Using short polyethylene glycol side chains, we synthesize high molecular weight bottlebrush polymers (>3 × 106 g/mol) that remain amorphous at room temperature. We identify an entanglement threshold of 2.4 × 106 g/mol with an entanglement modulus of ∼1.3 kPa, nearly 1000 times lower than that of linear counterparts. While unentangled bottlebrush networks exhibit strain-stiffening, entangled bottlebrush networks display pronounced strain-softening followed by delayed stiffening due to entanglement slippage. Despite their low modulus (∼1 kPa), these elastomers stretch up to ∼1800% and show a fatigue threshold of ∼63 J/m2, comparable to natural rubber. Their intrinsic fatigue strength-fatigue threshold normalized by modulus-surpasses that of highly entangled linear polymer networks by >40-fold. These results establish a new class of soft yet tough polymer networks and provide a model system for understanding nonlinear mechanics in architecturally complex polymers.

DOI: https://doi.org/10.1002/adma.73765