bims-enlima Biomed News
on Engineered living materials
Issue of 2025–08–10
forty-four papers selected by
Rahul Kumar, Tallinna Tehnikaülikool



  1. Sci Adv. 2025 Aug 08. 11(32): eadw9262
      Light-mediated manipulation of hydrogel physicochemical properties is attractive for numerous applications, yet the processing of such hydrogels via vat photopolymerization [e.g., digital light processing (DLP)] is challenging as photoresponsive chemistries may be consumed during printing. Here, we report a facile strategy to DLP print hydrogels that combines short light exposures to set the shape of a printed object and complementary dark polymerization to continue the reaction of macromers without disturbing photoresponsive groups. Postprinting, hydrogels are then programmed using single- or multiphoton light and photoinitiator-free reactions: tetrazole-alkene click reaction (for photofunctionalization), dithiolane ring-opening polymerization (for photostiffening), and o-nitrobenzyl cleavage (for photosoftening). We demonstrate the versatility of this approach through applications that include the patterning of ligands to direct cell-material interactions, four-dimensional shape morphing, and bottom-up construction of multiscale models, including microscale perfusable channels. This approach provides access to highly tunable 3D-printed photoresponsive hydrogels for a range of soft matter applications.
    DOI:  https://doi.org/10.1126/sciadv.adw9262
  2. Adv Mater. 2025 Aug 03. e09812
      Hydrogels have emerged as a new generation of functional materials with a broad range of applications in diverse fields. They usually cannot be reshaped or recycled, restricting their ability to respond to evolving demands and emerging applications, and contributing to the accumulation of synthetic polymer waste and associated environmental concerns. Here, a robust and general strategy is reported to engineer fully reshapeable and recyclable protein hydrogels by integrating protein folding-unfolding with reversible disulfide crosslinking. Taking advantage of the substantial stiffness contrast between protein hydrogels in their folded and unfolded protein states, protein hydrogels are reversibly reshaped across one-, two-, and three-dimensional geometries. Due to the denaturant concentration dependency and reversibility of the protein folding-unfolding process, the resulting reshaping is highly tunable, reproducible, and chemically erasable, enabling consecutive shape transformations from a single hydrogel precursor. To impart full recyclability, irreversible crosslinking chemistry is replaced with a dynamic disulfide-based one. The resulting hydrogels can be fully recycled, and the recovered proteins can be reused to form new hydrogels, allowing for complete recycling and repeated remolding of hydrogels into new shapes without compromising their mechanical properties. This approach establishes a robust platform for developing next-generation protein-based materials with dynamic formability and true material circularity.
    Keywords:  denature crosslinking; protein folding‐unfolding; protein hydrogel; recycling; reshaping; stiffness
    DOI:  https://doi.org/10.1002/adma.202509812
  3. Nature. 2025 Aug;644(8075): 89-95
      Data-driven methodologies have transformed the discovery and prediction of hard materials with well-defined atomic structures by leveraging standardized datasets, enabling accurate property predictions and facilitating efficient exploration of design spaces1-3. However, their application to soft materials remains challenging because of complex, multiscale structure-property relationships4-6. Here we present a data-driven approach that integrates data mining, experimentation and machine learning to design high-performance adhesive hydrogels from scratch, tailored for demanding underwater environments. By leveraging protein databases, we developed a descriptor strategy to statistically replicate protein sequence patterns in polymer strands by ideal random copolymerization, enabling targeted hydrogel design and dataset construction. Using machine learning, we optimized hydrogel formulations from an initial dataset of 180 bioinspired hydrogels, achieving remarkable improvements in adhesive strength, with a maximum value exceeding 1 MPa. These super-adhesive hydrogels hold immense potential across diverse applications, from biomedical engineering to deep-sea exploration, marking a notable advancement in data-driven innovation for soft materials.
    DOI:  https://doi.org/10.1038/s41586-025-09269-4
  4. J Mater Chem B. 2025 Aug 08.
      Precise control over hydrogel biodegradation kinetics is of importance for drug delivery and tissue engineering. However, existing strategies usually rely on fixed material chemistries and offer limited tunability once implanted. Here, we introduce mechanical strain as a programmable cue to regulate hydrogel degradation in situ. Using peptide-crosslinked tetra-PEG hydrogels and proteinase K as a model system, we developed a real-time stress-monitoring platform to quantitatively study strain-dependent enzymatic degradation. Time-resolved measurements reveal that mechanical strain significantly accelerates degradation by simultaneously enhancing diffusion and reaction rates. For thick hydrogel samples, uniaxial stretching significantly reduces the degradation time by four-fold from 7.6 hours (undeformed) to 1.9 hours (stretched), shifting the process from slow, surface-limited to rapid, volumetric degradation. A multiscale theoretical model that we developed identifies three synergistic effects of mechanical strain: reduced diffusion path due to geometric thinning, increased network mesh size for enhanced enzyme penetration, and elevated chain tension that promotes bond cleavage. These findings establish mechanical loading as a universal tool in biological systems to dynamically modulate hydrogel lifetimes, offering new opportunities for programmable drug release and scaffold-guided tissue remodeling.
    DOI:  https://doi.org/10.1039/d5tb01056j
  5. ACS Biomater Sci Eng. 2025 Aug 04.
      An interpenetrating polymer network (IPN) hydrogel was developed for the three-dimensional (3D) culture of multipotent mesenchymal stromal cells (MSCs) with the aim of independently controlling cell spreading and material modulus. Based on our previous studies, we formulated a semisynthetic material composed of two networks: a covalent network of poly(ethylene glycol) (PEG)-fibrinogen (PF) and a second guest-host (GH) network of hyaluronic acid (HA) coupled to β-cyclodextrin (CD) and adamantane (Ad). The PF network provided cell attachment, precise control over modulus through the incorporation of additional PEG-diacrylate (PEG-DA) cross-linking, and proteolytic degradability. The GH-HA network contributed to the hydrogel's dynamic properties through enhanced viscoelasticity. This dynamic versatility enabled MSCs to better spread and grow in the IPN, even within highly cross-linked formulations. We also observed that the IPN facilitated significantly faster cell spreading kinetics, independent of the material modulus, when compared to single-network PF hydrogels. Hydrogel biodegradation was also characterized after subcutaneous implantation for up to 8 weeks by using MRI analysis. Increasing the PEG-DA cross-linking of the IPN significantly accelerated the in vivo bioresorption, whereas the biodegradation in single-network PF hydrogels was significantly delayed by the additional PEG-DA. We conclude that the covalent cross-links maintain the bulk structural integrity of the hydrogel, whereas the reversible GH interactions provide more localized adaptability for cell-mediated proteolysis and matrix remodeling, possibly through increased network heterogeneity. This design effectively mimics the ECM by providing a more supportive environment for encapsulated cells that allows them to adhere, spread, and proliferate, which may be useful in various MSC-based tissue engineering and regenerative medicine applications.
    Keywords:  biomaterials; hydrogels; interpenetrating polymer network; scaffolds; stem cells; tissue engineering
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00980
  6. Small. 2025 Aug 08. e03602
      Ferromagnetic 4D printing offers rapid shape deformations via external magnetic fields, enabling innovations in soft robotics, adaptive structures, and biomedical devices. However, achieving both high load-bearing capacity and large deformation requires a balance of mechanical properties, traditionally addressed by integrating rigid and soft components in multi-material systems. Such approaches increase complexity, slow down manufacturing with vat exchanges and cleaning, and limit design flexibility. Here, a ferromagnetic grayscale 4D printing strategy is introduced that combines digital light processing (DLP) grayscale 3D printing with ferromagnetic particles within a single-material system. By precisely controlling light intensity during printing, this method allows localized mechanical property programming and, fabrication structures with coexisting soft and rigid domains. This approach is validated by fabricating grayscale cantilever beams and analyzing their bending and response under magnetic fields. The technique achieves high load-bearing capacity (supporting up to 42.6 times its weight), suitable bending angles (98.6% improvement at 200 mT), and rapid responsiveness (87% increase at 2 s). These capabilities are demonstrated through the crawling robot and "M", "U" structures, showcasing practical potential. This study offers a streamlined approach to ferromagnetic 4D printing, reducing the need for complex multi-material processes while expanding the scope of advanced material applications.
    Keywords:  ferromagnetic 4D printing; grayscale digital light processing; magneto active soft materials; programmable mechanical properties
    DOI:  https://doi.org/10.1002/smll.202503602
  7. Nat Commun. 2025 Aug 04. 16(1): 7148
      Design of shock absorbers requires a delicate balance between mechanical properties and geometric design, allowing them to be compressible yet strong enough to withstand crushing loads. Here, we present a unified framework for designing compact and lightweight shock absorbers by employing a streamlined kinematic model and dimensional analysis. We derive geometric constraints on the thickness and cross-sectional area of a protective foam with a given stress-strain response to ensure that acceleration and compressive strain remain within critical limits. Additionally, we identify the optimal mechanical properties that yield the most compact and lightweight protective foam pads for absorbing impact energy. Contrary to common belief, we demonstrate that foams with a nonlinear stress-strain response can effectively achieve thin and lightweight protective pads, particularly when a large cross-sectional area is required. Guided by this design framework, we introduce optimal architected designs of vertically aligned carbon nanotube (VACNT) foams-a low-density hierarchical material system.
    DOI:  https://doi.org/10.1038/s41467-025-60300-8
  8. ACS Appl Mater Interfaces. 2025 Aug 07.
      Plasmonic nanoparticles are important building blocks in contemporary nanoscience and nanotechnology and have demonstrated promising applications in biosensing, biodiagnostics, and drug delivery. However, nanoplasmonic structures are mainly based on inorganic materials that are typically rigid and lack adaptiveness. A viable solution is to attach soft ligands─including molecules, polymers, and biospecies─to plasmonic nanoparticles to offer adaptive and stimuli-responsive functionalities at biointerfaces. Among these, polymeric ligands offer several advantages, such as highly tunable ligand lengths, diverse functionalities, and modularity in the architectural design. This perspective focuses on the dynamic control of both individual plasmonic nanoparticles and their aggregates or assemblies at biological interfaces through the use of smart polymer ligands. We begin by outlining various polymer grafting strategies onto plasmonic nanoparticles, followed by a classification of representative examples of stimuli-responsive polymers that guide adaptive nanoplasmonics, organized by the type of external stimulus. We also discuss the underlying molecular mechanisms driving these responses. Finally, we provide a summary of the field and offer perspectives on future directions for soft, stimuli-responsive nanoplasmonics at biointerfaces.
    Keywords:  biological applications; plasmonic nanoparticles; self-assembly; smart polymers; stimuli responses
    DOI:  https://doi.org/10.1021/acsami.5c07664
  9. Small. 2025 Aug 08. e04139
      Gel materials have tremendous potential for application in future electronics and robotics due to their intriguing merits, like flexibility and biocompatibility. Nonetheless, conventional hydrogels' limited mechanical property and functionality have remarkably impeded their practical applications. Drawing inspirations from hierarchical anisotropic composite structure of natural hard biomaterials, this study proposes a freezing-casting assistant salting-out and solvent displacement with polyol strategy for the fabrication of composite organohydrogels with all-weather strong, tough, and fatigue-resistant mechanical features and functionalities (environmental stability and conductivity). By combining the hierarchical anisotropic fibrous microstructure with high crystallinity and abundant polymer-solvent interactions, the resulting organohydrogel displays exceptional stiffness (8.74 MPa), strength (21.20 MPa), stretchability (1556%), toughness (184.26 MJ m-3), fracture energy (768.3 kJ m-2), and fatigue threshold (7.86 kJ m-2). More importantly, the mechanical performances and conductivity of the gel are well-maintained at both cold and hot conditions, thus guaranteeing the application feasibility of the gel in extreme conditions. These intriguing merits enable the gel to exhibit superior potential in cutting-edge load-bearing applications, like electronic artificial ligaments. Therefore, this study presents a model approach that extends the fundamental design principles of natural biomaterials to engineer composite gels with synergistic mechanical and functional enhancements.
    Keywords:  artificial ligament; extreme conditions; fatigue‐resistant; organohydrogel
    DOI:  https://doi.org/10.1002/smll.202504139
  10. Nature. 2025 Aug;644(8075): 47-48
      
    Keywords:  Machine learning; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-02252-z
  11. Chemistry. 2025 Aug 06. e00778
      Exploring a reasonable network design to develop highly stretchable hydrogels with over 1,000% extension is still a big challenge in the field of hydrogel chemistry and materials. Micellar copolymerization with hydrophobic monomers and surfactants/proteins is a well-studied approach to provide stretchable hydrogels with hydrophobic association domains as sacrificial bonds when subjected to large deformation, but some limitations, such as dose increase of such monomers and surfactant-free synthesis have not yet been well considered. In this study, we demonstrate a simple but powerful approach to produce transparent, ultra-stretchable hydrogels expressing more than 3,000% elongation by surfactant-free copolymerization of low hydrophobic monomer and amphiphilic monomer. We believe that this result offers wider availability of low hydrophobic groups in various water-containing polymer materials, including gels, micelles, etc.
    Keywords:  N‐vinylamide; copolymer; hydrogel; hydrophobicity; stretchable
    DOI:  https://doi.org/10.1002/chem.202500778
  12. ACS Appl Mater Interfaces. 2025 Aug 05.
      Fibrillar protein hydrogels are promising sustainable biomaterials for biomedical applications, but their practical use is often limited by insufficient mechanical strength and stability. To address these challenges, we transformed native proteins into amyloid fibrils (AFs) and incorporated a fibrillar polysaccharide, phytagel (PHY), to engineer interpenetrating polymer network (IPN) hydrogels. Notably, we report for the first time the formation of an amyloid-based hydrogel from apoferritin (APO), with PHY reinforcing the network's mechanical integrity. In situ self-assembly of APO within the PHY matrix yields fully natural, biopolymer-based IPNs. Rheological analyses confirm synergistic interactions between AF and PHY fibers, with the composite hydrogels exhibiting significantly enhanced viscoelastic moduli compared with individual components. The AF-PHY hydrogels also demonstrate excellent self-healing behavior, rapidly restoring their storage modulus after high-strain deformation. A major advancement of this study is the application of deep learning (DL)-based image analysis, using convolutional neural networks, to automate the identification, segmentation, and quantification of fibrillar components in high-resolution scanning electron microscopy images. This AI-driven method enables precise differentiation between AF and PHY fibers and reveals the three-dimensional microarchitecture of the IPN, overcoming key limitations of traditional image analysis. Complementary real-time confocal laser scanning microscopy, with selective fluorescent labeling of protein and polysaccharide components, further validates the IPN structure of the hybrid hydrogels. Our results demonstrate that DL significantly enhances structural characterization and provides insights into gelation processes. This approach sets a new guide for the analysis of complex soft materials and underlines the potential of AF-PHY hydrogels as mechanically robust, self-healing, and fully sustainable biomaterials for biomedical engineering applications.
    Keywords:  IPN networks; deep learning; fibrillar polysaccharide; hydrogels; protein fibers; real-time CLSM imaging
    DOI:  https://doi.org/10.1021/acsami.5c11459
  13. J Mater Chem B. 2025 Aug 05.
      Thiol-Michael addition reactions are widely used for forming cytocompatible and well-defined hydrogels. Numerous types of Michael acceptors have been implemented in these reactions; while maleimides enable rapid crosslinking under physiological conditions and are commonly used for their simplicity, slower-reacting electrophiles such as vinyl sulfones and acrylates offer distinct advantages including improved network homogeneity and ease of handling because of the slower reaction rates. Additionally, thiol-acrylate adducts are hydrolytically labile, whereas thiol-vinyl sulfone adducts are comparably more stable in aqueous environments. Building on our previous work demonstrating radical-mediated degradation of thiol-maleimide hydrogels, we sought to determine whether other thiol-Michael adducts are similarly susceptible to cleavage by radical species. Using both linear and network-forming polymer systems, we found that both Michael-adduct types undergo radical-mediated degradation to varying extents. Furthermore, acrylates are far more prone to radical homopolymerization, enabling semi-orthogonal degradation modes in hydrogels, wherein hydrolytic and radical responses are independently programmed according to the chemical structure and stoichiometric excess of the Michael acceptor. Extending the results of these findings in networks synthesized via thiol-Michael addition, we also observed similar radical-mediated degradation behavior in thiol-norbornene networks formed via thiol-ene photopolymerization, suggesting that even electron-rich thioethers are degradable under sufficiently aggressive initiation conditions where the concentration of radicals exceeds that of the crosslinks. Together, these results extend the chemical space for engineering hydrogels with variable degradation profiles and illustrate design principles for tuning material responses to multiple chemical stimuli.
    DOI:  https://doi.org/10.1039/d5tb01237f
  14. ACS Macro Lett. 2025 Aug 05. 1189-1194
      The effect of interchain interactions such as hydrogen bonding on crystallinity is well understood in linear polymers but not in network polymers. To this end, we synthesized aliphatic polyester networks and polyamide networks, both by thiol-ene free-radical photopolymerizations. These polymer networks were directly synthesized from low-viscosity neat liquid resins comprising an aliphatic dithiol, an ester or amide containing dialkene, and a trifunctional cross-linker. Interchain hydrogen bonding from the amide groups enhanced backbone rigidity, raising glass transition temperatures by 35-40 °C compared to the polyester systems. In the crystalline domain, hydrogen bonding raised the equilibrium melting temperature by 60 °C but reduced the melting enthalpy. Further, hydrogen bonding did not alter the threshold of chain length between cross-links for crystallization (>2500 g/mol). We believe these network polyamides present a robust platform for synthesizing high-performance 3D printing polymers and shape-programmable materials.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00406
  15. Nat Commun. 2025 Aug 07. 16(1): 7292
      Soft and miniaturized robots possess the capability to operate inside narrow, confined environments. However, powering soft robots inside these environments with on-board batteries or wired connections to external power supplies can significantly restrain their mobility. Similarly, wireless actuation approaches are constrained by near-field actuation, line-of-sight operation, or indiscriminate actuation of many actuators. To provide higher mobility for wireless soft robot to operate inside non-line-of-sight scenarios, we present a radio-frequency system that introduces frequency-selective actuation of liquid crystal elastomer actuators. We create liquid crystalline elastomer actuators with a low actuation temperature and embed them with conductive traces that resonate and heat by selected frequencies of radio-frequency excitation in the 2.40 GHz range. We further develop a wireless actuation platform that infers the wireless channel and beamforms towards the actuator to achieve efficient beamforming. Demonstrations show our system is capable of selectively actuating different actuators while the robot is in motion and obstructed by occlusions.
    DOI:  https://doi.org/10.1038/s41467-025-62313-9
  16. Trends Biotechnol. 2025 Aug 02. pii: S0167-7799(25)00303-8. [Epub ahead of print]
      Beyer et al. and Hua et al. developed platforms for precise chemical editing of proteins in living mammalian cells. These approaches enabled site-specific tagging at diverse protein sites without disrupting function. Demonstrated on several key proteins, this technology opens new possibilities for studying protein dynamics and functions in live cells.
    Keywords:  chemical biology; intein splicing; live-cell protein labeling; noncanonical amino acids; protein engineering
    DOI:  https://doi.org/10.1016/j.tibtech.2025.07.021
  17. Nat Commun. 2025 Aug 08. 16(1): 7327
      Structured porous materials, including metal-organic frameworks (MOFs) and covalent-organic frameworks (COFs), are being intensely developed because they can separate small molecules via precisely constructed and uniformly sized pores, despite challenges that hinder practical use. Polymers are structurally amorphous; hence, they are not considered fundamentally capable of separating different organic molecules. This manuscript reports that amorphous polymers can be prepared to separate different small organic molecules (i.e., solutes dissolved in a solvent) effectively, with very large separation factors of ~1000 and ~100,000. Effective separation involves fundamentally a delicate balance between hydrophobicity and hydrophilicity and dynamic mobility of polymeric chains to produce optimal pores. Therefore, structured pores are not fundamentally essential for molecular separation - amorphous pores are effective. These stimuli-responsive polymers have reversibly switchable states with completely opposite selectivities. They are multifunctional: they separate by polarity, size, and with opposite selectivities. Hence, they can separate many different molecules in complex solutions. These polymers are simple and inexpensive to fabricate for widespread use.
    DOI:  https://doi.org/10.1038/s41467-025-62560-w
  18. Nat Commun. 2025 Aug 03. 16(1): 7127
      Lightweight, high-performance electromagnetic shielding materials rely on the precise design of electromagnetic response structures. Conventional shielding materials often involve complex fabrication of conjugated composites or graphitization of organic materials, facing challenges in balancing their performance and processability. As such, seeking and designing intrinsically conjugated materials with superior processability is crucial. In this work, we have innovatively engineered those bioinspired polymers with highly ordered microstructures, using a 5, 6-dihydroxyindole ring tetramer framework to construct highly ordered melanin-like nanofibers by tuning π-π stacking. The resulting melanin-like aerogels represent surprising microwave absorption performance, a maximum reflection loss of -68.87 dB, and an effective absorption bandwidth of 5.25 GHz. In the X-band, the aerogel reached the specific EMI shielding efficiency of 47909.9 dB cm2/g. This work represents the first successful extension of melanin-like polymers into the microwave spectrum, demonstrating great potential in the electromagnetic field.
    DOI:  https://doi.org/10.1038/s41467-025-62367-9
  19. Nat Commun. 2025 Aug 04. 16(1): 7160
      Engineering mammalian cells with synthetic circuits drives innovation in next-generation biotherapeutics and industrial biotechnology. However, applications often depend on cellular productivity, which is constrained by finite cellular resources. Here, we harness computational biology to identify drugs that boost productivity without additional genetic modifications. We perform RNA-sequencing on cells expressing an incoherent feed-forward loop (iFFL), a genetic circuit that enhances operational capacity. To find drugs that mimic this effect, we use DECCODE (Drug Enhanced Cell COnversion using Differential Expression), an unbiased method that matches our transcriptional data with thousands of drug-induced profiles. Among the compound candidates, we select Filgotinib, that enhances expression of both transiently and stably expressed genetic payloads across various experimental scenarios and cell lines, including AAV and lentivirus transduction. Our results reveal cell-specific responses, underscoring the context dependency of small-molecule treatments. Altogether, we present a versatile tool for biomedical and industrial applications requiring enhanced productivity from engineered cells.
    DOI:  https://doi.org/10.1038/s41467-025-62529-9
  20. Nat Mater. 2025 Aug 05.
      Peptides are promising building blocks of designer materials with wide-ranging applications. These materials are stabilized by directional hydrogen-bonding patterns, giving rise to one-dimensional or two-dimensional assembly. It remains a challenge to mimic biology's context-adaptive and flexible structures. Here we introduce minimalistic tripeptide sequences that form highly soluble dynamic ensembles through multivalent side-chain interactions. We observe these supramolecular dispersions undergo drying-induced sequential liquid-liquid phase separation followed by solidification, resulting in the formation of films of stiff, densely packed and porous peptide microparticles that can be instantaneously redispersed upon the re-introduction of water. Air-drying of peptide dispersions in the presence of proteins or small-molecule payloads results in efficient encapsulation and the retention of protein stability after redispersion, showing promise for the emulsification, encapsulation, protection and storage of biomacromolecules. The mechanism resembles the protective strategies in natural systems during desiccation, which rely on liquid-liquid phase separation to survive extreme conditions.
    DOI:  https://doi.org/10.1038/s41563-025-02300-z
  21. Nano Lett. 2025 Aug 05.
      Living organisms exhibit exceptional mechanical adaptability under external stresses by integrating hierarchical inorganic-organic structures. Inspired by their biomineralization, this study presents a synthetic strategy to fabricate mechanically reinforced, hyperelastic, mineralized hydrogels via in situ silicification. Based on the natural bio-silicification process, we first mineralize silica nanoparticles from a nanocomplex containing high amounts of amine moieties in the hydrogel matrix. The size, shape, and distribution of silica nanoparticles were adjustable through the consecutive in situ process, which enables interlocking/entrapment of silica nanoparticles and polymer networks. The resulting silicified hydrogels overcome the conventional trade-off between strength/stiffness and toughness, thereby achieving the enhanced mechanical properties with hysteresis-free and deformation-rate-independent hyperelastic behaviors. Their superior mechanical characteristics allow the hydrogel to function as a strain sensor with exceptional durability under cyclic loading-unloading deformation. This strategy offers a versatile platform for the design of mechanically robust hydrogels.
    Keywords:  biomimetic silica; hysteresis-free; in situ silicification; mineralization; reinforced hydrogel
    DOI:  https://doi.org/10.1021/acs.nanolett.5c02338
  22. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2421122122
      Lubricated contacts in soft materials are important in various engineering systems and natural settings. Three major lubrication regimes are boundary (BL), mixed (ML), and elastohydrodynamic (EHL) lubrication, where the contact region is dry, partially wetted, or fully wetted, respectively. The transition between these regimes is insufficiently understood, especially for soft contacts, which impedes desired control of lubricated sliding friction. Here, we report on the role of solid wettability and adhesion on these transitions. Wettability of glycerol on polydimethylsiloxane (PDMS) surfaces and adhesion between a glass indenter and PDMS were varied by exposure of the PDMS to an ultraviolet light-ozone cleaner. By combining friction tests and visualization, we demonstrate that the transition from ML to BL regime is dominated by the wettability of the lubricant; increasing wettability of glycerol makes removal of liquid from the contact region more difficult. Transition from EHL to ML is related to a series of events with increasing normal load, which are thinning of the lubricant layer, sudden jump to contact between the glass indenter and solid substrate across a gap of tens of nanometers, and attendant mechanical instabilities such as wrinkling and stick-slip. These results provide a deeper understanding of transitions in lubricated frictional behavior of soft materials which govern the maximum and minimum friction achievable.
    Keywords:  adhesion; lubricated sliding; soft materials; wetting
    DOI:  https://doi.org/10.1073/pnas.2421122122
  23. Biomater Sci. 2025 Aug 06.
      Articular cartilage exhibits a limited capacity for self-repair, prompting extensive research into advanced biomaterials that can support tissue regeneration. Among these, injectable hydrogels have gained attention for their minimally invasive delivery and suitability for bioprinting applications. However, conventional nanoporous bulk hydrogels often lack the necessary microporosity and architectural complexity to fully support effective tissue regeneration. To overcome these shortcomings, recent innovations have turned toward granular hydrogels-injectable materials fabricated by dense packing of hydrogel microparticles into cohesive, microporous bulk hydrogels. These granular systems offer improved injectability, superior microporosity, and the ability to form heterogeneous bioinks/injectables that better replicate the natural extracellular matrix, thereby promoting more efficient regeneration. This review delves into the advancements in granular hydrogel technology, with a focus on the fabrication of hydrogel microparticles and the jamming strategies used to assemble them into granular injectables/bioinks. It further explores their potential in cartilage tissue repair, emphasizing the benefits of such emerging microporous bulk assemblies in minimally invasive procedures (MIPs) or as smart bioinks for fabricating patient specific implants. Finally, the review outlines key opportunities and challenges in translating these innovative materials into clinical applications, highlighting the growing promise of granular hydrogels in addressing current limitations in cartilage regeneration.
    DOI:  https://doi.org/10.1039/d5bm00801h
  24. Nat Commun. 2025 Aug 05. 16(1): 7177
      Digital light processing 3D printing is a powerful manufacturing technology for shaping materials into complex geometries with high resolution. However, the rheological and chemical requirements for printing limit the use of materials to photoactive resins. Here, we propose a versatile manufacturing platform for constructing versatile materials using DLP-printed water-soluble granular polyacrylamide as sacrificial molds. The polymerization-induced phase separation during printing results in a close packed granular geometry with intrinsic micropores, which greatly accelerates the dissolution rate of polyacrylamide. Combined with precise control over the molecular weight, this salt-like sacrificial mold can be fully dissolved in neutral water at room temperature within 30 min. Furthermore, significant surface oxygen inhibition promotes the leveling and spreading of liquid resin on the cured part surfaces, achieving a printing speed of 375 mm/h in a top-down printer. Due to the mild conditions for mold removal, complex-shaped architectures can be created from a variety of compositions, including temperature-sensitive low-melting alloys, alkaline-degradable polyesters, as well as widely used materials such as silicone rubber, polyurethane, polyolefin elastomer, and epoxy. Considering the fast mold dissolution rate and mild dissolution conditions, the present platform represents a potential low-cost, and universal indirect 3D printing method for shaping versatile materials.
    DOI:  https://doi.org/10.1038/s41467-025-62674-1
  25. Nature. 2025 Aug 06.
      
    Keywords:  Biomaterials; Machine learning; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-02485-y
  26. Adv Mater. 2025 Aug 05. e2504765
      Cardiac patches to repair myocardial defects require mechanically stable materials that prevent bleeding and can be implanted via suturing. The current clinical standard, bovine pericardial patches (BPPs), serve this purpose but do not degrade or integrate with the myocardium, limiting their long-term effectiveness. Here, we present the reinforced cardiac tissue patch (RCPatch). This multimaterial patch comprises a stiffness-tuned, cardiomyocyte-infiltrated 3D metamaterial and a suturable, hydrogel-infiltrated mesh to reduce permeability and bleeding. Anisotropic metamaterials are designed and computationally optimized using a generative modeling approach and fabricated from poly(ε-caprolactone) (PCL) via volumetric 3D printing (VP). The metamaterial supports the infiltration of cardiomyocytes, which are viable and contract in vitro. The implantability and low blood permeability of the patch is enabled by adding a melt-electrowritten (MEW) mesh infiltrated with a fibrin hydrogel. In an acute large animal trial, the RCPatch was applied on an induced myocardial defect, where it withstood intraventricular blood pressure, prevented bleeding, and enabled hemodynamic restabilization (intraventricular pressure of 81 mmHg before, vs 66 mmHg after implantation). These findings establish a scalable framework for fabricating cardiac tissue patches that integrate mechanical reinforcement with biological function, offering a surgically implantable and future regenerative solution for intraventricular myocardial repair.
    Keywords:  biofabrication; cardiac patches; cardiac regeneration; cardiac tissue engineering; cardiomyocytes; implants; melt‐electrowriting; volumetric 3D printing
    DOI:  https://doi.org/10.1002/adma.202504765
  27. Langmuir. 2025 Aug 07.
      The implantation of medical devices such as stents and heart valves, which are in contact with blood, can lead to thrombosis. To prevent this undesirable blood clot formation, there is a need for antitrombogenic coatings. Here, we exploit sol-gel technology to generate a coating that prevents the first step of coagulation, the adhesion of proteins, and, by that, prevents clot formation on the surface. We studied the correlation between surface wettability to the antithrombogenic property of the surface. Our findings show that a combination of zwitterion precursor with tetraethyl orthosilicate yields a robust hydrophilic coating that significantly reduces platelet adhesion to the surface. This coating might be applied to artificial materials used for the formation of medical devices to prevent thrombosis.
    DOI:  https://doi.org/10.1021/acs.langmuir.5c01529
  28. Nat Commun. 2025 Aug 05. 16(1): 6984
      Accomplishing multiple synthetic tasks in parallel, including substrate capture, separation, and reaction, along with controlled arrangement of product, all in one system has remained a long-standing challenge in synthetic chemistry. Here, we report a sorting polymerization strategy that harnesses the multifunctional nature of a bichannel metal-organic framework (MOF). The MOF, [Cu(5-methylisophthalate)]n, featuring two distinct one-dimensional channels arranged in a single Kagome lattice, allows selective adsorption of monomers to different sites based on their polarity and size. This enables the sorting of different vinyl monomers and their in-situ parallel homo-polymerization within the respective channels. The process produces alternating single-chain arrays of homopolymers in a single step, a configuration unattainable by conventional approaches. Additionally, the introduction of inter-chain cross-linking allows for the isolation of the binary polymer array by removing the MOF template. This work highlights the potential of MOFs as versatile reaction platforms for the synthesis of complex, well-ordered molecular architectures from chaotic mixtures of raw materials.
    DOI:  https://doi.org/10.1038/s41467-025-62322-8
  29. Commun Mater. 2025 ;6(1): 174
      Muscle loss can severely affect movement and physiological functions, driving interest in artificial muscle development. Although various soft actuators exist, ensuring biocompatibility-especially in terms of heat transfer and non-cytotoxicity-remains a key challenge. To address these issues, here we develop Bio35, a low-voltage (3.6 V) electrothermal actuator that operates at mild hyperthermic temperatures (38.9 °C). Bio35 is synthesized using a one-pot, solvent-free process with Epikote 828, poly(propyleneglycol) bis (2-amino-propyl-ether) (PPG), and 1,4-diamino-diphenyl-sulfone (DDS). It demonstrates high chemical stability, maintaining actuation performance after more than 100 cycles over 200 min. Initial biological tests confirm that these materials are biocompatible and non-cytotoxic. As proof of concept, we demonstrate two systems: a simple gripper capable of holding objects up to 225 mg and a sphincter-like valve, showcasing its potential for use in treating conditions like urinary incontinence, where precise, muscle-like actuation is critical for function.
    Keywords:  Actuators; Polymers
    DOI:  https://doi.org/10.1038/s43246-025-00893-1
  30. Small Methods. 2025 Aug 07. e00845
      Polymers of intrinsic microporosity (PIMs) are a unique class of soft materials, which, unlike hard materials such as zeolites or carbons, are capable of both vapor adsorption (nanopore filling) and absorption (polymer plasticization/swelling). While adsorption is governed by pore structure and surface functionalization, adsorption depends on the chemical composition of the matrix material. Since both adsorption and absorption increase sorbent mass (vapor uptake), gravimetric and volumetric characterization methods exhibit severe limitations in isotherm interpretation. Thus, distinguishing between vapor adsorption and absorption remains a key challenge for understanding sub-nanometer-scale processes, which play a crucial role in many emerging applications of PIMs, including gas separation, water purification, organic solvent nanofiltration, and electrochemical energy storage/conversion. Herein, an alternative approach is presented based on in situ ellipsometric read out and concurrent optical modeling of adsorption and absorption. Ellipsometry is highly sensitive to changes in thickness and optical density of the thin film sorbents, enabling the acquisition of both adsorption and absorption isotherms. This study showcases four PIM sorbents with varied material chemistry, responding to various vapors. Their ad-/absorption contributions are studied and disentangled experimentally, with nanopore confinement and swelling models based on classical physisorption and polymer Flory-like theory.
    Keywords:  adsorption; ellipsometric porosimetry; microporous materials; polymers; thin films
    DOI:  https://doi.org/10.1002/smtd.202500845
  31. ACS Appl Bio Mater. 2025 Aug 05.
      DNA origami, a method of folding DNA into precise nanostructures, has emerged as a powerful tool for the design of complex nanoscale shapes. It has great potential as a technology to encapsulate and release cargos spanning small molecules through large proteins, while remaining stable in a variety of ex vivo processing conditions and in vivo environments. While DNA origami has been utilized for drug delivery applications, the vast majority of these structures have been flexible, flat 2D or solid 3D nanostructures. There is a crucial need for a hollow and completely enclosed design capable of holding and eventually releasing a variety of cargos. In this paper, we present the design and assembly of a hollow DNA origami box with two lids. We characterize the isothermal conditions for structural assembly within minutes. We demonstrate that passive loading of small molecules is charge dependent. We also outline an approach to design staple extensions pointing into the cavity or outside of the hollow DNA origami, allowing for the active loading of protein or the potential for decoration with passivating or targeting molecules.
    Keywords:  Smart nanomaterials; controlled release; helical twist; isothermal assembly; stability
    DOI:  https://doi.org/10.1021/acsabm.5c00907
  32. Nat Commun. 2025 Aug 02. 16(1): 7110
      Microbial production of chemicals may suffer from inadequate cofactor provision, a challenge further exacerbated in yeasts due to compartmentalized cofactor metabolism. Here, we perform cofactor engineering through the decompartmentalization of mitochondrial metabolism to improve succinic acid (SA) production in Issatchenkia orientalis. We localize the reducing equivalents of mitochondrial NADH to the cytosol through cytosolic expression of its pyruvate dehydrogenase (PDH) complex and couple a reductive tricarboxylic acid pathway with a glyoxylate shunt, partially bypassing an NADH-dependent malate dehydrogenase to conserve NADH. Cytosolic SA production reaches a titer of 104 g/L and a yield of 0.85 g/g glucose, surpassing the yield of 0.66 g/g glucose constrained by cytosolic NADH availability. Additionally, expressing cytosolic PDH, we expand our I. orientalis platform to enhance acetyl-CoA-derived citramalic acid and triacetic acid lactone production by 1.22- and 4.35-fold, respectively. Our work establishes I. orientalis as a versatile platform to produce markedly reduced and acetyl-CoA-derived chemicals.
    DOI:  https://doi.org/10.1038/s41467-025-62304-w
  33. J Am Chem Soc. 2025 Aug 05.
      The development of organic light-emitting diode (OLED) materials requires precisely engineered molecular architectures with tailored optoelectronic properties. Here, we present a strategy that synergistically integrates diversity-oriented synthesis (DOS) with virtual screening to systematically explore the chemical space of diaza-polycyclic aromatic hydrocarbons (diaza-PAHs) for OLED applications. DOS, originally developed for drug discovery, serves as a powerful tool to generate structurally diverse molecular libraries, granting access to previously unexplored diaza-PAHs with potential OLED functionality. Complementing this synthetic approach, virtual screening enables the rapid identification of optimal candidates from an extensive library of computationally generated structures, thereby streamlining the material discovery process. In this work, we introduce a rhodium-catalyzed method that combines sequential C-H activation and annulation, offering a modular synthetic protocol for diaza-PAH scaffolds with tunable electronic properties. By computationally screening 1,061 core structures, we identified two lead frameworks─2,6-diazaanthracene and 2,8-dipyridylthiophene─as potential prototypes for OLED applications. Guided by these computational insights, we synthesized four diaza-PAH derivatives, which exhibited exceptional performance as electron-transporting and host materials in high-efficiency phosphorescent OLEDs. This integrated experimental and computational approach not only accelerates the identification of functional materials but also significantly reduces experimental time and resource consumption. This paradigm shift underscores the potential of merging synthetic diversity with data-driven molecular discovery to advance optoelectronic materials research.
    DOI:  https://doi.org/10.1021/jacs.5c07594
  34. Adv Healthc Mater. 2025 Aug 07. e02380
      The development of mechanically robust, cell-instructive, and seweable small-diameter (≤ Ø 6 mm) tubular scaffolds remain a major challenge in vascular tissue engineering. Here, a hybrid biofabrication strategy is presented that combines 4D printing of alginate-methylcellulose (AlgMC) hydrogels with melt electrowritten (MEW) poly(ε-caprolactone) (PCL) reinforcement to produce tubular constructs with programmable shape-morphing capacity. The MEW fiber meshes significantly improve mechanical integrity, enabling suturing and perfusion, while preserving the anisotropic swelling behavior required for morphogenesis. Scaffold functionalization using human blood-derived protein coatings - such as fresh frozen plasma, platelet lysate, and fibrinogen - markedly enhances cellular adhesion and fibroblast proliferation without compromising structural transformation. Biological evaluation using mono and co-cultures of fibroblasts, endothelial cells (HUVEC), and vascular smooth muscle cells (vSMC) reveals the formation of organized bi-layers and phenotype-specific cell morphologies on AlgMC/PCL composites. Notably, a confluent endothelial layer promotes contractile marker expression in vSMC, while vSMC support endothelial coverage in the absence of a growth-arrested fibroblast feeder layer, indicating reciprocal stabilization. While further optimization is needed to meet the demands of small-diameter vascular grafts fully, the presented system offers a versatile and promising platform for engineering soft tissue constructs that benefit from topographical guidance, spatially controlled adhesion, and adaptive geometry.
    Keywords:  4D printing; additive manufacturing; alginate; extrusion 3D printing; melt electrowriting; methylcellulose; polycaprolactone
    DOI:  https://doi.org/10.1002/adhm.202502380
  35. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2505446122
      Conjugation accelerates bacterial evolution by enabling bacteria to acquire genes horizontally from their neighbors. Plasmid donors must physically encounter and connect with recipients to allow plasmid transfer, and different environments are characterized by vastly different encounter rates between cells, based on mechanisms ranging from simple diffusion to fluid flow. However, how the environment affects the conjugation rate by setting the encounter rate has been largely neglected, mostly because existing experimental setups do not allow for direct control over cell encounters. Here, we describe the results of conjugation experiments in Escherichia coli in which we systematically varied the magnitude of shear flow using a cone-and-plate rheometer to control the encounter rate. We found that the conjugation rate increases with shear until it peaks at an optimal shear rate ([Formula: see text]), reaching a conjugation rate fivefold higher than the baseline set by diffusion-driven encounters. This optimum marks the transition from a regime in which shear promotes conjugation by increasing the rate of cell-cell encounters to a regime in which shear disrupts conjugation. Regions of high fluid shear are widespread in aquatic systems, in the gut of host organisms, and in soil, and our results indicate that these regions could be hot spots of bacterial conjugation in the environment.
    Keywords:  bacterial conjugation; cell–cell encounters; horizontal gene transfer
    DOI:  https://doi.org/10.1073/pnas.2505446122
  36. Adv Mater. 2025 Aug 07. e03524
      Hydrogels, renowned for their biocompatibility and capacity to mimic biological tissues, are integral to many biomedical applications, such as implantable devices and wound dressings. However, their poor mechanical strength and the challenge of achieving durable adhesion to polymeric surfaces have hindered their broader utility. Current methods of creating hybrid solid-hydrogel (HSH) structures often rely on complex chemical linkers, adding steps, cytotoxic risks, and scalability issues. Here, a novel, reagent-free method that covalently bonds hydrogels to polymeric substrates directly via reactive oxygen species (ROS) generated by an atmospheric pressure plasma jet (APPJ) is introduced. Through an evaporation-induced enhanced concentration (EIEC) approach, robust hydrogel layers are formed on ROS-functionalized surfaces, eliminating the need for silane-based linkers and achieving up to 60 kPa adhesion strength in wet conditions. This strategy offers robust hydrogel adhesion, reduces processing complexity, and preserves cytocompatibility, as demonstrated by the culture of human mesenchymal stem cells (hMSCs) and THP-1 derived macrophages with minimal immune response. Applicable across various hydrogels, such as gelatin methacryloyl (GelMA), chitosan, and polymeric substrates, including Teflon, polyethylene, and polycaprolactone (PCL), this dry process holds substantial promise for integration into advanced biomanufacturing systems, such as 3D bioprinters, unlocking new potentials in tissue engineering and biomedical device fabrication.
    Keywords:  hydrogel coatings; hydrogel immobilization; plasma surface functionalization; solid‐hydrogel constructs
    DOI:  https://doi.org/10.1002/adma.202503524
  37. bioRxiv. 2025 Jul 24. pii: 2025.07.21.665160. [Epub ahead of print]
      Bacterial biofilms are complex communities protected in an extracellular matrix (ECM) composed of polysaccharides, extracellular DNA, proteins, lipids, and other molecules. These protected bacteria typically manifest enhanced antimicrobial resistance (AMR) which presents a major challenge in treating chronic infections. Here, we employ a combination of electron paramagnetic resonance (EPR), solid-state NMR (ssNMR), and dynamic nuclear polarization (DNP) ssNMR to investigate radical stability within native Pseudomonas fluorescens Pf0-1 colony biofilms towards efficient hyperpolarized DNP ssNMR applications. EPR measurements reveal that the native ECM is the primary contributor to radical reduction, whereas other biofilm components, such as planktonic cells, isolated ECM, and dried biofilms show minimal activity. Radical reduction rates vary with biofilm morphology and composition. ssNMR identifies both rigid and flexible polysaccharides and lipids within the ECM as primary radical interaction sites. These findings support a mechanism in which the ECM not only serves as a physical barrier but also has reductive activity that protects against xenobiotics. Importantly, we demonstrate that potassium ferricyanide preserves EPR signal intensity and radical lifetime in native biofilms, offering a promising biocompatible mitigation strategy. Our findings quantify and pinpoint the origins of the reductive nature of bacterial biofilms and provide a solid framework for improving radical stability in native biological systems for high efficiency structural studies. This work enables high efficiency DNP ssNMR on native biofilms and sets the stage for high-resolution measurements of structure-function relations in these medically relevant, complex biological assemblies.
    DOI:  https://doi.org/10.1101/2025.07.21.665160
  38. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2509525122
      In materials, the ability to retain the memory of applied stresses or strains opens up new opportunities for enhancing their performance adaptively via training. In dense suspensions, a stress-adaptive response is enabled by non-Newtonian rheology; however, typical suspensions have little memory, which implies rapid cessation of any adapted behavior. Here, we show how multiple adaptive responses can be achieved by designing suspensions where different stress levels trigger different memories. This is achieved through the interplay of particle interactions based on frictional contact and dynamic chemical bridging. These two interactions give rise to stress-activated memories associated with opposite time-dependent trends. As a result, a suspension can be trained to adapt to applied stress either by softening or stiffening, exhibiting targeted viscosity and energy dissipation in response to low-velocity impact. Such behavior, usually associated with mechanical metamaterials, suggests that dense suspensions with multiple memories can be viewed as trainable rheological metafluids.
    Keywords:  dense suspensions; metafluids; non-Newtonian rheology
    DOI:  https://doi.org/10.1073/pnas.2509525122
  39. Nat Comput Sci. 2025 Aug 07.
      Zeolites are industrially important catalysts and adsorbents, typically synthesized using specific molecules known as organic structure-directing agents (OSDAs). The templating effect of the OSDAs is pivotal in determining the zeolite polymorph formed and its physicochemical properties. However, de novo design of selective OSDAs is challenging because of the diversity and size of the zeolite-OSDA chemical space. Here we present ZeoBind, a computational workflow powered by machine learning that enables an exhaustive exploration of the OSDA space. We design predictive tasks that capture zeolite-molecule matching, train predictive models for these tasks on hundreds of thousands of datapoints and curate a library of 2.3 million synthetically accessible, hypothetical OSDA-like molecules enumerated from commercially available precursors. We use ZeoBind to screen nearly 500 million zeolite-molecule pairs and identified and experimentally validated two new OSDAs that template zeolites with novel compositions. The scale of the OSDA library, along with the open-access tools and data, has the potential to accelerate OSDA design for zeolite synthesis.
    DOI:  https://doi.org/10.1038/s43588-025-00842-5
  40. Small. 2025 Aug 03. e03956
      Finding new materials with previously unknown atomic structure or materials with optimal set of properties for a specific application greatly benefits from computational modeling. Recently, such screening has been dramatically accelerated by the invent of universal machine-learning interatomic potentials that offer first principles accuracy at orders of magnitude lower computational cost. Their application to the screening of defects with desired properties or to finding new stable compounds with high density of defects, however, has not been explored. Here, it is shown that the universal machine-learning interatomic potentials have reached sufficient accuracy to enable large-scale screening of defective materials. Vacancy calculations are carried out for 86,259 materials in the Materials Project database and the formation energies analyzed in terms of oxidation numbers. The application of these models is further demonstrated for finding new materials at or below the convex hull of known materials and for simulated etching of low-dimensional materials.
    Keywords:  2D materials; benchmark; defects; machine‐learning interatomic potential; vacancies
    DOI:  https://doi.org/10.1002/smll.202503956
  41. Nat Commun. 2025 Aug 07. 16(1): 7284
      Photoelectrochemical systems harness onsite solar energy to drive chemical processes, enabling improvements in sustainability and decarbonization. Photoelectrochemical systems have been extensively studied for reactions such as hydrogen production; however, competitive costs are difficult to attain due to the limited solar efficiency of low-cost photoelectrochemically stable materials. Building on this premise, we propose that applications that do not require high solar-efficiency materials to deliver meaningful throughput are needed for photoelectrochemical systems. Using rigorous thermodynamic modeling grounded in experimental data, we demonstrate the existence of such applications in chemical separations, which comprise processes critical to tackling global challenges in water treatment and resource recovery. Operating domains and scales at which photoelectrochemical separations utilizing low solar efficiency materials can be practical and cost-competitive against modular photovoltaic-electrochemical systems are identified. This study demonstrates that photoelectrochemical separations have a design space broader than classical applications, and establishes thermodynamic limits and targets, paving the way for real-world impact with photoelectrochemical technology.
    DOI:  https://doi.org/10.1038/s41467-025-61879-8
  42. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2427145122
      We explore the impact of excluded volume interactions on the local assembly of linear physical networks, where nodes are spheres and links are rigid cylinders with varying length. To focus on the effect of elongated links, we introduce a minimal 3D model that helps us zoom into confined regions of these networks whose distant parts are sequentially connected by the random deposition of physical links with a very large aspect ratio. We show that the nonequilibrium kinetics at which these elongated links, or spaghetti, adhere to the available volume without mutual crossings is logarithmic in time, as opposed to the algebraic growth in lower dimensions for needle-like packings. We attribute this qualitatively different behavior to a delay in the activation of depletion forces caused by the 3D nature of the problem. Equally important, we find that this slow kinetics is metastable, allowing us to analytically predict the kinetic scaling characterizing an algebraic growth due to the nucleation of local bundles. Our findings offer a theoretical benchmark to study the local assembly of physical networks, with implications for the modeling of nest-like packings far from equilibrium.
    Keywords:  bird-nest materials; nonequilibrium kinetics; physical networks; random packings
    DOI:  https://doi.org/10.1073/pnas.2427145122
  43. bioRxiv. 2025 Aug 02. pii: 2025.08.02.668298. [Epub ahead of print]
      Image-based phenotypic screening has emerged as a powerful tool for revealing single-cell heterogeneity and dynamic phenotypic responses in preclinical drug discovery. Compared to traditional static end-point assays, live-cell longitudinal imaging captures the temporal trajectories of individual cells, including transient morphological adaptations, motility shifts, and divergent subpopulation behaviors, enabling high content features and more robust early prediction of treatment outcomes. Fluorescence-based screening, while highly specific, is constrained in live-cell contexts by broad spectral overlaps (limiting multiplexing to fewer than six channels), bulky fluorophores that may perturb small-molecule interactions, and photobleaching or phototoxicity under repeated excitation. Stimulated Raman scattering (SRS) microscopy overcomes these barriers by delivering label-free, quantitative chemical contrasts alongside morphological information. Here, we present a low-cost, 3D printed cell culture platform compatible with the stringent optical requirements of SRS microscopy. This set up enables real-time drug delivery and continuous monitoring of biochemical and morphological changes in living cells during 24-hour time-lapse imaging with minimal photodamage. We outline a processing pipeline for longitudinal SRS images to extract chemical and morphological features of single live cells. Using this system, we showcase time-lapse SRS microscopy as a tool to map heterogenous drug-induced single-cell response over time, enabling the identification of varying trajectories within complex cell populations. By parallelizing multi-well perfusion with label-free chemical imaging, our approach offers a pathway toward high-throughput pharmacodynamic assays for the acceleration of phenotypic screening and personalized medicine.
    DOI:  https://doi.org/10.1101/2025.08.02.668298