Acta biomaterialia最新文献

Pyroptosis-based cancer therapy is often hindered by the overexpression of SLC7A11, which enhances glutathione (GSH) biosynthesis to maintain redox homeostasis and suppress pyroptotic cell death. To address this challenge, we developed a metal-free cascade nanoreactor (ITG@PCM) designed to disrupt redox balance via the cystine-GSH axis, thereby enabling synergistic disulfidptosis-pyroptosis therapy. This system employs an organic phase-change material (PCM) to co-encapsulate the photothermal agent IR825, copper chelator TPEN, and glucose oxidase (GOx), with on-demand payload release triggered by the thermal effect under 808 nm laser irradiation. Upon release, GOx catalyzes glucose oxidation, leading to nicotinamide adenine dinucleotide phosphate (NADPH) depletion and consequent actin cytoskeletal collapse, thereby inducing disulfidptosis through abnormal cystine accumulation via SLC7A11. Simultaneously, TPEN chelates Cu²⁺ from Cu-superoxide dismutase (Cu-SOD), forming Cu²⁺-TPEN complexes that abolish SOD activity and promote ·O₂^- accumulation due to impaired dismutation. Notably, Cu²⁺-TPEN is reduced by GSH to Cu⁺-TPEN, resulting in GSH depletion and catalyzing H₂O₂ into highly cytotoxic ·OH via a Fenton-like reaction. The combined effects of GSH depletion and cystine accumulation amplify oxidative stress, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome/caspase-1/gasdermin D (GSDMD) signaling pathway to trigger pyroptosis. Collectively, this cascade-driven dual cell-death mechanism provides a promising paradigm for tumor therapy by precisely disrupting intracellular redox homeostasis. STATEMENT OF SIGNIFICANCE: This work presents a metal-free cascade nanoreactor (ITG@PCM) that strategically disrupts redox homeostasis to induce a synergistic disulfidptosis-pyroptosis anticancer response. By integrating a photothermal agent (IR825), a copper-selective chelator (TPEN), and glucose oxidase within a phase-change matrix, the system enables on-demand, laser-controlled release of therapeutics that simultaneously target the cystine-GSH axis and Cu/Zn-SOD. This dual intervention amplifies oxidative stress through cystine accumulation, GSH depletion, and catalytic hydroxyl radical (·OH) generation, thereby activating the NLRP3 inflammasome to trigger pyroptosis. The approach achieves potent antitumor efficacy without relying on transition-metal nanocatalysts, offering a safer alternative with high translational potential. Notably, this work also provides mechanistic insight into the interplay between disulfidptosis and pyroptosis and establishes a promising paradigm for redox-mediated cancer therapy.

The mechanical properties of cerebral arteries are essential for maintaining normal brain function. Aging promotes arterial stiffening, which accelerates cerebral remodeling and contributes to cognitive impairment. As arterial mechanical behavior is closely related to microstructure, characterizing age-related structural alterations is crucial for elucidating the mechanisms driving neurodegenerative progression. In this study, we developed a structurally motivated constitutive model that incorporates age-dependent changes in adventitial collagen to investigate the mechanical behavior of human anterior cerebral arteries (ACAs). Multiphoton imaging of adventitial collagen was performed on human ACAs (n = 20, ages 28-92 years). Collagen fiber recruitment for each subject was characterized using a Gamma probability density function (PDF), under the assumption that collagen fibers contribute to load bearing only after full straightening. With aging, the recruitment distribution became narrower with its peak shifts towards lower stretch values, indicating earlier collagen fiber engagement. The age-dependent recruitment behavior was then incorporated into a two-fiber family constitutive model by expressing the Gamma PDF parameters as continues functions of age. The model was used to characterize the mechanical responses of human ACAs (n = 49) from our previous study and successfully captured age-related arterial stiffening, reflected by increased initial slopes in the stress-stretch response of older ACAs. Furthermore, the model revealed that collagen increasingly dominates load bearing with age, particularly at physiological pressures, as evidenced by a significant increase in circumferential stiffness (p <0.05). These findings provide mechanistic insights into the microstructural origins of cerebral arterial stiffening and its potential role in age-related neurodegenerative progression. STATEMENT OF SIGNIFICANCE: Cerebral arterial stiffening with aging increases the risk of cognitive decline and neurodegenerative disease, yet the coupled structural-mechanical mechanisms driving this process remain poorly understood. This study introduces a structurally motivated, age-dependent constitutive model for human anterior cerebral arteries (ACAs) that explicitly incorporates collagen fiber recruitment behavior as a continuous function of age. Collagen fiber recruitment was directly quantified from multiphoton imaging and characterized using a Gamma probability density function. By embedding imaging-informed microstructural changes into a two-fiber family model, this framework provides mechanistic insights into cerebrovascular aging and offers a generalizable approach for modeling arterial mechanics informed by tissue-specific microstructure.

Absorbable self-gelling hemostatic powders derived from natural polyelectrolytes (e.g. gelatin (Gel), starch, chitosan) have been explored for controlling non-compressible hemorrhage. However, their hemostatic efficacy is limited by the inherent polyelectrolyte effect, where salt ions in blood inhibit polymer chain hydration and extension, thereby weakening their rapid self-gelling and wet adhesion. Here, a bioinspired self-gelling powder (PGSB-Gel) based on Gel crosslinked by zwitterionic poly(glycidyl methacrylate-co-sulfobetaine methacrylate) (PGSB) is reported. Owing to the anti-polyelectrolyte effect and electrostatic interactions of zwitterionic poly-sulfobetaine (PSB) moieties, PGSB-Gel powder rapidly absorbs blood, simultaneously triggering its in situ transformation into a robust hydrogel within 6 s. The resulting hydrogel exhibits high adhesive strength (25 ± 2 kPa) and burst pressure (162 ± 9 mmHg) exceeding arterial pressure, ensuring reliable sealing of high-pressure wounds. Together with its bioinspired zwitterionic structure's affinity for blood cell membranes, the hydrogel enhances platelet and red blood cell capture, thus accelerating hemostasis. In multiple in vivo models of non-compressible wounds, PGSB-Gel reduced hemostasis time and blood loss by over 50% compared with commercial powders Celox^TM and Bleedstop^TM, demonstrating superior hemostatic efficacy. Furthermore, this zwitterionic hydrogel serves as an antifouling physical barrier around wounds to prevent tissue adhesion. Overall, this study offers a transformative approach to polyelectrolyte-based hemostats for rapid hemostasis and improved recovery. STATEMENT OF SIGNIFICANCE: Absorbable self-gelling hemostatic powders derived from natural polyelectrolytes have been explored for controlling non-compressible hemorrhage. However, their hemostatic efficacy is limited by the inherent polyelectrolyte effect, where salt ions in blood inhibit polymer chain hydration and extension, thereby weakening their rapid self-gelling and adhesion. Herein, we present a bioinspired self-gelling powder based on natural gelatin crosslinked by a zwitterionic crosslinker. The powder rapidly absorbs blood and instantly self-gels in situ owing to the anti-polyelectrolyte effect and electrostatic interactions. The resulting hydrogel exhibits high adhesive strength, ensuring reliable wound sealing. Together with its zwitterionic structure's affinity for blood cell membranes, the hydrogel enhances blood cell capture, thus accelerating hemostasis. Furthermore, it serves as an antifouling physical barrier to prevent tissue adhesion.

Cobalt-chromium-molybdenum (CoCrMo) alloys are widely used in orthopedic implants, where their long-term performance depends on maintaining corrosion resistance in the complex synovial joint environment. While phospholipids are well known for their lubricating properties, their direct influence on electrochemical reactivity of implant alloys remains largely unexplored. This study investigates the corrosion behavior of CoCrMo in a biomimetic medium containing hyaluronic acid-phospholipid vesicles, compared with a standard cell culture solution, across immersion times of 1, 5, 24, 120, and 168 hours. Electrochemical tests, including open circuit potential, anodic polarization, and electrochemical impedance spectroscopy, were complemented by scanning electron microscopy to evaluate surface changes. Results show that phospholipids exert a time-dependent, ambivalent effect: at short immersion times, vesicle adsorption perturbs the passive oxide film, reducing corrosion resistance; with longer exposures, vesicle self-assembly stabilizes the surface, increases capacitance, and enhances the protective nature of the passive layer. This study demonstrates that phospholipids at CoCrMo implant surfaces influence electrochemical behavior locally and dynamically rather than uniformly across the implant's surface. Clinically, these findings highlight that phospholipid adsorption may transiently limit corrosion and reduce metal ion release immediately after implantation, though mechanical loading could disrupt the protective coverage and promote localized tribocorrosion. These insights expand the understanding of implant-biomolecule interactions and suggest new directions for surface engineering and the design of advanced coatings or synthetic synovial fluids to improve implant longevity. STATEMENT OF SIGNIFICANCE: Phospholipids in synovial fluid are widely recognized for their lubricating role, yet their direct electrochemical interactions with metal alloys remain poorly understood. This work is the first to demonstrate the time-dependent, ambivalent influence of hyaluronic acid-phospholipid vesicles on the corrosion resistance of cobalt-chromium-molybdenum (CoCrMo) alloys. Unlike traditional corrosion studies that rely on simple saline or buffer solutions, our approach employs a biomimetic medium to capture clinically relevant interactions. The finding that phospholipids can both destabilize and later stabilize the alloy surface challenges current assumptions and opens a new research direction in implant science. This study provides mechanistic insights with broad implications for implant longevity, surface engineering, and the design of next-generation biomaterials.

Surgical intervention involving grafts is often required to treat ruptured Achilles tendons. Synthetic grafts for this purpose have a number of advantages but have yet to be translated to clinic, due to an inability to reproduce the complex architecture and thus biomechanics of the native collagen fibre structure. This study examined the influence of scaffold fibre architecture in combination with intermittent dynamic culture on the composition of extracellular matrix (ECM) deposited by isolated rabbit tenocytes. Scaffolds were prepared using melt electrowriting having fibre patterns similar to those reported for tendon tissue, with either bi-directionally crimped fibres or unidirectionally crimped with orthogonal linear fibres. The bi-directionally crimped scaffolds were designed such that they had a negative Poisson's ratio (auxetic nature) similar to that reported for the human Achilles tendon (AT). The scaffolds were seeded with rabbit tenocytes, precultured under static conditions for one week, then either dynamically stimulated in intermittent uniaxial tension (4% strain, 1 Hz, 1 h/day) or maintained in static culture for 2 weeks. Dynamic intermittent stimulation promoted increased cell proliferation and ECM synthesis on both scaffold architectures in comparison to static controls. However, the tenocytes cultured on the bi-directional, auxetic scaffolds produced more total collagen and less sulfated glycosaminoglycans (sGAG) per cell with an overall collagen:sGAG ratio within the range reported for healthy human tissue at 10:1 in contrast to the 4:1 ratio of the ECM deposited on the scaffolds with the unidirectional crimped, non-auxetic fibre pattern. The increase in collagen content on the auxetic scaffolds was also reflected in a higher tensile modulus. These findings demonstrate the impact of fibre crimp unfolding on tenocyte response to mechanical loading and highlight the benefits of replicating the complexity of the AT fibre architecture in developing grafts for surgical repair of ruptured ATs. STATEMENT OF SIGNIFICANCE: Synthetic grafts for Achilles tendon (AT) repair have predominantly used a uniaxial crimped fibre architecture. However, the collagen fibre architecture of the AT is more complex, having multidimensional fibre crimping. This crimp pattern is considered responsible for the auxetic nature of the human AT, and tenocyte response to scaffolds with multidimensional fibre architectures has not been explored to date. Our findings demonstrate the importance of replicating the multidimensional nature of fibre architecture and suggest the benefits of incorporating an auxetic response in graft designs.

Spinal cord injury (SCI) represents a major public health challenge, leading to persistent neurological deficits and disabilities that impose substantial medical and economic burdens on individuals and society. This study introduces a sequential therapeutic strategy aligned with the dynamic pathological progression of SCI. We developed a biomimetic hydrogel integrating hyaluronic acid methacryloyl (HAMA), decellularised extracellular matrix (dECM), edaravone, and sustained-release serotonin (5-HT). This system enables acute-phase damage control and promotes chronic-phase repair. Using in vitro and in vivo models, we demonstrated that edaravone effectively mitigated oxidative stress and inflammation in the acute phase. Specifically, it reduced reactive oxygen species and pro-inflammatory cytokine levels. Furthermore, it suppressed the NF-κB-NLRP3-caspase-1-GSDMD signalling axis in microglia, resulting in decreased pyroptosis. In the chronic phase, the sustained release of 5-HT within the sequential dual-drug delivery biomimetic hydrogel facilitated axonal regeneration and remyelination, supporting functional recovery, as indicated by marked improvements in behavioural scores and electrophysiological assessments. Notably, the combination of edaravone and 5-HT optimised the regenerative microenvironment to promote specific axonal growth. In conclusion, this innovative hydrogel system, tailored to different stages of injury, offers a highly promising comprehensive approach for translational SCI therapy. STATEMENT OF SIGNIFICANCE: Spinal cord injury treatment remains challenging due to temporal pathological progression requiring phase-specific interventions. Current therapeutic approaches typically target single injury phases, limiting overall efficacy. We developed a sequential dual-drug delivery biomimetic hydrogel combining hyaluronic acid methacryloyl with decellularised spinal cord matrix, enabling rapid edaravone release for acute-phase microglial pyroptosis suppression and sustained serotonin release for chronic-phase axonal regeneration. In rat complete transection models, this temporally coordinated strategy reduced inflammatory damage whilst promoting axonal regrowth and remyelination, resulting in improved locomotor and electrophysiological outcomes. This work demonstrates that biomimetic hydrogels with stage-matched drug delivery can address the complex temporal requirements of spinal cord injury repair.

Postoperative adhesions pose a significant clinical challenge, contributing to chronic pain, organ dysfunction, increased morbidity, mortality, and substantial healthcare costs. Current adhesion prevention strategies often rely on physical barriers such as solid films, polymer solutions, and hydrogels. Leveraging nature's own effective barrier, mucus, and specifically mimicking mucus' bottlebrush-structured mucins (its core glycoprotein composition) that provide lubrication and hydration, we chemically engineered a mucin-inspired bottlebrush polymer (MIBP) hydrogel. It features zwitterionic polysulfobetaine bottlebrush polymers dynamically crosslinked by ionic interactions with poly(sodium 4-styrenesulfonate). This design enables rapid, injectable gelation and autonomous self-healing, which achieves the similar adaptability of natural mucus. Its superior zwitterionic antifouling properties resist protein and cell adhesion, forming a low-friction, biocompatible barrier. Our work elucidates how the bottlebrush architecture leads to enhanced lubricity and solubility compared to analogous linear polymers, notably by mitigating issues like coacervation. In vivo evaluation in a rat sidewall defect-cecum abrasion model demonstrated anti-adhesion efficacy and biosafety, with mitigated local inflammation. Thus, the MIBP hydrogel, embodying natural, dynamic, and biocompatible barrier principles, offers a highly effective and adaptable strategy to prevent postoperative adhesions and improve surgical outcomes. STATEMENT OF SIGNIFICANCE: Postoperative adhesions are a major surgical complication. Our research introduces a mucin-mimetic hydrogel that replicates the self-healing and lubricating properties of natural mucus. We achieve this using a molecularly engineered bottlebrush polymer that mimics the core architecture of mucin glycoproteins. This unique hydrogel functions as a dynamic barrier, isolating surgical sites and mitigating the physical irritation that causes inflammation, before safely decomposing after treatment. By leveraging this biomimetic design, our material provides a highly effective and adaptable anti-adhesion barrier, offering a significant advance for improving surgical outcomes.

Magnetic Resonance Elastography (MRE) noninvasively maps brain biomechanics and is highly sensitive to alterations associated with aging and neurodegenerative disease. Most implementations use a single frequency or a narrow frequency band, limiting the analysis of frequency-dependent viscoelasticity parameters. We developed a dual-actuator wideband MRE (5-50 Hz) protocol and acquired wave fields at 13 frequencies in 24 healthy adults (young: 23-39 years; older: 50-63 years). Shear wave speed (SWS) maps were generated as a proxy for stiffness, and SWS dispersion was modeled using Newtonian, Kelvin-Voigt, and power-law rheological models. Whole-brain stiffness declined with age, with the strongest effect observed at low frequencies (5-16 Hz: -0.24%/year; p=0.038) compared with mid (20-35 Hz: -0.12%/year; p=0.040) and high frequencies (40-50 Hz: -0.10%/year; p=0.123). Compared to older brains, younger adults showed 8.96% higher baseline stiffness in the power-law model (p=0.013) and 8.15-8.39% higher viscosity according to the Newtonian and Kelvin-Voigt model (p<0.05). White and cortical gray matter exhibited similar age-related decreases, while deep gray matter showed an increase in the power-law exponent (+0.001/year; p=0.046), suggesting a transition toward more fluid-like properties associated with aging. Wideband MRE revealed frequency-dependent and region-specific biomechanical alterations with aging, with the strongest effects observed at low frequencies. Extending brain MRE into the low frequency regime potentially enhances sensitivity to solid-fluid interactions. Therefore, low frequency MRE may serve as an early biomechanical marker of microstructural brain changes due to aging and neurodegeneration. STATEMENT OF SIGNIFICANCE: Magnetic Resonance Elastography (MRE) is a noninvasive imaging modality that quantifies the mechanical properties of brain tissue. Conventional approaches are typically restricted to single or narrow vibration frequency ranges, limiting their ability to characterize frequency-dependent viscoelastic behavior. In this study, we establish a wideband MRE framework spanning 5-50 Hz and apply it in vivo to healthy adults across different age groups. Our results demonstrate that age-related brain softening is most pronounced at low frequencies, indicating sensitivity to microstructural alterations and potentially enhancing sensitivity to fluid-solid interactions. These findings highlight diagnostic potential of low frequency MRE for advancing biomechanical biomarkers of brain aging and for future applications in early detection of neurodegenerative disease.

The development of biomaterials that mimic native bone remains a major challenge in regenerative medicine. Here, we present a bioinspired platform using high-density collagen hydrogels with tunable mineral content. These engineered microenvironments promote rapid osteogenesis in vitro without osteogenic supplements and accelerate bone regeneration in vivo in critical-sized defects. By modulating mineralization, we demonstrate that early mechanosensitive signaling in human mesenchymal stem cells is linked to matrix stiffness and biochemical composition. Within two hours, focal adhesion formation decreased with increasing mineral content, and fully mineralized scaffolds significantly increased nuclear YAP1 localization. By 24 hours, RUNX2 expression was markedly increased in fully mineralized scaffolds, with 40.7 ± 3.9% RUNX2⁺ nuclei (p < 0.0001), and this trend persisted at the gene expression level at 3 days. In a rat calvarial defect model, fully mineralized microgels significantly increased bone volume in males at 12 weeks (18.99 ± 2.66 mm³) compared to empty defects (11.60 ± 2.12 mm³, p = 0.0242), whereas females showed no added benefit of full mineralization. Two-way ANOVA confirmed significant effects of sex (p = 0.0006), treatment (p < 0.0001), and their interaction (p = 0.0158). Histological analyses confirmed osteoinductive behavior across all microgel groups and highlighted reduced scaffold degradation and limited cellular infiltration in mineralized conditions. Together, these results demonstrate that tunable intrafibrillar mineralization modulates early stem cell mechanosensing and osteogenic priming in vitro and drives sex-dependent regenerative outcomes in vivo, emphasizing the need to balance scaffold mechanics and degradation to suit the biological context and improve clinical outcomes. STATEMENT OF SIGNIFICANCE: This study introduces a strategy to fine-tune the properties of implantable materials for bone repair using microscale scaffolds with controlled mineral content. By adjusting composition at the nanoscale, our work identifies how early cellular responses can be directed to influence long-term healing. Importantly, the findings reveal that regenerative outcomes vary by sex, emphasizing the need to consider biological differences in biomaterial design. This work offers new insight into how tailored physical environments can guide tissue repair and highlights the potential for precision approaches in bone graft development.