Advanced Healthcare Materials最新文献

Microphysiological Systems

In the Research Article (DOI: 10.1002/adhm.202502711), Curtis R. Warren, Roger D. Kamm, and co-workers develop a microphysiological system that interfaces human engineered muscle tissue with an inflamed adipose-macrophage co-culture to recapitulate obesity-associated muscle dysfunction, revealing impaired contractility, elevated pro-inflammatory cytokine secretion, and metabolically dysregulated gene expression.

Endometritis, a common gynecological disease caused by ascending bacterial infection, is a leading cause of infertility. Currently, the clinical treatment relies primarily on antibiotic therapy, administered via intravenous injection, oral administration, or local delivery (e.g., intrauterine infusion). Nevertheless, intravenous injection aggravates hepatic and renal burdens, whereas oral administration elicits gastrointestinal reactions; intrauterine infusion suffers from drug leakage from the uterus due to gravity. Therefore, we developed mucoadhesive doxycycline hydrochloride-loaded air microbubbles (Mad-Doxy-MBs) for intrauterine infusion therapy of endometritis to overcome these limitations. The results showed that Mad-Doxy-MBs exhibited an ultrasound contrast-enhancement property so that they could be tracked by clinicians under ultrasound to achieve their precise localization on the endometrium when infused transvaginally. Subsequently, Mad-Doxy-MBs adhered to the endometrial surface and continuously released Doxy, exhibiting robust bactericidal and anti-inflammatory capacities. Compared with daily oral Doxy administration, two once-weekly intrauterine infusions of Mad-Doxy-MBs achieved superior therapeutic efficacy against endometritis while exhibiting markedly lower gastrointestinal toxicity. This drug delivery platform that integrates the properties of ultrasound visualization, mucoadhesion, and sustained drug release offers a clinically translatable strategy for intrauterine infusion therapy of endometritis and opens new avenues for precise and long-term drug delivery in other luminal diseases.

Fe₃O₄ nanoparticles exhibit therapeutic and diagnostic capabilities by inducing ferroptosis through reactive oxygen species generated by the Fenton reaction and enhancing magnetic resonance imaging (MRI) contrast. However, the efficacy of ferroptosis induced by Fe₃O₄ is limited by several factors, including low Fe²⁺ concentration, restricted Fenton-active sites, excessive glutathione (GSH), and insufficient acidity of tumor cells. In this study, MoS₂-doped Fe₃O₄, with peroxidase and glutathione oxidase-like activities, was functionalized with tamoxifen (TAM) and coated with bovine serum albumin (BSA) to construct Fe₃O₄/MoS₂@TAM/BSA (FMTB) nanoparticles. The incorporation of MoS₂ facilitated the generation of abundant oxygen vacancies, which increased the number of active sites, acted as a co-catalyst to accelerate the reduction of Fe³⁺ to Fe²⁺, and promoted GSH consumption, resulting in a 51.3% increase in Fenton activity and a 4.3-fold enhancement in GSH consumption compared to Fe₃O₄ alone. The released TAM inhibited mitochondrial complex I and improved tumor cellular acidity, thereby creating a conducive environment for the Fenton reaction. By enhancing peroxidase-like activity through co-catalysis and reducing cellular pH, FMTB achieved a 70.6% tumor growth inhibition, in contrast to the 20.8% inhibition observed with Fe₃O₄ alone. Furthermore, the FMTB-mediated tumor T₂-weighted MRI signal was attenuated by 17% compared to that of Fe₃O₄. Thus, this multienzyme-based platform presents a novel strategy for highly efficient ferroptosis therapy against tumors by enhancing Fenton reaction efficiency and depleting GSH.

Osteosarcoma (OS) is the most common bone cancer, characterized by high mortality rates and limited treatment options, due to its heterogeneity, metastatic potential, and chemoresistance. This highlights the urgent need for robust preclinical models that accurately represent the disease in order to facilitate the discovery of new therapeutics. Compared to traditional 2D cultures and animal models, 3D in vitro models offer a better representation of the tumor's 3D structure and cell-extracellular matrix (ECM) interactions, which play a key role in drug response, while reducing the need for animal testing. In this work, we present a novel 3D bioprinted OS model by incorporating OS spheroids into an OS-tailored bioink, enriched with OS cell-derived decellularized ECM. The bioink exhibits high water content, minimal mass loss, fast UV-induced gelation, and enhanced printability and biocompatibility. Despite having a compressive modulus at the lower end of the range associated with OS, the bioprinted model shows an increased expression of OS prognostic markers, lower sensitivity to doxorubicin, and overexpression of P-glycoprotein. This is likely due to the model's ability to mimic both the 3D structure and composition of the OS-ECM, emphasizing its enhanced reliability and potential for exploring novel alternative OS therapeutic approaches in future research.

Natural Nanomaterials

The cover is inspired by the Chinese tale of Sun Wukong, the “Great Sage Equaling Heaven,” and depicts him fiercely battling tumor cells. The golden hoop staff he wields forward represents the pentacyclic triterpenoid small molecule (NSM) for chemotherapy. The flame in his eyes symbolizes the nanomaterial's photodynamic therapy effect, and the little monkey stands for its anti-angiogenic function. These three roles jointly inhibit tumor growth and metastasis. More details can be found in the Research Article by Xin Yang and co-workers (DOI: 10.1002/adhm.202501960).

Complicated and dynamic tissue niches that determine the fate of regeneration and the reconstruction of complex niches in vitro remains a challenge. Silk protein nanofiber-based biomaterial matrices with hierarchical cortical and cancellous-like microstructures were developed to induce bone regeneration. Here, hydrophobic simvastatin (SIM) was loaded onto silk nanofibers and further immobilized in the cortical region to mimic natural angiogenesis during bone healing. The matrices maintained biomimetic hierarchical structures after introducing SIM, forming complex microenvironments that contained physical and chemical cues to direct the regenerative mechanisms. The biomimetic niches improved angiogenesis, anti-inflammatory behavior, and osteogenesis, favoring bone regeneration. In vivo studies in rats revealed that blood vessels rapidly grew from the periosteum into the cortical area and then expanded into the cancellous area, similar to natural angiogenesis processes in bone. The bone healing process, characterized by complex anisotropic structures and dynamic vascularization, stimulated high-quality bone regeneration with desirable anisotropic compositions similar to those of natural cortical and cancellous bone. These bioactive matrices with multiple bionic features guided vascular remodeling and bone reconstruction, suggesting potential clinical applications.

Developing asymmetric adhesive hydrogel simultaneously with the anti-swelling capability for internal wound remains a great challenge. Herein, a facile one-step approach was designed to prepare a versatile hydrogel patch with highly asymmetric adhesion between two sides (21 times), robust tissue adhesion of the bottom side (557.3 J/m²), and ultra-low swelling ratio (0.25). The asymmetric distribution of self-assembled emulsion droplets within the precursor induces the anti-adhesion of the top side yet strong adhesion of the bottom side. The incorporation of a hydrophobic crosslinker into the core of emulsion droplets endows the ultra-low swelling of the hydrogel. This optimized hydrogel achieves high burst pressure even after being soaked in water, and effectively seals the defects of isolated organs under water. The vivo rat experiment confirms that this hydrogel not only can firmly adhere to the gastric defect but also address the postoperative adhesion issue. This work provides a simple yet effective strategy to prepare the high-performance hydrogel for treating internal wound.

The development of small-caliber tissue-engineered vascular grafts (sTEVGs) presents several challenges, including achieving balanced endothelialization, facilitating smooth muscle cell infiltration, preventing leakage, and ensuring anti-thrombogenic properties, while maintaining mechanical strength sufficient to withstand physiological pressures, surgical handling, and suturing. Here, we present a multi-layered polycaprolactone (PCL)-based sTEVG using a combination of electrospinning and 4-axis printing, providing precise control over scaffold porosity, fiber alignment, and tunable mechanical properties. To improve biocompatibility and hemocompatibility, the PCL nanofibers were functionalized with sulfated polysaccharides purified from the marine invertebrate Holothuria tubulosa, which significantly enhanced endothelialization and provided strong anti-thrombogenic properties. The inner layer of tightly aligned electrospun nanofibers supported rapid formation of a mature endothelium, while preventing graft leakage even at supraphysiological pressure (>1100 mmHg). The middle layers, combining circumferential electrospun nanofibers and 4-axis printed microfibers, increased scaffold porosity, and promoted adhesion, orientation and infiltration of human coronary artery smooth muscle cells (HCASMCs), facilitating functional tunica media formation. The outer layer of randomly oriented electrospun nanofibers contributed significantly to the mechanical properties of the graft, namely elasticity, toughness, burst pressure, and resistance to physiological vessel pressures, thus mimicking the tunica adventitia. The customizable four-layered graft integrates structural and biological cues to address key limitations of sTEVGs, representing a valuableoff-the-shelf alternative to autologous grafts.

Dynamic mechanical stimulation plays an important role in determining the function and health of cells and tissues, and it is therefore highly relevant to study the real-time response of cells to time-dependent forces. We introduce a platform for providing controllable dynamic mechanical stimulation to single cells, suitable for investigating large cell populations and enabling live cell imaging, and we present proof-of-principle experiments that demonstrate the platform's capabilities. Cells are cultured on a hydrogel surface with magnetic artificial cilia made from a magnetic elastomer using a tailored micromolding process. The cilia are actuated with an electromagnet integrated with an in-incubator fluorescent microscope. We show that cells attach to the cilia and exhibit widely different morphologies than cells on flat surfaces. Cellular forces involved can be estimated by measuring cilia deflection. We demonstrate that cells can be exposed to continuous dynamic forces by cilia actuation and that their response can be monitored by real-time observation of Yes-Associated Protein (YAP). These experiments indicate rare events of mechanotransduction due to cilia actuation, but the low response prohibits drawing final conclusions about the biological response. Our artificial cilia-based platform offers new opportunities for studying mechanical cell stimulation in real time and understanding dynamic mechanotransduction.