bims-enlima Biomed News
on Engineered living materials
Issue of 2025–08–17
forty-six papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Light-based fabrication and 4D customization of hydrogel biomaterials.
  2. Targeted delivery of diverse biomolecules with engineered bacterial nanosyringes.
  3. Hydrogel Viscoelasticity Modulates Cell Nascent Extracellular Matrix Deposition.
  4. Unraveling the Constrained Cell Growth in Engineered Living Materials.
  5. Engineered bacteria launch and control an oncolytic virus.
  6. Hydrogels with Tethered Transcription Circuit Elements for Chemical Communication and Collective Computation.
  7. Genetic Surfaceome E. coli Reprogramming Enables Selective Water Oxidation.
  8. Designing lipid nanoparticles using a transformer-based neural network.
  9. Toward Next-Generation Ingestible Hydrogels.
  10. Sustainable DNA-polysaccharide hydrogels as recyclable bioplastics.
  11. Fully Synthetic Hydrogels Promote Robust Crypt Formation in Intestinal Organoids.
  12. Direct laser writing of electronically conductive microstructures within soft hydrogel substrates.
  13. Norbornene Homopolymerization Limits Cell Spreading in Thiol-Ene Photoclick Hydrogels.
  14. 3D-Printing Thermo-Responsive Photonic Inks Based on Cellulose Semi-Interpenetrating Liquid Crystal Networks.
  15. Engineered Gram-Positive Based Quorum Sensing for Metabolic Control in Escherichia coli.
  16. Bio-orthogonally double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity for cardiac tissue engineering.
  17. YTK Display-and-Secrete: Screening for Optimal Protein Secretion Elements in Saccharomyces cerevisiae.
  18. Building a Synthetic Cell Together.
  19. Boosting energy metabolism and biosynthesis in diverse organisms by a common bacterial salvage lipoylation protein.
  20. Engineering morphogenesis of cell clusters with differentiable programming.
  21. 3D Printing of Interconnection-Tunable Porous Ink.
  22. Merging Natural Biopolymers with Supramolecular Chemistry: Emulating the Native Extracellular Matrix's Complexity.
  23. Optimizing Green Light Photoredox Catalyzed Polymerizations for 3D Printing of Cell-Laden Hydrogels.
  24. High-performance reverse thermoresponsive hydrogel enabled by one-pot PDMS-enriched domain crosslinking.
  25. A Synthetic Hydrogel with Tunable Stiffness for Engineering Pancreatic Cancer Organoids and Drug Testing.
  26. Single Amino Acid Derived Rudimentary Catalytic Hydrogel for Reaction Engineering.
  27. Polyelectrolyte Complex-Based Artificial Biofilms as Versatile Living Biomaterials.
  28. Clicktetrazine dECM-alginate hydrogels for injectable, mechanically mimetic, and biologically active vocal fold biomaterials.
  29. Designing supramolecular pastes by controlling host-guest dynamics in reconfigurable networks.
  30. Polymer Colloids: Evolution of the Field toward Biomacromolecules.
  31. Target sequence-conditioned design of peptide binders using masked language modeling.
  32. Assembly and Processing of One-Dimensional Subnanomaterials.
  33. A generative deep learning approach to de novo antibiotic design.
  34. Engineered Extraocular Muscle with Decellularized Tissue and Synthetic Biodegradable Polymers: Design, Properties, and In Vivo Studies.
  35. Supramolecular Self-Assembly of Polyaniline Embedded Enzyme-Mimicking GMP-Condensate Hydrogel for Electrochromic Energy Storage Applications.
  36. OptoBarrier: An Optogenetic Platform for Modulating Endothelial Barriers In Vitro.
  37. Protocol for fabricating a reusable plate-well insert with a 3D-printed mounter and hydrogel scaffolds for 3D cell culture and functional assays.
  38. Suppressing mechanical property variability in recycled plastics via bioinspired design.
  39. Engineering Extracellular Microenvironments: The Impact of Fibrous Materials on Cell Behavior.
  40. Supramolecular Assembly of Magnetic Microrobots for Controllable Cell Delivery and Release.
  41. Development of Photocurable NorHA-dECM Hybrid Hydrogels to Study Cell-Matrix Interactions.
  42. Constraint-Based Sub-Graph Partitioning for Multi-Cellular Biological Networks.
  43. Cellulose hydrogel with in-situ confined nanopores for boosting moist-electric conversion.
  44. Protein language models reveal evolutionary constraints on synonymous codon choice.
  45. Glucose-Responsive Self-Rolling Antioxidant Hydrogel Actuators for a Cell Culture Platform.
  46. Determining intrinsic optical properties of 3D printing materials.
  1. Nat Rev Bioeng. 2025 Feb;3(2): 159-180
    Light-based fabrication and 4D customization of hydrogel biomaterials.
    Irina Kopyeva, Ryan P Brady, Cole A DeForest.
      Light has become an essential tool to make and manipulate living systems in the increasingly intertwined fields of cell biology and materials science. With the ever-expanding interdisciplinary nature of current scientific research and the ongoing hunt for orthogonal, high-precision stimuli for biomaterial synthesis and modification, light has emerged as the gold standard with its low cytotoxicity and high bioorthogonality, enabling the modulation of properties in both 3D space and time (that is, 4D). Not only can light govern when and where changes occur, dosage modulation permits control over the extent of material customization, providing a route to engineered constructs approaching the 4D complexity of native tissue. Recent technological innovations span advances in stereolithography, digital light processing, volumetric bioprinting, multiphoton lithography and grayscale fabrication. Material chemistries have matched pace with the technologies: novel photochemistries permit the building of dynamic materials with complex mechanical and biochemical functionalities, such as on-demand protein activation, rapid gel formation/degradation and immobilization/release of signalling factors. Herein, we discuss the union of rapid light-based manufacturing and photoresponsive chemistries and highlight future opportunities using photochemistry in the design and user-defined customization of hydrogel biomaterials. We anticipate that these areas will continue to evolve in tandem and be influenced by new insights from traditionally disparate disciplines (such as protein engineering and inorganic chemistry), facilitating further discoveries in cellular development and disease progression, as well as orchestrating advanced tissue construction.
    DOI:  https://doi.org/10.1038/s44222-024-00234-w
  2. Nat Biotechnol. 2025 Aug 12.
    Targeted delivery of diverse biomolecules with engineered bacterial nanosyringes.
    Joseph Kreitz, Victoria Yang, Mirco J Friedrich, Julie Pham, Rhiannon K Macrae, Feng Zhang.
      The Photorhabdus virulence cassette is a microbial nanosyringe that can be engineered to deliver protein cargos into human cells. Here we further modify this system to incorporate exogenous cargos and targeting moieties in vitro. We show that this method, termed SPEAR, enables loading of different types of cargo (including folded ribonucleoproteins and single-stranded DNA) and targeting of defined cell types both in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41587-025-02774-x
  3. Macromol Rapid Commun. 2025 Aug 14. e00435
    Hydrogel Viscoelasticity Modulates Cell Nascent Extracellular Matrix Deposition.
    Matthew L Tan, Avinava Roy, Eleanor M Plaster, Haguy Wolfenson, Adam Abraham, Claudia Loebel.
      Polymeric hydrogels are valuable platforms for determining how specific mechanical properties of native tissue extracellular matrix (ECM) regulate cell function. Recent research has focused on incorporating viscous and elastic properties into hydrogels to investigate cellular responses to time-dependent mechanical properties of the ECM. However, a critical aspect is that cells continuously remodel their microenvironment in hydrogels, such as by the deposition of newly secreted (nascent) ECM. While this nascent ECM has been demonstrated to play a vital role in transmitting mechanical signals across various biological contexts, the mechanisms by which it regulates cellular function in response to time-dependent mechanical properties remain poorly understood. In this study, we developed an interpenetrating polymer network that enables independent control of viscous and elastic hydrogel properties. We show that cells cultured on high-viscosity hydrogels deposit increased nascent ECM, which also correlates with enhanced hydrogel remodeling. Interestingly, higher nascent ECM deposition on high-viscosity hydrogels was decoupled from intracellular contractility. These results establish a relationship between hydrogel viscosity and nascent ECM deposition that may extend to diverse cell types and offer new insights into cell-hydrogel interactions.
    Keywords:  extracellular matrix deposition; hydrogels; mechanotransduction; viscoelasticity
    DOI:  https://doi.org/10.1002/marc.202500435
  4. ACS Synth Biol. 2025 Aug 14.
    Unraveling the Constrained Cell Growth in Engineered Living Materials.
    Shuang-Shuang Sun, Cheng-Cheng Ding, Hai-Yan Yu, Xian-Zheng Yuan, Shu-Guang Wang, Peng-Fei Xia.
      Engineered living materials (ELMs) leverage the integrative advantages of materials science and synthetic biology for advanced functionalities. Predicting and controlling cellular behavior are essential for designing and building ELMs, requiring a fundamental understanding of the growth dynamics of encapsulated cells. Here, we interrogate the interference of constrained growth with the engineered functionalities and cellular physiology of cyanobacteria and unveil the dynamic interaction between cell growth and spatial confinements within photosynthetic ELMs. We observed that engineered cyanobacteria within ELMs exhibited compromised performances in growth, uptake of nonutilizable substrate, and synthesis of customized products, while ELMs could protect encapsulated cells from external stresses. Besides commonly accepted external influences, we identified abnormally high levels of reactive oxygen species and impaired oxygen photosynthesis inside the cells encapsulated in the ELMs. Finally, we illustrated the dynamics of cell growth within the confined spaces enveloped by the material matrices, forming clustered cell aggregates and compressed growth bubbles until the spatial limits. Our study provides a fundamental yet often overlooked connection between cellular behavior and spatial confinement, consolidating the foundation for advanced ELM innovations.
    Keywords:  confined growth; cyanobacteria; engineered living materials; hydrogel
    DOI:  https://doi.org/10.1021/acssynbio.5c00378
  5. Nat Biomed Eng. 2025 Aug 15.
    Engineered bacteria launch and control an oncolytic virus.
    Zakary S Singer, Jonathan Pabón, Hsinyen Huang, William Sun, Hongsheng Luo, Kailyn Rhyah Grant, Ijeoma Obi, Courtney Coker, Charles M Rice, Tal Danino.
      The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice. Finally, we engineer the virus to require a bacterially delivered protease to achieve virion maturation, demonstrating bacterial control over the virus. Together, we refer to this platform as 'CAPPSID' for Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery. This work extends bacterially delivered therapeutics to viral genomes, and shows how a consortium of microbes can achieve a cooperative aim.
    DOI:  https://doi.org/10.1038/s41551-025-01476-8
  6. ACS Nano. 2025 Aug 12.
    Hydrogels with Tethered Transcription Circuit Elements for Chemical Communication and Collective Computation.
    Kuan-Lin Chen, Joshua Cole, Cheng-Hung Chou, Chloe W Lindeman, Samuel W Schaffter, Pepijn Moerman, Moshe Rubanov, Keren Sneh, Rebecca Schulman.
      Tissues, robots, and other distributed systems must communicate to make decisions about information originating from different physical locations and then orchestrate the responses. In tissues, for example, cell-cell communication is essential for morphogenesis, immune response, and wound healing. However, devising methods for programming distributed communication in synthetic materials to program behaviors such as multiscale pattern formation, motion, and self-assembly remains a challenge. Here, we devise a design principle for reliable distributed chemical computation and communication and then construct a library of transcription circuit elements, termed tethered genelets (TGs), that implement this design principle within networks of 50 μm hydrogel nodes (HNs). TGs exhibit digital behavior in the form of a "distance-response curve"─they switch off in response to signals emanating from HNs within a specific distance, but are unaffected by faraway signals. In experiments, we verify that TGs send and receive signals as designed and validate the function and modularity of a library of 15 TG circuit elements. The principle of "digital distance-response" and the library of circuit elements we construct together will allow a diverse range of distributed chemical behaviors, communication, and dynamics to be programmed into materials such as soft robots and responsive surfaces.
    Keywords:  DNA computing; DNA nanotechnology; digital abstraction; in vitro transcription; programmable matter
    DOI:  https://doi.org/10.1021/acsnano.4c14232
  7. Adv Mater. 2025 Aug 15. e08100
    Genetic Surfaceome E. coli Reprogramming Enables Selective Water Oxidation.
    Graziela C Sedenho, Jéssica C Pacheco, Melanie Gut, Filipe C D A Lima, Sunanda Dey, Frank N Crespilho, Ariel L Furst.
      Programming catalytic behavior at the microbial genome level is a frontier in synthetic biology with direct impact on bioelectrocatalysis. A key challenge is the coordinated control of gene expression, localization, folding, and cofactor maturation required to achieve proper bioelectrocatalytic activity. Here, a synthetic operon in Escherichia coli is engineered to reprogram its surfaceome for selective water oxidation. Using orthogonal IPTG-inducible control and codon-optimized expression, a fungal bilirubin oxidase (BOD) displayed at the cell surface is produced by ice nucleation protein anchoring (BOD-E. coli). Post-overexpression copper catalytic site reconstitution provides an active holoenzyme. The developed engineered living material performs water oxidation at near-zero overpotential (27 mV at pH 9.1), with complete suppression of the oxygen reduction reaction. These results show how regenerable microbial platforms can be designed for selective catalysis and artificial photosynthesis.
    Keywords:  bilirubin oxidase; biomaterials; electrocatalysis; water oxidation
    DOI:  https://doi.org/10.1002/adma.202508100
  8. Nat Nanotechnol. 2025 Aug 15.
    Designing lipid nanoparticles using a transformer-based neural network.
    Alvin Chan, Ameya R Kirtane, Qing Rui Qu, Xisha Huang, Jonathan Woo, Deepak A Subramanian, Rajib Dey, Rika Semalty, Joshua D Bernstock, Taksim Ahmed, Rowan Honeywell, Charles Hanhurst, Isaac Diaz Becdach, Leah S Prizant, Ashley K Brown, Hao Song, Justin Law Cobb, Louis B DeRidder, Bruna Santos, Miguel Jimenez, Michelle Sun, Yuebin Huang, Ceara Byrne, Giovanni Traverso.
      The RNA medicine revolution has been spurred by lipid nanoparticles (LNPs). The effectiveness of an LNP is determined by its lipid components and their ratios; however, experimental optimization is laborious and does not explore the full design space. Computational approaches such as deep learning can be greatly beneficial, but the composite nature of LNPs limits the effectiveness of existing single molecule-based algorithms to LNPs. Addressing this, our approach integrates the multi-component and multimodal features of composite formulations such as LNPs to predict their performance in an end-to-end manner. Here we generate one of the largest LNP datasets (LANCE) by varying LNP formulations to train our deep learning model, COMET. This transformer-based neural network not only accurately predicts the efficacy of LNPs but is adaptable to non-canonical LNP formulations such as those with two ionizable lipids and polymeric materials. Furthermore, COMET can predict LNP performance in a cell line outside of LANCE and predict LNP stability during lyophilization using only small training datasets. Experimental validation showed that our approach can identify LNPs that exhibit strong protein expression in vitro and in vivo, promising accelerated development of nucleic acid therapies with extensive potential across therapeutic and manufacturing applications.
    DOI:  https://doi.org/10.1038/s41565-025-01975-4
  9. Biomacromolecules. 2025 Aug 15.
    Toward Next-Generation Ingestible Hydrogels.
    Gary W Liu, Ruitao Su, Bianca Lorraine Garcia Osterling, Ruben Carrazco, Vivian R Feig.
      Ingestible hydrogels have long been used in food and therapeutic applications. Their polymeric composition endows these materials with programmable and dynamic properties to operate within the complex gastrointestinal tract. Recent advances have pushed the boundaries of hydrogel behavior and function; incorporating these features may enable new strategies to manage gastrointestinal and systemic diseases. In this perspective, we highlight some commercial ingestible hydrogel products to establish their current capabilities. We then discuss some recent advances of ingestible hydrogels that push these capabilities in the areas of tissue-specific activity, ultralong retention within the gastrointestinal tract, and incorporation into ingestible electronics and robots. Finally, we discuss some key considerations for translating ingestible macroscale hydrogels, which requires early consideration of in vivo models and regulation, safety, and manufacturing.
    DOI:  https://doi.org/10.1021/acs.biomac.4c00902
  10. Nat Commun. 2025 Aug 12. 16(1): 7467
    Sustainable DNA-polysaccharide hydrogels as recyclable bioplastics.
    Yujie Ke, Kai Lan, Jing Yi Wong, Hongfang Lu, Shujun Gao, Keunhyuk Ryu, Feng Chen, Wei Wei Loh, Zhili Dong, Jason Y C Lim, Zhaogang Dong, Xi Chen, Itamar Willner, Yuwei Hu.
      Traditional petrochemical-derived plastics are challenging to recycle and degrade, and the existing (re)process methods are organic solvent-based and/or energy-intensive, resulting in significant environmental contamination and greenhouse gas emissions. This study presents a sustainable bioplastic material characterized by multi-closed-loop recyclability and water (re)processability. The bioplastics are derived from abundant polysaccharide sources of dextran, alginic acid, carboxymethyl cellulose, and DNA of plant and living organism waste. The process involves chemical oxidation of polysaccharides to produce aldehyde-functionalized derivatives, which subsequently form reversible imine covalent bonds with amine groups in DNA. This reaction yields water-processable polysaccharide/DNA crosslinked hydrogels, serving as raw materials for producing sustainable bioplastics. The bioplastic products exhibit (bio)degradability and recyclability, enabling aqueous recovery of the hydrogel constituents through plastic hydrolysis and the natural biodegradability of DNA and polysaccharides. These products demonstrate excellent resistance to organic solvents, self-healing, scalability, and effective processing down to nanometer scales, underscoring their potential for broad and versatile applications. The work provides potential pathways for advancing sustainable and environmentally friendly bioplastic materials.
    DOI:  https://doi.org/10.1038/s41467-025-62682-1
  11. Adv Mater. 2025 Aug 15. e09672
    Fully Synthetic Hydrogels Promote Robust Crypt Formation in Intestinal Organoids.
    Ella A Hushka, Michael R Blatchley, Laura J Macdougall, F Max Yavitt, Bruce E Kirkpatrick, Kaustav Bera, Peter J Dempsey, Kristi S Anseth.
      Initial landmark studies in the design of synthetic hydrogels for intestinal organoid culture identify precise matrix requirements for differentiation, namely decompression of matrix-imposed forces and supplementation of laminin. But beyond stating the necessity of laminin, organoid-laminin interactions have gone largely unstudied, as this ubiquitous requirement of exogenous laminin hinders investigation. In this work, a fast stress relaxing, boronate ester-based synthetic hydrogel is used for the culture of intestinal organoids, and it is fortuitously discovered that unlike all other synthetic hydrogels to date, laminin does not need to be supplemented for crypt formation. This highly defined material provides a unique opportunity to investigate laminin-organoid interactions and how it influences crypt evolution and organoid function. Via fluorescent labeling of non-canonical amino acids, it is further shown that adaptable boronate ester bonds increase deposition of nascent proteins, including laminin. Collectively, these results advance the understanding of how mechanical and matricellular signaling influence intestinal organoid development.
    Keywords:  biomaterials; extracellular matrix; intestinal organoids; laminin; stress relaxing hydrogels
    DOI:  https://doi.org/10.1002/adma.202509672
  12. Mater Today Bio. 2025 Oct;34 102140
    Direct laser writing of electronically conductive microstructures within soft hydrogel substrates.
    Lorenzo Lucherini, Veronica Navello, Outman Akouissi, Stéphanie P Lacour, Esther Amstad.
      Hydrogels have emerged as promising materials for bioelectronic interfaces due to their tissue-like properties and high-water content. However, conventional hydrogels often suffer from poor electrical conductivity and mechanical stability, limiting their performance in long-term bioelectronic applications. Electronic conductivity can be imparted to hydrogels by functionalizing them with conductive particles. However, patterning of electronically conductive features within hydrogels remains challenging. Electronically conductive μm-sized patterns embedded in soft hydrogels would open up new possibilities to integrate hydrogel bioelectronics with electronic devices. Here, we introduce covalently crosslinked hydrogels with Young's moduli below 30 kPa that can be functionalized with metallic electronically conductive paths reaching an electronic conductivity up to (1505 ± 518) S cm-1. By tailoring the hydrogel substrate composition, we achieve writing fidelity up to ±5 %, with feature width as narrow as 5 μm. Using two-photon direct laser writing, we demonstrate the ability to pattern encapsulated conductive structures at the surface or within the bulk of the hydrogels. These patterned hydrogels offer new opportunities for creating soft, miniaturized bioelectronic interfaces, with potential applications in cellular and tissue electrophysiology.
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102140
  13. Adv Healthc Mater. 2025 Aug 15. e02172
    Norbornene Homopolymerization Limits Cell Spreading in Thiol-Ene Photoclick Hydrogels.
    James L Gentry, Steven R Caliari.
      Thiol-ene click chemistry is a powerful tool for engineering tissue-mimicking hydrogels permissive to 3D cell spreading. Thiol-norbornene chemistry allows precise control over crosslinking while seemingly avoiding alkene homopolymerization that can restrict 3D cell spreading. However, limited stress relaxation of a guest-host crosslinked norbornene-modified hyaluronic acid (NorHA) hydrogel employing a thiol-norbornene photoclick reaction prompts investigation into unintended norbornene homopolymerization. Norbornene conversion exceeds 1:1 thiol-ene expectations across various formulations, implicating homopolymerization. Reducing the number of norbornenes per NorHA chain (f) mitigates network formation via norbornene homopolymerization. Guest-host hydrogels fabricated with Nor8HA (f = 8) exhibit 93.0 ± 1.6% relaxation, while those fabricated with Nor40HA (f = 40) achieve only 42.3 ± 0.1% relaxation. As early as day 3 of culture, Nor8HA hydrogels facilitate spreading of encapsulated human mesenchymal stromal cells (hMSCs) into a spindle-like morphology (aspect ratio: 2.95 ± 0.38), while Nor40HA hydrogels appear to constrain cells into a spherical or compact star morphology (aspect ratio: 1.22 ± 0.01). Inference of a single-cell morphological space validates the two distinct hMSC morphological phenotypes primarily associated with polymer f. These results demonstrate that thiol-norbornene crosslinking is not fully stoichiometric in dilute aqueous systems and that network topology, modulated by f, is critical for restoring hydrogel permissivity and enabling cell spreading.
    Keywords:  cell spreading; hydrogels; norbornene homopolymerization; stress relaxation
    DOI:  https://doi.org/10.1002/adhm.202502172
  14. Small. 2025 Aug 13. e04244
    3D-Printing Thermo-Responsive Photonic Inks Based on Cellulose Semi-Interpenetrating Liquid Crystal Networks.
    Dong Li, Qiang-Wu Tan, Chun-Xia Zhao, Yuan-Peng Wu, Xiu-Li Wang, Yu-Zhong Wang, Fei Song.
      3D-printable photonic crystals are widely utilized in sensors, painting decoration, and information encryption. The development of photonic inks capable of forming complex shapes and exhibiting flexible color changes enables the fabrication of structural-color devices with unique structures and specialized functions, while achieving collaborative control over 3D printability and dynamic color-changing function remains a significant challenge. Here, printable and thermosensitive photonic inks are demonstrated through the co-assembly of hydroxypropyl cellulose (HPC) and hydroxyethyl acrylate into cholesteric liquid crystals. The semi-interpenetrating network created by HEA polymerization, along with the hydrogen bonding between the co-phases, facilitates the 3D printing of complex objects. Moreover, this network maintains the cholesteric phase structure while reducing the phase separation of HPC, enabling the manipulation of varying degrees of color change, with sensitivities ranging from 6.4 to 3.0 nm °C-1. Through 3D printing, these photonic inks can be utilized to create both 2D and 3D objects with dynamic thermochromic properties. This work offers a simple and instructive strategy for developing flexible and responsive photonic materials.
    Keywords:  3D printing; information encryption; photonic crystals; structural color; temperature response
    DOI:  https://doi.org/10.1002/smll.202504244
  15. ACS Synth Biol. 2025 Aug 10.
    Engineered Gram-Positive Based Quorum Sensing for Metabolic Control in Escherichia coli.
    Michael J Ream, Kristala L J Prather.
      Quorum sensing (QS) is a cell-to-cell communication system that allows microbial communities to collaborate and function as a collective. QS functions as a population-dependent regulator by producing signals that scale with cell concentration, allowing surrounding cells to recognize the signal and activate the associated genes at a certain population density. Though many regulatory systems have been characterized, much of the engineering focus has been on a small subset of the expansive QS circuits that exist within nature. To expand the available QS circuits for use in Escherichia coli, two Gram-positive systems were identified as useful candidates: the Agr system, from the therapeutically relevant Staphylococcus aureus, and the Com system, from the model Gram-positive organism Bacillus subtilis. These QS systems were implemented and improved for functionality by modifying the expression strength of circuit components. Each system displayed tight control of their cognate promoters with the Com system reaching a final dynamic range of 2.27 ± 0.05, while the Agr system was improved to a dynamic range of 4.05 ± 0.43. The Agr system was then applied to downregulate endogenous genes tyrA, pheA, trpE, ppc, and pabB via CRISPRi. This regulation strategy allowed for the production of salicylic acid in E. coli MG1655 by diverting metabolic flux toward the target pathway, demonstrating the utility of Agr as a tightly regulated control system in E. coli.
    Keywords:  autoinducing peptides (AIPs); dynamic regulation; metabolic engineering; metabolic flux; quorum sensing; synthetic biology
    DOI:  https://doi.org/10.1021/acssynbio.5c00433
  16. Mater Today Bio. 2025 Oct;34 102121
    Bio-orthogonally double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity for cardiac tissue engineering.
    Daniele Testore, Alice Zoso, Camilla Paoletti, Sara Groppo, Elena Marcello, Valeria Chiono.
      Growing evidence has shown that cells respond to the viscoelastic properties of the extracellular matrix (ECM), particularly its stress-relaxation, which influences their spreading, proliferation, and remodeling. Since cardiac tissue viscoelasticity plays a key role in modulating cellular mechanosensing, the development of biomimetic viscoelastic hydrogels is highly needed in cardiac tissue engineering (CTE). This work presents bio-orthogonal double cross-linked alginate-gelatin hydrogels with tunable viscoelasticity, designed to replicate the dynamic mechanical properties of cardiac ECM. Alginate and gelatin were functionalized with azide groups and cross-linked by a 4-arm-dibenzocyclooctyne (DBCO) crosslinker using strain-promoted azide-alkyne cycloaddition (SPAAC) with 0.5:1 (AG_Click(R0.5)) and 1:1 (AG_Click(R1)) DBCO:azide molar ratios. Calcium ions were also introduced to obtain double cross-linked hydrogels (AG_DC(R0.5) and AG_DC(R1)). Rheology showed that hydrogels exhibited tunable stiffness and stress relaxation, closely mimicking the properties of native cardiac tissue. The behavior of human cardiac fibroblasts (HCFs), seeded on hydrogels, was analyzed. When compared to purely elastic polyacrylamide (pAAm) hydrogels with comparable stiffness, soft stress-relaxing hydrogels (AG_Click(R0.5) and AG_DC(R0.5)) were found to promote cell spreading area, while stiffer stress-relaxing hydrogels (AG_Click(R1) and AG_DC(R1)) enhanced asymmetric cell elongation, reflecting substrate-mediated mechanosensing. Additionally, HCFs showed high viability when cultured in 3D hydrogels over 7 days. Overall, rapid gelation, biocompatibility, and tunable viscoelastic properties of bio-orthogonal double cross-linked alginate-gelatin hydrogels support their use as injectable formulations or engineered cardiac tissues for CTE.
    Keywords:  Bio-orthogonal; Cardiac tissue engineering; Click chemistry; Hydrogels; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102121
  17. ACS Synth Biol. 2025 Aug 10.
    YTK Display-and-Secrete: Screening for Optimal Protein Secretion Elements in Saccharomyces cerevisiae.
    Anastasiya Kishkevich, Klaudia Ciurkot, Tom Ellis.
      Engineering yeast to secrete target proteins requires searching for optimal combinations of promoters and signal peptides so that genes can be composed that give a high expression and efficient secretion. Most methods for this involve laborious, one-by-one assessments or require the use of enzymatic reporter proteins in order to achieve high-throughput capacity. Here, we introduce a novel modular method for the high throughput screening of yeast strains designed to secrete proteins of interest. Our approach integrates combinatorial DNA assembly, yeast surface display, flow cytometry, and nanopore DNA sequencing to facilitate rapid screening. Building on a widely used yeast toolkit (YTK) for modular cloning, our system creates surface display libraries with N- and C-terminal epitope tags by fast DNA assembly and genome-integration into Saccharomyces cerevisiae. Flow cytometry with fluorescently labeled epitope-binding antibodies identifies strains that secrete and display the most full-length protein and can rapidly sort these from low secretors. We demonstrate our system by optimizing the secretion of the enzyme beta-lactamase and several elastin-like polypeptides (ELPs), first identifying strains with modular genetic element combinations that give the best surface display and then validating that removal of the surface-display anchor protein in these strains gives a high target protein secretion. We then show how pooled long read sequencing of sorted cells can determine the effectiveness of numerous combinations of promoters and signal peptides for a target protein in a single experiment. The data sets from this offer new insights into an optimal element choice for efficient protein secretion and could train machine learning models.
    Keywords:  nanopore sequencing; protein secretion; yeast surface display; yeast toolkit
    DOI:  https://doi.org/10.1021/acssynbio.5c00264
  18. Nat Commun. 2025 Aug 12. 16(1): 7488
    Building a Synthetic Cell Together.
    S Giaveri, Z Abil, S Kohyama, M Fu, A Levrier, K Adamala, W Chinantuya, C Dekker, N Deng, J Fredens, K Hagino, K Jahnke, X Li, A B Lindner, C Liu, S Majumder, V Noireaux, P Schwille, I N Westensee.
      Synthetic cells (SynCells) are artificial constructs designed to mimic cellular functions, offering insights into fundamental biology, as well as promising impact in the fields of medicine, biotechnology, and bioengineering. Achieving a functional SynCell from the bottom up, i.e. by assembling it from molecular components, requires a global collaboration to overcome the many challenges of engineering and assembling life-like modules while addressing biosafety, equity, and ethical concerns in order to guide responsible innovation. Here, we highlight major scientific hurdles, such as the integration of functional modules by ensuring compatibility across diverse synthetic subsystems, and we propose strategies to advance the field.
    DOI:  https://doi.org/10.1038/s41467-025-62778-8
  19. Nat Commun. 2025 Aug 14. 16(1): 7540
    Boosting energy metabolism and biosynthesis in diverse organisms by a common bacterial salvage lipoylation protein.
    Runqing Yang, Yingying Wang, Minghua Kong, Zhijuan Hu, Zhe Zhang, Kun Shen, Jiali Meng, An-Ping Zeng.
      Lipoylation is a highly conserved post-translational modification (PTM) crucial for energy metabolism enzymes, with distinct pathways across organisms. Whereas bacteria like Escherichia coli inherit both salvage and de novo pathways, only the latter is found in eukaryotes. Here, we present a PTM-based strategy that achieves multiple metabolic benefits with a single intervention. By expressing E. coli-derived lipoate protein ligase A (LplA) from the salvage pathway, we enhance lipoylation and the activities of the pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase complexes and glycine cleavage system in mammalian, algal and fungal cells, leading to improved energy metabolism, cofactor supply, mitochondrial function, and overall cell physiology. Our approach specifically targets multiple metabolic hubs through PTM modulation. Beyond its fundamental significance, our finding presents a unified and efficient way to boost biosynthesis across organisms, demonstrated in antibody production in Chinese hamster ovary cells, fatty acids synthesis in cyanobacteria and diatoms, and organic acid production in fungi.
    DOI:  https://doi.org/10.1038/s41467-025-62638-5
  20. Nat Comput Sci. 2025 Aug 13.
    Engineering morphogenesis of cell clusters with differentiable programming.
    Ramya Deshpande, Francesco Mottes, Ariana-Dalia Vlad, Michael P Brenner, Alma Dal Co.
      Understanding the fundamental rules of organismal development is a central, unsolved problem in biology. These rules dictate how individual cellular actions coordinate over macroscopic numbers of cells to grow complex structures with exquisite functionality. We use recent advances in automatic differentiation to discover local interaction rules and genetic networks that yield emergent, systems-level characteristics in a model of development. We consider a growing tissue with cellular interactions mediated by morphogen diffusion, cell adhesion and mechanical stress. Each cell has an internal genetic network that is used to make decisions based on the cell's local environment. Here we show that one can learn the parameters governing cell interactions in the form of interpretable genetic networks for complex developmental scenarios. When combined with recent experimental advances measuring spatio-temporal dynamics and gene expression of cells in a growing tissue, the methodology outlined here offers a promising path to unraveling the cellular bases of development.
    DOI:  https://doi.org/10.1038/s43588-025-00851-4
  21. ACS Appl Mater Interfaces. 2025 Aug 11.
    3D Printing of Interconnection-Tunable Porous Ink.
    Wongi Kim, Minseong Kang, Jongkyeong Lim.
      An interconnection-tunable porous ink (ITPI) platform is introduced for fabricating three-dimensional (3D) porous structures with programmable pore connectivity. The ITPI is a multiphasic suspension consisting of a polymer precursor solution as the continuous medium, sacrificial solid particles, and a surface-wetting liquid that forms capillary bridges. The formulation is tailored to possess rheological properties suitable for 3D printing via direct ink writing, facilitating the patterning of elastic porous architectures. This ITPI design allows fine control of the interconnection width between pores by adjusting the wetting liquid content while maintaining the overall porosity and pore size. As a representative case, p-ITPI, composed of polydimethylsiloxane, sugar particles of approximately 30 μm, and glycerol, is used to fabricate highly elastic 3D sponges with tunable interconnection widths ranging from a few to several tens of micrometers. The resulting structures exhibit excellent shape fidelity, adjustable permeability, and long-term superelasticity over 1000 compression cycles. Demonstrated applications include selective oil absorption, programmable-delay passive fluid release in microfluidics, and piezoresistive sensing via liquid metal (LM) infusion. Notably, LM-infused sponges enable real-time tactile feedback in robotic coil embolization simulations. This strategy offers a generalizable route for engineering porous materials with tunable interconnectivities for filtration systems, microfluidics, soft robotics, and biomedical systems.
    Keywords:  3D printing; flexible electronics; interconnection-tunable; oil/water separation; passive pump; porous ink
    DOI:  https://doi.org/10.1021/acsami.5c10388
  22. ACS Nano. 2025 Aug 15.
    Merging Natural Biopolymers with Supramolecular Chemistry: Emulating the Native Extracellular Matrix's Complexity.
    Vera Sousa, Bruno Ladeira, Elisabeth Garanger, Sébastien Lecommandoux, E W Meijer, Patricia Y W Dankers, João F Mano, João Borges.
      The extracellular matrix (ECM) is one of the most striking natural self-assembled landscapes, essential for tissue integrity and cellular functions, where it orchestrates cell fate through a dynamic interplay of noncovalent interactions. Despite decades of research, there is still no scaffold that can replicate its nanostructural elegance and functional dynamic behavior. In this Perspective, we summarize cutting-edge approaches to reconstruct the ECM, putting an emphasis on either dynamic supramolecular designs or naturally sourced biopolymers. We then propose merging the natural with the synthetic world to enable hybrid cell-instructive materials that combine the dynamic mechanical profile, biomolecular composition and structural features of the ECM at all scales, from the nano- to the mesoscale, aiming to create a fully functional artificial ECM.
    DOI:  https://doi.org/10.1021/acsnano.5c10088
  23. Biomacromolecules. 2025 Aug 12.
    Optimizing Green Light Photoredox Catalyzed Polymerizations for 3D Printing of Cell-Laden Hydrogels.
    Lynn M Stevens, Kathleen N Halwachs, Elizabeth A Recker, Vincent G Garcia, Adrianne M Rosales, Zachariah A Page.
      3D bioprinting is a powerful tool for fabricating complex tissue-like constructs, with digital light processing (DLP) offering exceptional speed and precision. However, conventional DLP relies on harmful UV light, limiting its application for cell-laden structures. Here, we developed green light-reactive photosystems for high-resolution hydrogel 3D printing. A polyacrylamide-based formulation (Resin 1) with Eosin Y as a photoredox catalyst enabled rapid prototyping (<10 s/100 μm) with low-intensity green light, achieving ∼50 μm resolution in structures such as vessel models with up to 90 wt % water. To improve cytocompatibility, we introduced a methacrylated-gelatin formulation (Resin 2), followed by a system with Eosin Y, dithiothreitol, and norbornene-functionalized gelatin (NorGel, Resin 3). Resin 3 enabled DLP printing of cell-laden constructs encapsulating human dermal fibroblasts in a cylindrical geometry with ∼90% viability after 3 days. This green light DLP platform integrates high resolution, rapid processing, and cytocompatibility to advance fabrication of physiologically relevant tissue models.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00830
  24. Mater Horiz. 2025 Aug 11.
    High-performance reverse thermoresponsive hydrogel enabled by one-pot PDMS-enriched domain crosslinking.
    Qianqian Liang, Wanting Yuan, Yi He, Ziqi Wang, Yong Liu, Jinrong Wu, Lijuan Zhao, Yi Wang.
      Reverse thermoresponsive hydrogels, which exhibit low transparency at ambient temperature and become transparent upon heating, offer distinct advantages in information encryption, thermal display, and emergency signaling. However, integrating such optical responsiveness with mechanical robustness, moisture retention, and interfacial adhesion remains a challenge. Herein, we report a highly stretchable and reverse thermoresponsive hydrogel based on polyacrylamide (PAM) crosslinked by PDMS-enriched microgel-like domains, synthesized via an emulsion-assisted one-pot strategy. During polymerization, hydrophobic PDMS chains form domain aggregates and covalently integrate with PAM at the interface, resulting in a robust and deformable domain network. The hydrogel exhibits excellent mechanical performance (5680% stretchability, 5.8 MJ m-3 toughness) and reversibly transitions from opaque to transparent upon heating, due to entropy-driven domain reorganization that reduces interfacial light scattering. This enables rapid thermal decryption and high-contrast visual display without external energy inputs. The hydrogel also shows enhanced water retention, strong adhesion to various substrates, and sodium chloride (NaCl)-enabled strain sensing. This work provides a structurally simple yet multifunctional platform for next-generation optical encryption materials and flexible photonic devices.
    DOI:  https://doi.org/10.1039/d5mh01141h
  25. ACS Biomater Sci Eng. 2025 Aug 11. 11(8): 5000-5011
    A Synthetic Hydrogel with Tunable Stiffness for Engineering Pancreatic Cancer Organoids and Drug Testing.
    Tingting Tao, Haitao Liu, Zhongqiao Gan, Jia He, Xu Zhang, Xianliang Li, Jianhua Qin.
      Pancreatic cancer organoids (PCOs) have gained extensive attention as promising in vitro models that can advance our understanding of translational cancer biology and biomedical research. To date, PCOs are mostly cultured in animal-derived matrices, which are limited by their low similarity with native tumors due to batch-to-batch variations, stringent operating conditions, and uncontrollable physicochemical properties. Here, we developed a more controllable hydrogel matrix comprising sodium alginate (NaA) and hyaluronic acid (HA) that can mimic the mechanical properties of native tumor tissue, such as extracellular matrix (ECM) components and stiffness. The PCOs cultured in the hydrogel matrix exhibited similar viability and growth rate with that in commercial Matrigel. Furthermore, we observed improvements of PCOs in 1% NaA-HA hydrogel matrices over tumor-specific features observed previously in animal-derived matrices. Transcriptional analysis revealed the activation of signaling pathways associated with ECM organization in the PCOs generated in hydrogel. Moreover, we noted that the biomimetic stiffness of hydrogel enhanced the drug resistance of PCOs of conventional chemotherapy agents but improved the sensitivity to targeted antitumor drugs (Erlotinib) of the PCOs with EGFR mutation. This work represents foundation for the customizing hydrogel stiffness that can be utilized to mimic the native tumor tissue, as well as a new platform for performing pancreatic cancer research and antitumor drug screening in the future.
    Keywords:  defined hydrogels; drug testing; pancreatic cancer; tunable stiffness
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00705
  26. ACS Appl Mater Interfaces. 2025 Aug 12.
    Single Amino Acid Derived Rudimentary Catalytic Hydrogel for Reaction Engineering.
    Ipsita Sahu, Debolina Saha, Shreya Pande, Jaya Verma, Priyadarshi Chakraborty.
      Despite being structurally rudimentary, single amino acids and their derivatives demonstrate a remarkable ability to self-assemble into ordered nanostructures that renders potential catalytic activity. While many reports of catalysis utilizing amyloid-inspired peptide nanostructures are available, single amino acid derived hydrogel-based catalysts are rare. Herein, we report an elementary amino acid derivative, fluorenylmethoxycarbonyl-L-tryptophan (FT), based hydrogel that catalyzed the hydrolysis of p-nitrophenyl acetate, courtesy of the suitable positioning of indole residues in its ordered nanostructures. Exhibiting pathway complexity, the hydrogel nanofibers, initially formed as a kinetically trapped phase, underwent a morphological transition into thermodynamically stable semicrystalline microstructures, displaying better catalytic prowess than the hydrogel. Composite hydrogels with carbon nanomaterials improved the FT gels' mechanical properties and catalytic efficiency, ultimately bestowing enzyme-like hydrolytic activity. The FT hydrogel was finally utilized to engineer nanohybrid gels with gold nanoparticles as an efficient catalyst for dye degradation. The handling scope of these nanohybrid gels, along with morphological control, was improved by preparing core-shell hydrogel beads with alginate, realizing their practical catalytic potential for water remediation. Strikingly, a single hydrogel bead was capable of driving almost complete degradation for both cationic and anionic dyes. This reflects the optimized microenvironment for electron transfer and substrate diffusion within the porous structure of the developed beads. The efficacious catalysis by the bulk hydrogels/beads demonstrates the role of confinement, high surface area, and substrate diffusion through their porous architecture. Moreover, the hydrogels' semisolid nature offered excellent reusability, underscoring their role in sustainable and cost-effective catalytic applications.
    Keywords:  catalysis; gel nanocomposites; pathway complexity; supramolecular hydrogel; water remediation
    DOI:  https://doi.org/10.1021/acsami.5c09633
  27. ACS Appl Mater Interfaces. 2025 Aug 11.
    Polyelectrolyte Complex-Based Artificial Biofilms as Versatile Living Biomaterials.
    Yihao Cui, Zhe Wang, Haiyang Yu, Peng Fu, Changwei Shi, Ximing Xu, Lei Liu, Shuai Hou.
      Bacterial biofilms, while recognized as promising functional biomaterials, are constrained by intricate growth dynamics, complex extracellular polymer compositions, and limited processability. Here, we address these challenges by employing polyelectrolyte complexes (PECs) to create artificial biofilms via a one-step synthesis with predefined extracellular composition and enhanced processability, achieving natural biofilm-like bacterial density and properties across diverse bacterial species. The PEC matrix confers robust bacterial protection, resisting antibiotic concentrations 1000-fold above the minimal inhibitory level, lyophilization, and acidic environments. Its shear-thinning behavior enables versatile processing via extrusion, molding, or coating. As recyclable biocatalysts, these biofilms preserve the enzymatic activity at elevated temperatures (up to 80 °C). In simulated probiotic delivery, they enhance bacterial survival under gastrointestinal-like conditions and offer tunable, composition-dependent release profiles, achieving therapeutic efficacy in a murine colitis model. This platform combines flexible fabrication with customizable functionality, establishing a versatile strategy for engineered living biomaterials with broad applications in biotechnology and biomedicine.
    Keywords:  bacterial encapsulation; biofilms; extracellular polymeric substances; living biomaterials; polyelectrolyte complexes
    DOI:  https://doi.org/10.1021/acsami.5c06236
  28. Biomaterials. 2025 Aug 05. pii: S0142-9612(25)00509-5. [Epub ahead of print]325 123590
    Clicktetrazine dECM-alginate hydrogels for injectable, mechanically mimetic, and biologically active vocal fold biomaterials.
    Mika Brown, Hideaki Okuyama, Ling Li, Zhen Yang, Jianyu Li, Maryam Tabrizian, Nicole Y K Li-Jessen.
      Current injectable biomaterials for vocal fold disorders suffer from fast degradation and require frequent re-injection. Decellularized extracellular matrix (dECM) hydrogels are a tissue-derived, injectable biomaterial with intrinsic regenerative capacity. However, dECM hydrogels often exhibit mechanical instability and share the same problems with degradation as existing vocal fold biomaterials. In this work, we developed a composite dECM-alginate hydrogel with bioorthogonal click tetrazine ligation with improved stability, biocompatibility and regenerative capacity. dECM was extracted from two sources: tissue-specific vocal fold mucosa and scalable small intestinal submucosa for comparative analysis. Click dECM hydrogels from both sources were tunable and matched mechanical properties of native human vocal folds. The click dECM hydrogels showed capacity to resist contraction and modulate bioactive molecule secretion by fibroblasts, as well as stimulate the initial endothelial cell elongation phase of vasculogenesis. When injected subcutaneously into rats, both gels exhibit a strong initial immune response, followed by integration with the surrounding tissue by day 21. Overall, our click dECM hydrogels showed improved stability over previous dECM hydrogels and their performance was independent of tissue source.
    Keywords:  Click chemistry; Composite hydrogels; Natural biomaterials; Tissue engineering; Vocal folds
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123590
  29. Nat Commun. 2025 Aug 15. 16(1): 7618
    Designing supramolecular pastes by controlling host-guest dynamics in reconfigurable networks.
    Jinrong Wang, Weibin Lin, Valeriia O Nikolaeva, Rukhma Javaid, Niveen M Khashab.
      Stimuli-responsive phase transitions endow smart systems with adaptive functionalities, yet reversible paste-to-gel transitions remain largely unexplored. Here, we report a protonated trianglamine (TA)-based supramolecular paste, in which competitive supramolecular interactions-host-guest binding and electrostatic forces-drive the formation of a dynamic TA-clay-polymer ternary network with paste-like rheology. The material exhibits reversible paste-to-gel transitions under mild thermal stimuli, enabling shape reprogramming, temperature-triggered self-healing, and shape fixation. DFT calculations and molecular simulations reveal the molecular basis of the host-guest interactions in guiding network dynamics and healing behavior. Furthermore, incorporating graphene as conductive filler renders the paste functions as a stretchable, self-healing conductive wire, with potential in flexible electronics and responsive devices. This work introduces supramolecular pastes as a versatile class of smart materials that go beyond traditional hydrogels in structural adaptability and multifunctionality.
    DOI:  https://doi.org/10.1038/s41467-025-63033-w
  30. Biomacromolecules. 2025 Aug 11. 26(8): 4733-4734
    Polymer Colloids: Evolution of the Field toward Biomacromolecules.
    Michael J Monteiro, Michael F Cunningham.
      
    DOI:  https://doi.org/10.1021/acs.biomac.5c00747
  31. Nat Biotechnol. 2025 Aug 13.
    Target sequence-conditioned design of peptide binders using masked language modeling.
    Leo Tianlai Chen, Zachary Quinn, Madeleine Dumas, Christina Peng, Lauren Hong, Moises Lopez-Gonzalez, Alexander Mestre, Rio Watson, Sophia Vincoff, Lin Zhao, Jianli Wu, Audrey Stavrand, Mayumi Schaepers-Cheu, Tian Zi Wang, Divya Srijay, Connor Monticello, Pranay Vure, Rishab Pulugurta, Sarah Pertsemlidis, Kseniia Kholina, Shrey Goel, Matthew P DeLisa, Jen-Tsan Ashley Chi, Ray Truant, Hector C Aguilar, Pranam Chatterjee.
      The computational design of protein-based binders presents unique opportunities to access 'undruggable' targets, but effective binder design often relies on stable three-dimensional structures or structure-influenced latent spaces. Here we introduce PepMLM, a target sequence-conditioned designer of de novo linear peptide binders. Using a masking strategy that positions cognate peptide sequences at the C terminus of target protein sequences, PepMLM finetunes the ESM-2 protein language model to fully reconstruct the binder region, achieving low perplexities matching or improving upon validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-based docking, we experimentally validate the efficacy of PepMLM through both binding and degradation assays. PepMLM-derived peptides demonstrate sequence-specific binding to cancer and reproductive targets, including NCAM1 and AMHR2, and enable targeted degradation of proteins across diverse disease contexts, from Huntington's disease to live viral infections. Altogether, PepMLM enables the design of candidate binders to any target protein, without requiring structural input, facilitating broad applications in therapeutic development.
    DOI:  https://doi.org/10.1038/s41587-025-02761-2
  32. Small. 2025 Aug 11. e06167
    Assembly and Processing of One-Dimensional Subnanomaterials.
    Rongzhu Ma, Shouyuan Li, Simin Zhang.
      1D subnanomaterials (SNMs), encompassing nanowires and nanobelts with a diameter or thickness approximate to the size of a single unit cell, possess the inherent functionality of inorganic materials, polymer-analogue properties, intrinsic order, and multilevel interactions. These distinctive characteristics establish 1D SNMs as highly processable building blocks, offering significant advantages for the fabrication of advanced materials, including polarization materials, organogels, photothermal conversion devices, fluorescent materials, stimuli-responsive platforms, and catalysis. This paper summarizes assembly methods, including self-assembly, wet-spinning, electrospinning, directional coating, freezing-casting and Langmuir-Blodgett technique, which facilitate the integration of 1D SNMs into free-standing fibers, films, and 3D assemblies without polymeric additives. In contrast to rigid and fragile traditional inorganic materials, 1D SNMs-based assemblies are flexible and resilient with multifunctionality. Current research focuses on developing 1D SNMs with dynamic characteristics, stimuli-responsiveness, enhanced mechanical properties, and recyclability, promising further improvements in the aforementioned functional materials. Additionally, advancing large-scale, automated assembly and processing techniques is a key research emphasis.
    Keywords:  assembly; one‐dimensional subnanomaterials; processing
    DOI:  https://doi.org/10.1002/smll.202506167
  33. Cell. 2025 Aug 07. pii: S0092-8674(25)00855-4. [Epub ahead of print]
    A generative deep learning approach to de novo antibiotic design.
    Aarti Krishnan, Melis N Anahtar, Jacqueline A Valeri, Wengong Jin, Nina M Donghia, Leif Sieben, Andreas Luttens, Yu Zhang, Seyed Majed Modaresi, Andrew Hennes, Jenna Fromer, Parijat Bandyopadhyay, Jonathan C Chen, Danyal Rehman, Ronak Desai, Paige Edwards, Ryan S Lach, Marie-Stéphanie Aschtgen, Margaux Gaborieau, Massimiliano Gaetani, Samantha G Palace, Satotaka Omori, Lutete Khonde, Yurii S Moroz, Bruce Blough, Chunyang Jin, Edmund Loh, Yonatan H Grad, Amir Ata Saei, Connor W Coley, Felix Wong, James J Collins.
      The antimicrobial resistance crisis necessitates structurally distinct antibiotics. While deep learning approaches can identify antibacterial compounds from existing libraries, structural novelty remains limited. Here, we developed a generative artificial intelligence framework for designing de novo antibiotics through two approaches: a fragment-based method to comprehensively screen >107 chemical fragments in silico against Neisseria gonorrhoeae or Staphylococcus aureus, subsequently expanding promising fragments, and an unconstrained de novo compound generation, each using genetic algorithms and variational autoencoders. Of 24 synthesized compounds, seven demonstrated selective antibacterial activity. Two lead compounds exhibited bactericidal efficacy against multidrug-resistant isolates with distinct mechanisms of action and reduced bacterial burden in vivo in mouse models of N. gonorrhoeae vaginal infection and methicillin-resistant S. aureus skin infection. We further validated structural analogs for both compound classes as antibacterial. Our approach enables the generative deep-learning-guided design of de novo antibiotics, providing a platform for mapping uncharted regions of chemical space.
    Keywords:  Neisseria gonorrhoeae; Staphylococcus aureus; antibiotics; bacterial infection; de novo design; drug discovery; fragments; generative artificial intelligence; graph neural networks; machine learning
    DOI:  https://doi.org/10.1016/j.cell.2025.07.033
  34. ACS Biomater Sci Eng. 2025 Aug 12.
    Engineered Extraocular Muscle with Decellularized Tissue and Synthetic Biodegradable Polymers: Design, Properties, and In Vivo Studies.
    Fatma Yülek, Özge Ekin Akdere, Sena Koç Akbayrak, Menemşe Gümüşderelioğlu, Sevil Çaylı, Ebru Alimoğulları, Ayşen Erdem, Meltem Tuncer, Özbeyen Atalay.
      The study aims to develop graft materials suitable for treating severe muscle loss and thyroid ophthalmopathy. A new hybrid graft combining poly(caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), and decellularized bovine extraocular muscle (dEOM) was created. PLGA membranes were formed via solvent casting, and aligned PCL (aPCL) nanofibers were electrospun onto these membranes, resulting in aPCL-PLGA. Lyophilized dEOM was then powdered and deposited onto the aPCL-PLGA membranes through gelation, creating g-dEOM/aPCL-PLGA grafts. These three-layer grafts were characterized physically and chemically, and their muscle regeneration capabilities were assessed through in vitro and in vivo experiments. In vitro results showed that the materials supported mouse myoblast cell (C2C12) adhesion and proliferation. For in vivo studies, 30 rabbits underwent surgical procedures to create muscle defects, and tissue samples were collected after 15 and 45 days for analysis. Electrophysiological tests and immunohistological studies indicated that both dEOM and the hybrid graft supported the regeneration of extraocular muscles, enhancing surgical efficacy and providing a viable alternative to autografts by promoting regular fiber development over time.
    Keywords:  decellularization; electrospinning; extraocular muscle; extraocular muscle regeneration; poly(caprolactone) (PCL); poly(lactic-co-glycolic acid) (PLGA)
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00073
  35. ACS Appl Mater Interfaces. 2025 Aug 13.
    Supramolecular Self-Assembly of Polyaniline Embedded Enzyme-Mimicking GMP-Condensate Hydrogel for Electrochromic Energy Storage Applications.
    Suryakamal Sarma, Nishita Jain, Love Bansal, Ravindra Vishwakarma, Aditya Prasun, Tarun Kumar Sahu, Rajesh Kumar, Tridib K Sarma.
      Conductive polymer hydrogels combine the electrical conductivity of organic polymers with the high water content, porosity, and tissue-mimicking properties of hydrogels, making them ideal for bioelectronic interfaces. However, traditional polymer matrices often lack biocompatibility, self-healing ability, dynamic reconfigurability, and tunable mechanical properties. To address these challenges, herein we report a dimeric guanosine monophosphate (GMP)-based supramolecular hydrogel that self-assembles into a fibrillar network with intrinsic peroxidase-mimetic activity in a metal-free, microconfined environment. This unique catalytic property enables the in situ oxidative polymerization of aniline into polyaniline nanofibers, forming a hybrid conductive hydrogel with excellent mechanical strength, self-healing capability, stimuli-responsive sol-gel transitions, and high ionic conductivity. The resulting hydrogel was used to fabricate electrochromic energy-storing electrodes and "all-solid-state" supercapacitors with high capacitance (343 mF cm-2) and energy density (93.36 Wh cm-2). This work highlights the potential of small biomolecules as artificial enzyme mimics and structural matrices for transforming biomolecular self-assemblies into functionally conductive hydrogels. The integration of biomolecules for enzyme-mimetic catalysis for generating the conducting polymer hydrogels might provide a versatile platform for advancing bioelectronic technologies.
    Keywords:  G-dimer; conductive hydrogels; guanosine monophosphate; peroxidase-mimicking; polyaniline; supercapacitor
    DOI:  https://doi.org/10.1021/acsami.5c08151
  36. ACS Biomater Sci Eng. 2025 Aug 14.
    OptoBarrier: An Optogenetic Platform for Modulating Endothelial Barriers In Vitro.
    Sharon Fleischer, Martin Liberman, Max Summers, Vanessa Li, Trevor R Nash, Gordana Vunjak-Novakovic.
      Organ-on-a-chip platforms have emerged as promising human tissue models for drug screening and mechanistic studies, offering alternatives to traditional animal models. Integration of vascular structures into these platforms is pivotal for creating physiologically faithful models of individual organs and studying interorgan crosstalk. However, most vascular structures grown in vitro do not account for organ-specific endothelial permeability or its modulation in response to disease. Here, we present optoBarrier, an optogenetic organ-on-a-chip platform designed to modulate endothelial barrier permeability through light stimulation. By optically activating RhoA signaling in engineered optogenetic endothelial cells, we demonstrate the formation of stress fibers, disruption of vascular endothelial cadherin (VE-cadherin) and increased barrier permeability. We further show that permeability is tunable in a reversible and dose-dependent manner in response to light. We therefore propose that optoBarrier offers a user-defined, controlled and simple method to manipulate endothelial permeability for in vitro studies of human vasculature.
    Keywords:  engineered vasculature; in vitro modeling; optogenetics; organ-on-a-chip; vascular permeability
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00708
  37. STAR Protoc. 2025 Aug 07. pii: S2666-1667(25)00420-4. [Epub ahead of print]6(3): 104014
    Protocol for fabricating a reusable plate-well insert with a 3D-printed mounter and hydrogel scaffolds for 3D cell culture and functional assays.
    Saloua Saghir, Jana Hlinkova, Athina Samara, Giuseppe Schiavone.
      We present a protocol for the fabrication of reusable inserts for standard 24-well plates, comprising a 3D-printed mounter and a hydrogel scaffold for 3D cell culture studies. We cover the design and production of the mounter, hydrogel scaffold synthesis, lyophilization for storage, sterilization, and hydrophilization before cell culture. Downstream applications include cytotoxicity assessment, imaging, and qPCR. Streamlining hydrogel preparation and mounting minimizes batch-to-batch variation, reduces costs, and supports synthetic biology studies.
    Keywords:  Biotechnology and bioengineering; Cell culture; Material sciences
    DOI:  https://doi.org/10.1016/j.xpro.2025.104014
  38. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2502613122
    Suppressing mechanical property variability in recycled plastics via bioinspired design.
    Dimitrios Georgiou, Danqi Sun, Xing Liu, Christos E Athanasiou.
      Over 350 million metric tons of plastic waste are generated annually, with most ending up in landfills, dumps, or the environment, posing significant risks. Mechanical recycling remains underutilized, largely due to the high variability in the mechanical properties of recycled plastics (recyclates). This variability undermines performance reliability and hinders the adoption of recyclates in demanding industrial applications. Inspired by natural materials, known for their mechanical robustness despite microstructural stochasticity, we propose a universal, chemistry-agnostic, brick-and-mortar design tailored for recycled polymers. In this design, stiff recycled plastic platelets (bricks) are embedded in a soft virgin polymer matrix (mortar), which accommodates deformation and redistributes stress. To predict the effective modulus, strength, and property variability of such structures, we developed an uncertainty-aware tension-shear-chain model, combining Monte Carlo simulations with literature-based distributions of recyclates' stiffness and conservative interfacial parameter stochasticity assumptions. We validated our model using nacre-inspired composites fabricated from recycled high-density polyethylene (rHDPE) platelets and polydimethylsiloxane (PDMS) mortar. The experimental results matched model predictions, confirming significant suppression of variability. In a case study on industrial HDPE stretch film, our design reduced modulus variability by up to 93% and maximum permissible strain variability by at least 68% compared to input rHDPE, while matching the modulus of virgin HDPE film. This work introduces a design-enabled variability-suppression strategy for recycled plastics, able to transform highly heterogenous materials into structurally robust products. By supporting virgin-plastic substitution and circular design strategies, our approach can enable the broader adoption of recyclates by several industries.
    Keywords:  bioinspired design; mechanical property variability; recycled plastics; tension-shear-chain model; uncertainty in material properties
    DOI:  https://doi.org/10.1073/pnas.2502613122
  39. Adv Healthc Mater. 2025 Aug 11. e01942
    Engineering Extracellular Microenvironments: The Impact of Fibrous Materials on Cell Behavior.
    Zan Lamberger, Gregor Lang.
      The development of tissue models and replacements that closely mimic native biological structures is a central goal in tissue engineering and biofabrication. These models aim to reduce animal testing and improve the relevance and translatability of experimental results. A key step is the transition from simple two-dimensional cultures to three-dimensional systems that better reflect the architecture of the extracellular matrix. Replicating the hierarchical organization of native tissues is essential, particularly the fibrous networks mainly composed of collagen, which regulate cell alignment, migration, proliferation, and differentiation. Incorporating such structures has proven highly effective and often necessary to induce cell behaviors resembling those in vivo. This review first examines the cellular mechanisms that govern interactions with fibrous microenvironments. It then outlines key design parameters for fiber-based substrates, including chemical composition, diameter, surface topography, and alignment. These factors can be tuned to guide cell organization and function. Strategies for translating these principles into three-dimensional fiber-reinforced constructs and bioinks are then discussed, with a focus on current approaches for creating biomimetic environments. The article concludes with future perspectives, highlighting the potential of fibrous scaffolds and advanced fabrication techniques to enable next-generation tissue models and regenerative therapies.
    Keywords:  3D models; artificial matrices; electrospinning; fibers; melt electrowriting
    DOI:  https://doi.org/10.1002/adhm.202501942
  40. ACS Appl Bio Mater. 2025 Aug 12.
    Supramolecular Assembly of Magnetic Microrobots for Controllable Cell Delivery and Release.
    Yuzhou Liu, Hao Zhou, Wenjun Chen, Zihan Ye, Xing Ma, Ping Wen.
      Cell therapy has emerged as a highly effective treatment for degenerative diseases in recent years, and micro/nanorobots, with their small size and versatile mobility, have proven to be reliable carriers for active, targeted cell delivery. However, conventional cell delivery strategies rely on preseeded cells on the micro/nanorobots' surfaces, with in situ retention and subsequent release usually achieved by self-degradation of the carrier robots, which greatly limits their applicability and brings additional biosafety concerns. In this study, we propose an innovative approach to control cell capture and release by a microrobot using host-guest supramolecular interactions between azobenzene and β-cyclodextrin. We designed polystyrene microspheres modified with β-cyclodextrin molecules and specific nucleic acid aptamers as a Janus linker microsphere, which were then combined with a three-dimensional-printed (3D-printed) helical microrobot modified with azobenzene. The connection and disconnection between the microrobot and the Janus linker microspheres can be effectively controlled by irradiation with ultraviolet and visible light. The nucleic acid aptamers enable targeted binding to specific cells, facilitating selective capture and on-demand release. We demonstrate that a single microrobot can capture more than 20 cells on average and can be effectively maneuvered using a rotating magnetic field. Under ultraviolet (UV) light control, the system achieved a release rate exceeding 90%. More importantly, the specific recognition capabilities of nucleic acid aptamers, combined with the customizability of micronano 3D printing technology, suggest a promising pathway for the design and assembly of multifunctional cell delivery microrobot systems tailored to specific biological applications based on targeted cell delivery.
    Keywords:  3D printing; Janus nanoparticle; cell delivery; host−guest interaction; magnetic microrobot; supramolecular assembly
    DOI:  https://doi.org/10.1021/acsabm.5c01095
  41. ACS Macro Lett. 2025 Aug 13. 1241-1247
    Development of Photocurable NorHA-dECM Hybrid Hydrogels to Study Cell-Matrix Interactions.
    Tuba Marjan, Alyson R Owen, Taimoor H Qazi.
      Biomimetic culture platforms aid in understanding cell behavior in vitro and are useful for studying mechanisms of disease progression and tissue regeneration. Synthetic hydrogels are widely used for this purpose, but while they offer advantages such as tunability and mechanical stability, they lack the range of biochemical signals present in the native microenvironment. On the other hand, decellularized extracellular matrices (dECMs) retain native biochemical signals but their adoption as stable in vitro culture platforms is limited due to batch variability, poor mechanical stability, and limited tunability. Here we report the development of hybrid hydrogels comprising dECM and a photocurable norbornene-modified hyaluronic acid (NorHA) polymer. To overcome structural heterogeneity of dECM that inhibits its solubility, uniform gelation, and spatial uniformity during cell culture, we physically process dECM by grinding, shearing, or both, prior to incorporation within NorHA. Both processing methods reduce microscale dECM aggregation and improve physical gelation at 37 °C. The addition of dECM up to 10 mg/mL within NorHA hydrogels neither affects rapid UV cross-linking nor compromises mechanical properties, as evaluated using oscillatory shear rheology and uniaxial compression testing. Both processes significantly improve the uniform distribution of dECM within 3D hybrid hydrogels, as evaluated by staining hydrogel cryosections. Fibroblasts show significantly higher spreading area and proliferation on hybrid hydrogels compared with control NorHA hydrogels. Taken together, photocurable hybrid hydrogels having uniformly distributed dECM combine the biochemical complexity of native dECM with the tunability of a synthetic polymer and represent an advance in the engineering of biomimetic platforms to investigate cell-matrix interactions.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00339
  42. IEEE Trans Comput Biol Bioinform. 2025 Jul-Aug;22(4):22(4): 1888-1901
    Constraint-Based Sub-Graph Partitioning for Multi-Cellular Biological Networks.
    Yangruirui Zhou, Christopher A Voigt, Douglas Densmore.
      Synthetic consortia represent an emerging research area in synthetic biology, promising to solve various industrial challenges through the metabolic diversity, division of labor, and spatial organization inherent in microbial consortia. As synthetic biology advances into multi-cellular systems, new design strategies are essential for engineering distributed functions across networks of cells. However, existing strategies either lack scalability or require extensive reformulation, limiting their usage to various applications. In this work, we propose an application-agnostic approach to partitioning networks of interacting biological components using graph-based algorithms. We develop a three-stage algorithm, named "Oriole", that verifies and optimizes the subgroup distribution of all entities within a network, considering biological constraints and objectives for engineering these systems. We validate our algorithm on three types of networks, including 30 small-graph benchmarks, 537 regular electronic circuit designs, and 56 large circuit benchmarks. One large circuit benchmark was recently implemented experimentally. Compared with the other sub-graph partitioning solutions, the results generated by our new algorithm reduced design time from days to hours and decreased the total number of cells required for the multi-cellular system by 3%. This case study demonstrates that our algorithm provides a more efficient approach to designing multi-cellular systems.
    DOI:  https://doi.org/10.1109/TCBBIO.2025.3575288
  43. Nat Commun. 2025 Aug 13. 16(1): 7527
    Cellulose hydrogel with in-situ confined nanopores for boosting moist-electric conversion.
    Xuejiao Lin, Shenming Tao, Jilong Mo, Xijun Wang, Yizhe Shao, Yingfan Hu, Changjing Qiu, Kaiyuan Shen, Chao Dang, Haisong Qi.
      Hydrogels are promising for moist-electric generator, yet their performance is limited by microscale pores, low charge density, and unstable pore structures. Here, a delignified pomelo peel-confined carboxymethyl cellulose nanofluidic hydrogel is designed to address these limitations. Leveraging the hierarchical porous architecture of delignified pomelo peel, the nanofluidic hydrogel achieves sub-Debye-length nanopores with high stability and charge density. At 80% relative humidity, a single device unit exhibits an open-circuit voltage of 1.32 V and a short-circuit current density of 693.2 µA cm-2, which are nearly triple and twenty times higher than delignified pomelo peel. The output voltage exceeds that of conventional hydrogel without nanopores by about 0.4 V. This enhanced performance is due to sub-Debye-length nanopores synergizing H+/Cu2+ gradient diffusion and Debye screening effect. Moreover, the integrated devices reach an ultrahigh output voltage exceeding 5000 V. We report the prototype of a moisture-stimulated negative air ion generator for efficient air purification. This work advances moisture energy harvesting through pore engineering and expands its applications.
    DOI:  https://doi.org/10.1038/s41467-025-61716-y
  44. bioRxiv. 2025 Aug 05. pii: 2025.08.05.668603. [Epub ahead of print]
    Protein language models reveal evolutionary constraints on synonymous codon choice.
    Helen Sakharova, Liana F Lareau.
      Evolution has shaped the genetic code, with subtle pressures leading to preferences for some synonymous codons over others. Codons are translated at different speeds by the ribosome, imposing constraints on codon choice related to the process of translation. The structure and function of a protein may impose pressure to translate the associated mRNA at a particular speed in order to enable proper protein production, but the molecular basis and scope of these evolutionary constraints have remained elusive. Here, we show that information about codon constraints can be extracted from protein sequence alone. We leverage a protein language model to predict codon choice from amino acid sequence, combining implicit information about position and protein structure to learn subtle but generalizable constraints on codon choice in yeast. In parallel, we conduct a genome-wide screen of thousands of synonymous codon substitutions in endogenous loci in yeast, reliably identifying a small set of several hundred synonymous variants that increase or decrease fitness while showing that most positions have no measurable effect on growth. Our results suggest that cotranslational localization and translational accuracy, more than cotranslational protein folding, are major drivers of selective pressure on codon choice in eukaryotes. By considering both the small but wide-reaching effects of codon choice that can be learned from evolution and the strong but highly specific effects determined via experiment, we expose unappreciated biological constraints on codon choice.
    DOI:  https://doi.org/10.1101/2025.08.05.668603
  45. ACS Appl Mater Interfaces. 2025 Aug 14.
    Glucose-Responsive Self-Rolling Antioxidant Hydrogel Actuators for a Cell Culture Platform.
    Zhiyu Zheng, Ruxin Xiao, Xiaochen Ma, Ziqian Yu, Jiaxin Zeng, Liqiong Liao.
      Three-dimensional (3D) cell culture technology can mimic the physiological characteristics of tissues and organs, making it highly suitable for cell therapy, organ chips, and tissue engineering applications. However, achieving a uniform cell distribution within the 3D matrix while mitigating the effects of reactive oxygen species (ROS) accumulation generated during the 3D cell culture remains a critical challenge. Hydrogel actuators, with their excellent bioactivity and controllable self-rolling behavior, provide an optimal microenvironment for the 3D cell culture. To support normal cellular function, hydrogel actuators must be triggered by external stimuli that are biocompatible with the cell culture process. Glucose, a key intermediate in energy metabolism and biological processes, is ubiquitous in cell culture media and physiological systems. In this work, a glucose-responsive hydrogel actuator (AP@Que/gelatin) with controllable self-rolling behaviors and ROS scavenging capability was constructed for 3D cell culture, which consists of an active layer composed of phenylboronic acid (PBA)-quercetin (Que) complexes and a passive layer of a biocompatible gelatin hydrogel. The hydrogel actuator exhibited excellent glucose response performance, characterized by notable reswelling behavior, favorable ductility, and cytocompatibility. Its self-rolling behavior in high-glucose culture media was synchronized with cell adhesion timelines, enabling its application as a 2D-to-3D dynamic substrate for cell culture and expansion. Meanwhile, Que was released from the hydrogel actuator through the competitive reaction of PBA with glucose and Que. The formation of the 3D tubular architecture during cell culture facilitated cell growth, while the sustained release of Que effectively eliminated ROS generated during cell passaging. These findings highlight the potential of AP@Que/gelatin hydrogel actuators as an advanced platform for a 3D cell culture.
    Keywords:  ROS; cell culture; glucose; hydrogel actuator; quercetin
    DOI:  https://doi.org/10.1021/acsami.5c11328
  46. Opt Express. 2025 Jun 30. 33(13): 28493-28510
    Determining intrinsic optical properties of 3D printing materials.
    Lubna Abu Rmaileh, Philipp Nguyen, Alexander Kissel, Philipp Urban.
      Accurate knowledge of the intrinsic optical properties of 3D printing materials, i.e., spectral absorption and scattering coefficients, phase function, and refractive index, is essential for simulating the appearance of translucent prints on displays (softproofing) or optimizing material arrangements to achieve desired optical effects in multi-material 3D prints. This information is also critical for designing printing materials that mimic the optical characteristics of other materials, a key requirement in applications like dental restorations. Current methods for measuring these properties rely on specialized laboratory equipment and expert knowledge. In this paper, we propose an approach that uses a commercial reflectance/transmittance spectrophotometer to determine the spectral absorption and scattering coefficients and refractive index of 3D printing materials. We model the light path of this device to simulate reflectance and transmittance measurements via a Monte Carlo path tracer. We then predict measurements for a large set of random but plausible intrinsic optical material properties for three different sample thicknesses. With these data, we train machine learning models to infer the intrinsic properties from phenomenological reflectance/transmittance measurements, considering a priori knowledge of smoothness as a regularization constraint. We validate our method by comparing results for real printing materials with accurate laboratory measurements and provide the trained machine learning models to the community.
    DOI:  https://doi.org/10.1364/OE.559881
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