Advanced Functional Materials

Damage to the skin by trauma, burns, or surgical procedures often results in uncontrolled bleeding, which remains a leading cause of preventable death following injury, yet most conventional hemostatic materials are engineered solely to arrest bleeding and often adhere strongly to the wound bed, causing pain, rebleeding, and disruption of newly formed tissue upon removal. Here, we report a DNA hydrogel that structurally mimics neutrophil extracellular traps (NETs) and is crosslinked using a bioactive small molecule with potent autophagy-inducing, cardioprotective, anti-inflammatory, antioxidant, and mitochondria-protective properties, integrating rapid hemostasis with active support for tissue regeneration in a single biomaterial. The DNA network provides an intrinsically biocompatible, biodegradable scaffold capable of recruiting platelets and erythrocytes to achieve rapid clot formation, while the bioactive crosslinker is released as the network degrades, delivering a sustained cytoprotective and anti-inflammatory stimulus directly at the wound site. The hydrogel was characterised physiochemically and evaluated for cytocompatibility, hemolytic potential, hemostatic efficacy, and wound-healing performance in a murine model. Results demonstrate that the bioactive-crosslinked DNA hydrogel achieves rapid, effective hemostasis, while accelerating wound closure and supporting regenerative tissue remodelling. This dual-function platform offers a promising strategy for next-generation wound-care biomaterials that unite immediate bleeding control with accelerated, natural tissue healing.

Scaling engineered living materials to clinically relevant dimensions is limited by diffusion-dependent depletion of oxygen and nutrients, which rapidly induces metabolic failure. We introduce glycogen as nutritional nanoparticle that provides cell-mediated, autonomous nutrient release to support long-term survival under extreme metabolic stress. We demonstrate that human mesenchymal stromal cells (hMSCs) survive for weeks in anoxia and serum deprivation when provided extracellular glycogen. Contrary to long-held assumptions, hMSCs secrete glycogen-degrading enzymes, enabling cell-density controlled extracellular glycogenolysis and sustained release of glucose and metabolic intermediates, positioning glycogen as the first-of-its-kind metabolic battery. This cell-responsive process maintains metabolic activity, limits glycolytic acidosis, and enhances pro-angiogenic signaling. To translate this mechanism into a versatile materials platform, we engineered core-shell dextran-tyramine microcapsules that stably encapsulate glycogen while permitting diffusion of enzymes and degradation products. Integrated into centimeter-scale GelMA constructs, these microcapsules maintained hMSC viability and function for at least one month under anoxia. In vivo, glycogen-loaded implants promote deep cellular infiltration, enhanced matrix remodeling, increased M2 macrophage polarization, and orchestrated accelerated vascularization. This work establishes the novel concept of glycogen-based nutritional nanoparticles as metabolic batteries to endow engineered tissues with autonomous self-feeding capacity, enabling scalable and functional living materials for regenerative medicine and related technologies.

Controlled biomineralization is central to engineering physiologically relevant hard-tissue models, yet achieving spatially organized, three-dimensional (3D) mineral deposition in microfluidic on-chip systems remains challenging. While cell-based bone-on-chip platforms offer biological complexity, they intrinsically couple mineral initiation to confounding factors such as matrix remodeling and paracrine signaling, obscuring the earliest biochemical drivers of nucleation. Drawing inspiration from bottom-up synthetic biology, we engineered an enzymatically active granular matrix that recapitulates a key osteogenic function within a perfusable 3D microenvironment. Alkaline phosphatase (ALP), the key driver of native bone formation, was covalently conjugated to poly(ethylene glycol)-based (PEG) microgels via thiol-ene photochemistry, retaining over 90% enzymatic activity after 48 h. These monodisperse microgels were assembled into a jammed, perfusable matrix within an on-chip chamber, enabling independent control over enzyme loading and substrate delivery. The system supported rapid in situ mineralization (24-48 h), yielding a carbonated, calcium-deficient, apatite-like phase characteristic of early-stage bone mineral. We demonstrate that the spatial 3D localization of enzymatic activity to discrete microscale compartments, coupled with interstitial perfusion, enables localized and near-physiological mineral formation. This mechanistically defined, acellular platform provides a programmable foundation for investigating ALP-driven 3D mineralization and establishes a modular route toward hybrid biosynthetic models of (patho)physiological tissue mineralization.

Purpose: Hyperthermia is emerging as an adjunct strategy in pediatric oncology, yet its translation is limited by poor understanding of how different modalities impact complex tumor microenvironments. Neuroblastoma (NB), the most common extracranial solid tumor in children, displays profound heterogeneity that hampers therapeutic predictability. Here, we performed the first systematic head-to-head comparison of photothermal therapy (PTT) and magnetic hyperthermia (MH) in tissue-engineered NB (TE-NB) models. Methods: TE-NB scaffolds incorporating five NB cell lines were loaded with magnetic nanoparticles (MNPs) and subjected to PTT (808-nm laser, 130 W/cm2, 10 min) or MH (285 kHz, 20 mT, 60 min). Constructs were analyzed at 24 h, 48 h, and 5 d post-treatment for DNA content, cell viability, proliferation (Ki67 immunohistochemistry), and apoptosis (caspase-3/7 staining). Results: MH produced consistent MNP-dependent heating with minimal background, while PTT was dominated by nonspecific medium absorption. Both modalities modulated proliferation within 24 h, but effects varied sharply by cell line and scaffold region, reflecting microenvironmental heterogeneity. By 48 h, PTT often triggered paradoxical increases in proliferation, whereas MH disrupted scaffold integrity, reduced DNA content, and suppressed Ki67 expression. Notably, neither modality induced sustained caspase-3/7 activation, indicating that cytotoxicity proceeds via non-apoptotic pathways. Conclusion: Our findings position MH as a superior modality for uniform heating and proliferation control in 3D NB models, but also highlight that hyperthermia should be considered a context-dependent modulator rather than a binary cytotoxic agent. By integrating patient-specific TE-NB platforms, precision hyperthermia could define individualized therapeutic windows, optimize combinations with pro-apoptotic or immunomodulatory agents, and accelerate translation of hyperthermia strategies for children with NB.

Mechanotransduction plays a fundamental role in regulating immune cell function, yet how engineered virus-like nanospikes engage mechanosensitive signaling pathways to modulate innate immunity remains poorly understood. Here, we report virus-like nanotopography as a previously unrecognized regulator of Piezo1-mediated mechanotransduction in macrophages using virus-like mesoporous silica nanoparticles (VLPSi) with tunable rigid nanospike lengths. We demonstrate a direct structure-activity relationship between nanospike geometry and Piezo1-dependent Ca{superscript 2}+ influx, with longer nanospikes inducing significantly greater intracellular Ca{superscript 2}+ signaling. Building on this mechanistic insight, we developed biomimetic cancer cell membrane (CM)-coated, MSA-2-loaded VLPSi nanoparticle (CM/MSA-2@VLPSi) and investigate the combination of nanospikes-activated Piezo1 with STING signaling and CM antigens presentation in macrophage immune reprogramming. The resulting biomimetic nanoparticles robustly activate the STING-TBK1-IRF3/NF-{kappa}B axis, increase IFN-{beta} and pro-inflammatory cytokine production, and promote macrophage polarization toward M1 phenotype in a spike-length-dependent manner. Collectively, the present study provides a biomimetic strategy for enhancing the M1 polarization of macrophage through the coordinated regulation of mechanical, inflammatory, and antigenic signals.

Resin three-dimensional (3D) printing is an increasingly popular manufacturing and prototyping method used to create microphysiological systems (MPS), but resin cytotoxicity significantly hinders its adoption, especially when sensitive cell models are incorporated. The mammalian oocyte and early preimplantation embryo consist of cells that are highly sensitive to toxicants and thus represent stringent cell-based models for biocompatibility testing. We developed a Multi-Endpoint Oocyte Safety Assay (MEIOSA) to evaluate the biocompatibility of four ISO 10993 biocompatible BioMed resins (Clear, Durable, Elastic 50A, and Flex 80A). MEIOSA assesses the viability, morphology, meiotic stage, and meiotic spindle morphology of the oocyte after in vitro maturation (IVM). Oocytes were in vitro matured in plate inserts 3D printed with the four BioMed resins. Oocytes cultured in rigid resins (Clear and Durable) or elastomeric resins (Elastic 50A, and Flex 80A) exhibited impaired meiotic progression and complete oocyte degeneration, respectively, relative to controls cultured in polystyrene which matured normally. To determine whether such cytotoxicity could be prevented, we coated the resin inserts with a 5 {micro}m impermeable Parylene-C (PC) barrier. PC coating completely rescued the degeneration and meiotic maturation defect phenotypes for all resins. Remarkably, when the most cytotoxic material (Flex 80A) was coated with PC, the resulting eggs were fertilization-competent and produced embryos capable of normal preimplantation development via in vitro fertilization. Our findings demonstrate that standardized viability-based biocompatibility tests do not identify cytotoxic effects for all cell types and establish MEIOSA as a high sensitivity test model to robustly evaluate biomaterial biocompatibility. Furthermore, PC coating prevents the toxic effects of all resin-3D-printed materials tested, opening up a new toolbox to create MPS compatible with reproductive, and by extension, other sensitive cell cultures. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/730268v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@18fab44org.highwire.dtl.DTLVardef@1352e5forg.highwire.dtl.DTLVardef@77889forg.highwire.dtl.DTLVardef@1aabd89_HPS_FORMAT_FIGEXP M_FIG C_FIG

Traumatic cranial defects often involve concurrent loss of soft and hard tissues and can progress to chronic defects due to delayed healing associated with infection or other co-morbidities. Despite autologous reconstruction remaining the clinical standard, it requires staged procedures using heterogeneous tissues, increasing operative time, costs, and surgical risks. Moreover, current tissue engineering approaches focus on single tissues or acute tissue defect models, limiting their clinical applications. Herein, we describe an acellular, material-driven 3D-printed composite scaffold designed to regenerate both bone and skin within composite cranial defects. The scaffold integrates controlled copper ion release from both organic and inorganic components with 3D-printed citrate polymer and citrate polymer-ceramic composites. Integrated thermoresponsive citrate-based hydrogels further enable spatially defined dermoconductive and osteoconductive properties, supporting a one-step surgical approach. At 12 weeks post-implantation, our scaffold enhanced keratinocyte organization, collagen deposition, and defect coverage with mature bone, achieving histological outcomes comparable to autografts. Furthermore, the system suppressed bacterial burden. Thus, this acellular platform represents a clinically promising synchronized strategy to address the complex demands of traumatic craniofacial composite defects.

Chronic diabetic wounds resist healing due to impaired angiogenesis, stalled cellular migration, and persistent inflammation, a challenge further compounded by the rapid degradation of therapeutic growth factors in the proteolytic wound bed. To overcome this, Traditional Chinese Medicine (TCM) compounds are employed not as standalone drugs, but as biomolecular stimuli to precondition the secretome of Wharton's Jelly-derived mesenchymal stem cells (WJMSCs). To overcome these critical translational barriers, this study engineers a core-shell coaxial electrospun nanofibrous scaffold (polyvinyl alcohol core/gelatin shell) designed for the stabilizing and sustained dual-delivery of biologics. We introduce a novel synergistic payload with WJMSCs conditioned medium (WJMSCs-CM) uniquely primed by two specific chinese herbal compounds, Astragaloside IV (AS-IV) and Formononetin (FMN). This core-shell architecture provides native-like contact guidance for cells while converting conventional burst release into a sustained, weeks-long elution. In vitro, this functionalized scaffold restores Akt/eNOS signaling, rescues cellular viability, and promotes robust tube formation in high-glucose-stressed fibroblasts and endothelial cells. In vivo, within an STZ-induced diabetic rat model, the application of this WJMSCs-CM-loaded coaxial scaffold actively inhibits early inflammation and comprehensively accelerates healing, driving near-complete wound closure (98.2 by day 21), mature collagen deposition, and hair follicle neogenesis. Ultimately, this bio-instructive platform successfully integrates physical structural cues with sustained biochemical signaling, offering a potent, multifaceted strategy for chronic wound regeneration.

With the push towards accessible benchtop models to capture biological events, many researchers are reaching for hydrogel platforms for 3D tissue engineering ex vivo. Recapitulating the dynamic mechanical environment cells experience in vivo requires dynamic hydrogel scaffolds whose mechanical properties can be reprogrammed with spatiotemporal precision. Here we describe a chemically simple hydrogel platform that undergoes visible-light photosoftening via a ruthenium-based photocleavable crosslinker, leveraging tetrazine-norbornene inverse electron demand Diels Alder (iEDDA) click chemistry between RuTetrazine crosslinker and norbornene-modified hyaluronic acid (NorHA). Nitrogen gas evolved during this reaction is repurposed as an intrinsic porogen, nucleating macropores (55-175 {micro}m) directly during gelation. Initial stiffness (1.5-10 kPa) and softening extent (from 50%-100% drop in storage modulus) are independently tunable through polymer and crosslinker composition. We have found RuTetrazine to be non-mutagenic and non-toxic (>80% live cell populations) once network-bound (IC50 = 0.27 mM). In a cell-instructive network co-crosslinked with an MMP-RGD-bearing peptide, human mesenchymal stromal cells (hMSCs) photosoftened in situ (2.27[-&gt;]0.54 kPa, [~]76%) spread approximately six-fold relative to stiff controls ([~]6,500 vs. [~]1,100 {micro}m2, p < 0.0001). This work demonstrates a synthetically accessible photocleavable crosslinker and a simple, macroporous hydrogel for modulating dynamic mechanical cues in three dimensions.

Implantable microdevices capable of autonomous operation over extended lifetimes are promising enablers for minimally invasive diagnostics and therapy. Microelectromechanical systems (MEMS)-based piezoelectric ultrasonic energy harvesters (PUEH) have emerged as a compelling approach for powering implantable microdevices, where both miniaturization and efficient wireless energy transfer are essential. Here, we present a highly miniaturized (5 x 5 x 5 mm3) ultrasonic energy-harvesting platform enabling sustained in vivo operation of implantable microdevices. The platform integrates a MEMS-PUEH, a high-efficiency power management system, an energy storage element, and representative functional electronics. We first investigate the effect of backside cavity boundary conditions on MEMS-PUEH performance and show that a sealed air-filled chamber significantly outperforms an open water-filled cavity, yielding a 46% increase in root-mean-square output voltage and a 117% increase in average output power across a 2 k{Omega} resistive load under identical incident acoustic intensity at the respective optimal operating frequencies. We then demonstrate system-level integration and characterization. In a tissue-mimicking phantom, under an incident acoustic intensity of approximately 257 mW/cm2, the device charges an 11.5 mF supercapacitor, a 5 {micro}Ah solid-state microbattery, and a 100 {micro}F capacitor to their nominal voltages in less than 5 min, 3 min, and 20 s, respectively. Finally, in vivo validation demonstrates fully autonomous operation of representative functional electronics following ultrasonic charging of the onboard energy storage element. These results establish a highly miniaturized and fully integrated ultrasonic energy-harvesting platform that advances MEMS-based power solutions for implantable biomedical microdevices.

Engineering biomimetic tissues with dynamically evolving 3D architectures represents an important direction for next-generation tissue engineering, as it enables recapitulation of the continuous morphogenesis of native tissues during development and regeneration. Here, a self-actuating 4D cell-strand bioprinting platform is developed to engineer complex tissue architectures through autonomous cell contractile force (CCF)-driven morphing without requiring external stimuli. The platform integrates a mechanically compliant and self-softening base hydrogel with embedded high-density cell strands printed using a fast-degrading carrier bioink. During culture, the carrier bioink rapidly degrades while the encapsulated cells proliferate and establish connected cellular networks, generating localized contraction that drives programmable shape transformation. Through spatial patterning of embedded cell strands, constructs with diverse morphologies, including V-shaped, helical, folded, and tubular architectures, are generated via controllable self-actuated morphogenesis. The platform further enables engineering of cartilage-like and bone-like tissues with well-defined curvature configurations and mechanically robust tissue matrices. In addition, programmable multi-tissue engineering is demonstrated through fabrication of a muscle-tendon junction-mimicking construct containing spatially organized fibroblast and myoblast compartments. This self-actuating 4D bioprinting strategy enables highly programmable and directionally controlled morphogenesis using a simple construct design with low cell amount requirements, providing a versatile platform for engineering dynamic tissue architectures.

Introduction: Advanced biomaterials for regenerative medicine are increasingly expected to combine multifunctionality and compatibility with tissue-specific cellular processes. In this context, hydroxyapatite-based platforms modified through ionic substitution represent promising candidates, as they may integrate structural similarity to bone mineral with additional biological functionality and luminescent properties, enabling diagnostic applications and real-time monitoring. In this study, we evaluated whether silicate-phosphate substituted calcium hydroxyapatite Ca10(PO4)6-x(SiO4)x(OH)2 (where x = 1.5) co-doped with lithium(I), europium(III), and gadolinium(III) ions (Si-HAp-LEG) affects the osteogenic, chondrogenic, and adipogenic differentiation potential of human bone marrow stromal/stem cells (BMSCs). Methods: Human BMSCs were cultured under lineage-specific differentiation conditions in the presence of undoped silicate-substituted phosphate hydroxyapatite (abbr. as Si-HAp), which served as a control, and two distinct Si-HAp-LEG formulations differing in gadolinium(III) (Gd3+) as well as lithium (Li+) and europium(III) (Eu3+) ion concentrations: Si-HAp-LEG-221 (1 mol% Gd3+ ion) and Si-HAp-LEG-222 (2 mol% Gd3+ ion). Differentiation-associated phenotypic outcomes, including extracellular matrix formation and lipid accumulation, were evaluated using Safranin O, Alizarin Red, and Oil Red O staining. In parallel, biomaterial-induced molecular responses were characterized at the transcriptomic and protein levels using RT-qPCR for selected coding and non-coding RNAs and Western blot analysis for representative lineage-associated proteins. Results: Histochemical evaluation confirmed that, across all tested biomaterial groups, BMSCs retained the ability to form mineralized calcium deposits, proteoglycan-rich extracellular matrix, and intracellular lipid accumulation under osteogenic, chondrogenic, and adipogenic conditions, respectively. Quantitative staining analysis revealed no significant Si-HAp-LEG-dependent enhancement of terminal differentiation outcomes compared with undoped Si-HAp. In turn, the molecular response differed between biomaterials modifications. Si-HAp-LEG-222 induced the most prominent changes in transcriptional and post-transcriptional regulators, particularly within BMP/SMAD-associated pathways under osteogenic and chondrogenic conditions, underlying a potential link between gadolinium concentration and osteogenic lineage commitment. However, these transcriptomic responses were not mirrored by consistent changes at the protein level. The results suggest that silicate-phosphate substituted hydroxyapatite co-doped with Li+, Eu3+, and Gd3+ ions primarily affects the early regulatory pathways associated with BMSCs differentiation rather than enhancing their terminal maturation. Discussion: In conclusion, the collective data indicate that Li+, Eu3+, and Gd3+ ions LEG co-doping broadens the multifunctional potential of Si-HAp by introducing imaging-related properties while preserving its underlying pro-regenerative character. Li+, Eu3+, and Gd3+ ions co-doped LEG-substituted Si-HAp may therefore be considered a compatible biomaterial platform that maintains BMSC cellular plasticity and supports balanced, differentiation-dependent modulation of lineage-associated molecular responses.

Engineered epithelial models require three-dimensional extracellular matrix environments that support organized cell growth and allow independent access to luminal and basal compartments. However, many organ-on-chip (OoC) fabrication strategies rely on planar geometries, non-native materials, or multi-step assembly workflows that limit architectural complexity and experimental control. Here, we report a direct in-chip volumetric printing strategy for fabricating stretchable and perfusable collagen-I scaffolds inside custom OoC devices. A vitamin C-regulated ruthenium/sodium persulfate photocrosslinking system enabled high-fidelity printing of collagen-I into open-lumen architectures with ductal- and alveolar-inspired features. By generating scaffolds directly within the final culture device, this workflow eliminates post-print transfer and integrates defined collagen architectures with compartmentalized fluidic access and a mechanically actuable chip format. To support chip-based culture, printed collagen constructs were stabilized after fabrication using EDC/NHS chemistry, which limited thermally induced collagen densification, improved shape retention, and maintained scaffold anchorage during perfusion. The chip design provided separate access to the printed lumen and surrounding basal compartment, which enabled compartment-specific fluid handling while preserving scaffold integrity during inflation, stretching, and perfusion of the printed construct. On the collagen-I scaffolds, human milk-derived mammary epithelial cells formed epithelial layers with tight junctions and lactation associated markers. The platform further supported perfusion culture, in situ staining, and whole-chip volumetric imaging. Together, this work establishes direct in-chip collagen-I volumetric printing as a biofabrication strategy for creating perfusable epithelial tissue chips with native matrix architecture and compartmentalized fluidic control.

Bioxolography enables high-resolution fabrication of geometrically complex, cell-laden constructs for tissue engineering. However, tissue-relevant cell densities conflict with the optical transparency required for efficient dual-color volumetric printing. In this work, we extend the Bioxolography toolbox to include refractive index (RI) matching for cell-laden bioresins using iodixanol (IDX). Remarkably, IDX enhances optical transparency and boosts reactivity -- a phenomenon unique to Xolography. Yet, excessive IDX compromises dual-color efficiency through increased absorption and undesired UV-only curing, underscoring a central trade-off between optical clarity and photochemical performance. Systematic tuning of resin compositions along an iso-refractive index line demonstrated the versatility of Bioxolography, with IDX enhancing polymerization and 4-Hydroxy-TEMPO providing biocompatible inhibition. Optimizing composition and printing parameters yielded GelMA hydrogels with cell densities up to 5{middle dot}106 cells{middle dot}mL-1. Cell-laden prints achieved sub-100 {micro}m resolution and complex geometries such as channels and gyroids. Using skeletal muscle tissue as a model, we validated RI matched Bioxolography as a promising strategy for tissue engineering by demonstrating cell alignment along printed grooves and formation of mature muscle fibers characterized by MyoHC+ staining and fusion index. By integrating physical, chemical, and biological perspectives, this work advances Xolography toward biomaterials development and reinforces its position as an emerging volumetric (bio)printing technology. Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/729865v1_ufig1.gif" ALT="Figure 1"> View larger version (86K): org.highwire.dtl.DTLVardef@407d86org.highwire.dtl.DTLVardef@1f116b4org.highwire.dtl.DTLVardef@109a437org.highwire.dtl.DTLVardef@1fc4ece_HPS_FORMAT_FIGEXP M_FIG C_FIG For printing higher cell density bioresins with Xolography, iodixanol (IDX) is added for refractive index-matching. The addition leads to an unexpected additional effect with increased reactivity in the dual-color photopolymerization. With careful adjustment of the resin composition and the printing parameters, Bioxolography is proven as a viable tool for tissue engineering.

Disruption of the wound healing cascade can result in pathological outcomes, including fibrosis due to myofibroblast-mediated contraction and collagen deposition. Despite the clinical significance, effective treatments for fibrosis remain limited as current therapies often show inconsistent efficacy, adverse effects, and patient discomfort. Combinatorial therapeutic strategies integrating biomaterial scaffolds with gene delivery have shown promise in regenerative healing. MicroRNAs (miRNAs) are key regulators of fibrotic signalling in cells, including fibroblasts and myofibroblasts. Specifically, miRNA-29b is notable for downregulating pro-fibrotic genes, including collagen type I, reducing ECM accumulation, and limiting fibroblast/myofibroblast overactivation. In this context, the present work develops a collagen-GAG (CG) scaffold platform for delivery of miRNA-29b complexed GET nanoparticles to inhibit fibrosis. Initially, bioinformatic analysis of miRNA-29b validated its involvement in ECM-associated pathways and processes, followed by successful nanoparticle internationalisation in primary dermal fibroblasts. The anti-fibrotic efficacy of the optimised miRNA-29b nanoparticles was subsequently demonstrated by significant reductions in collagen deposition and -SMA expression, both key indicators of myofibroblast differentiation and fibrosis. The optimised miRNA-29b formulation was then incorporated into 3D porous collagen-GAG (CG) scaffolds, which modulated fibrotic gene expression while preserving scaffold structure conducive to fibroblast/myofibroblast infiltration and proliferation. Finally, functional outcomes of seeded TGF-{beta}-stimulated fibroblasts, including reduced matrix contraction, -SMA expression, and ECM deposition, were comparable to those observed in non-fibrotic conditions, thereby confirming the therapeutic potential of scaffold-mediated miRNA-29b delivery. Together, these findings demonstrate that scaffold-mediated miRNA-29b delivery represents a promising anti-fibrotic strategy for wound healing by mitigating myofibroblast activation, limiting matrix contraction, and preventing pathological ECM accumulation.

Foreign body response is a common yet serious challenge for biomedical implants. It can trigger inflammation and eventually lead to the formation of a fibrotic capsule, which compromises device function. Although significant efforts have been made to develop antifibrotic surface coatings for implantable materials, developing broadly applicable solutions remains challenging due to the diversity of materials used in biomedical implants. Here, we propose a simple and versatile strategy to develop antifibrotic coatings for biomedical implants. Photoreactive benzophenone groups are incorporated into designer polymers to enable covalent attachment to various substrates. The effect of benzophenone group density within polymer chains on surface coating efficiency was investigated, and an optimal BP incorporation ratio was identified. Polymers incorporating varying ratios of an anti-fibrotic small molecule and anti-fouling zwitterionic moieties were synthesized and successfully attached to silicone implants. In vivo evaluation of these implants in C57BL/6 mice identified an optimized polymer composition that reduced fibrotic capsule thickness by around 60%. Coating of commercial medical catheters with this optimized polymer reduced collagen deposition by over 3.5-fold following 4 weeks of implantation in the peritoneal space of C57BL/6 mice. Finally, we demonstrated that the optimized polymer coating can be readily applied to a variety of commonly used biomedical materials using this straightforward method, highlighting the versatility of the approach. This work provides a facile and broadly applicable strategy for developing antifibrotic coatings, which has the potential to expand the design of surface modifications aimed at improving the performance of biomedical implants.

Bioprinting increasingly requires biomaterials that are not only printable, but structurally adaptive and biologically instructive. Here we establish an ovoprotein-derived microgel platform that couples intrinsic protein bioactivity with orthogonal interparticle photocrosslinking for modular bioprinting. Methacrylated ovoproteins yielded a photoresponsive protein-rich hydrogel matrix with retained proteomic complexity, tunable mechanics, and cell-regulatory biofunction. Endogenous tyrosine chemistry drove interparticle dityrosine coupling between ovoprotein microgels, producing cohesive, microporous, and intrinsically autofluorescent granular networks. The resulting systems displayed programmable rheology and broad compatibility across digital light processing, extrusion-based and aspiration-assisted bioprinting. Functionally, the ovoprotein microgel matrices attenuated sustained pro-inflammatory macrophage activation, promoted endothelial organization and host angiogenic invasion, and supported spheroid-mediated vascular morphogenesis with progressive sprouting, lumenization, branching and inosculation. It further enabled bioprinted osteogenic constructs with long-term maturation into bone-like mineralized tissues in vitro. These findings establish ovoprotein microgel-spheroid bioassembly as an adaptive, bioinstructive strategy for engineering vascularized and mineralized tissue constructs.

Recreating the complex spatial gradients and multi-material transitions of native tissues remains a fundamental challenge in 3D bioprinting. To address this, we introduce multi-modal photoFRESH, which integrates localized photochemistry into embedded printing by delivering light through a fiber-optic light-pipe. By tuning numerical aperture, print speed, and photoabsorber content, we achieve precise layer-by-layer control of crosslinking, stiffness, and bioorthogonal biomolecular tethering while preserving high print fidelity. Both photoactivatable support baths and extruded bioinks can be patterned, together with traditional FRESH printing. Utility of the platform is demonstrated by the fabrication of structurally complex tissue scaffolds and cellularized muscle constructs with distinct mechanical and biochemical domains. This multi-modal approach expands the boundaries of embedded bioprinting toward functional and heterogeneous tissue architectures.

Osteoarthritis, characterized by cartilage degradation and synovial inflammation, has spurred interest in mechano-piezoelectric bio-hydrogel therapies that can both relieve symptoms and reverse progression. However, current approaches lack sufficient piezoelectric output and dual cartilage/inflammation targeting. To address this, we demonstrated a mechano-piezoelectric peptide hydrogel composed of nanofibers integrating piezoelectric cues with mesenchymal stromal cells (MSCs) recruitment and PIEZO2 mechanosignaling. Molecularly, the hydrogel's seed peptide incorporated four functions: COL2A1 targeting, MMP-13 responsiveness, MSCs homing, and self-assembly. Overexpressed MMP-13 in the osteoarthritis niche triggers gelation, promoting MSCs recruitment and drug retention. Fluorination modulates hierarchical nanofiber assembly, enhancing mechanical and piezoelectric properties, as confirmed by morphological, biophysical, and computational analysis. The trifluoromethyl-modified, 4-octyl itaconate (4-OI) loaded formulation reverses osteoarthritis via PI3K/AKT activation and Wnt/{beta}-catenin suppression, as shown by improved Osteoarthritis Research Society International (OARSI) scores, bone microarchitecture, and cartilage matrix. This synergy of mechano-piezoelectric cues and 4-OI offers a clinically promising strategy for osteoarthritis.

The hierarchical organization of cellulose microfibrils and their intimate interactions with hemicelluloses such as xylan underpin the exceptional mechanical performance of plant cell walls. However, translating these biological design principles into sustainable nanocellulosic materials remains limited by conventional cellulose nanofibril production routes, which rely on harsh chemical treatments that disrupt the native cellulose-hemicellulose architecture. Here, we present an optimized isolation strategy for holocellulose nanofibrils (hCNFs) that preserves native cellulose structure, xylan substitution and conformation, and cellulose-xylan interactions. Using wild-type Arabidopsis thaliana, a xylan glucuronidation-deficient gux1/2 mutant, and Brassica napus straw as model systems, we systematically elucidate how xylan content and substitution pattern govern nanofibril isolation, interfacial interactions, and macroscopic properties. Two-dimensional 13C magic-angle spinning NMR demonstrates retention of native cellulose glucosyl environments, the presence of two-fold and three-fold helical xylan conformations, and cellulose-associated two-fold helical xylan. Cryogenic transmission electron microscopy reveals fibril widths of [~]3 nm, consistent with elementary cellulose I{beta} microfibrils. We show that xylan glucuronidation regulates colloidal stability, hydration behavior, and interfibrillar cohesion, whereas xylan content controls nanofibrillation efficiency. These multiscale structural features translate directly into moisture sorption, thermal behavior, and mechanical performance. Notably, Brassica napus hCNF films exhibit exceptional strength and extensibility, surpassing many chemically modified CNF systems. This work demonstrates that preserving the native cellulose-hemicellulose architecture enables high-performance, sustainable nanocellulosic materials without chemical reconstruction.