Acta Biomaterialia最新文献

Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn²⁺) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance.

Statement of significance

The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a “two birds with one stone” strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness.

Magnesium as a biodegradable material offers promising results in recent studies of different maxillo-facial fracture models. To overcome adverse effects caused by the fast corrosion of pure magnesium in fluid surroundings, various alloys, and surface modifications are tested in animal models. In specified cases, magnesium screws already appeared for clinical use in maxillofacial surgery. The present study aims to compare the bone healing outcome in a non-load-bearing fracture scenario of the forehead in sheep when fixed with standard-sized WE43 magnesium fixation plates and screws with plasma electrolytic oxidation (PEO) surface modification in contrast to titanium osteosynthesis. Surgery was performed on 24 merino mix sheep. The plates and screws were explanted en-bloc with the surrounding tissue after four and twelve weeks. The outcome of bone healing was investigated with micro-computed tomography, histological, immunohistological, and fluorescence analysis. There was no significant difference between groups concerning the bone volume, bone volume/ total volume, and newly formed bone in volumetric and histological analysis at both times of investigation. The fluorescence analysis revealed a significantly lower signal in the magnesium group after one week, although there was no difference in the number of osteoclasts per mm². The magnesium group had significantly fewer vessels per mm² in the healing tissue. In conclusion, the non-inferiority of WE43-based magnesium implants with PEO surface modification was verified concerning fracture healing under non-load-bearing conditions in a defect model.

Statement of significance

Titanium implants, the current gold standard of fracture fixation, can lead to adverse effects linked to the implant material and often require surgical removal. Therefore, degradable metals like the magnesium alloy WE43 with plasma electrolytic oxidation (PEO) surface modification gained interest. Yet, miniplates of this alloy with PEO surface modification have not been examined in a fracture defect model of the facial skeleton in a large animal model. This study shows, for the first time, the non-inferiority of magnesium miniplates compared to titanium miniplates. In radiological and histological analysis, bone healing was undisturbed. Magnesium miniplates can reduce the number of interventions for implant removal, thus reducing the risk for the patient and minimizing the costs.

Ischemic osteonecrosis, particularly glucocorticoid-induced osteonecrosis of the femoral head (GIONFH), is primarily due to the dysfunction of osteogenesis and angiogenesis. miRNA, as a therapeutic system with immense potential, plays a vital role in the treatment of various diseases. However, due to the unique microenvironmental structure of bone tissue, especially in the case of GIONFH, where there is a deficiency in the vascular system, it is challenging to effectively target and deliver to the ischemic osteonecrosis area. A drug delivery system assisted by genetically engineered cell membranes holds promise in addressing the challenge of targeted miRNA delivery. Herein, we leverage the potential of miR-21 in modulating osteogenesis and angiogenesis to design an innovative biomimetic nanoplatform system. First, we employed metal-organic frameworks (MOFs) as the core structure to load miR-21-m (miR-21-m@MOF). The nanoparticles were further coated with the membrane of bone marrow mesenchymal stem cells overexpressing CXCR4 (CM-miR-21-m@MOF), enhancing their ability to target ischemic bone areas via the CXCR4-SDF1 axis. These biomimetic nanocomposites possess both bone-targeting and ischemia-guiding capabilities, actively targeting GIONFH lesions to release miR-21-m into target cells, thereby silencing PTEN gene and activating the PI3K-AKT signaling pathway to regulate osteogenesis and angiogenesis. This innovative miRNA delivery system provides a promising therapeutic avenue for GIONFH and potentially other related ischemic bone diseases.

Statement of significance

• 1.

  CXCR4-Engineered Membranes Enhance Targeting for Ischemic Osteonecrosis.

• 2.

  miR-21-Based Gene Therapy for Regulating Osteogenesis and Angiogenesis.

• 3.

  Expanding the Use of Membrane-Cloaked MOF Nanoparticles.

Traditional robotic devices are often bulky and rigid, making it difficult for them to adapt to the soft and complex shapes of the human body. In stark contrast, soft robots, as a burgeoning class of robotic technology, showcase exceptional flexibility and adaptability, positioning them as compelling contenders for a diverse array of applications. High-performance electrically responsive artificial muscle materials (ERAMMs), as key driving components of soft robots, can achieve efficient motion and deformation, as well as more flexible and precise robot control, attracting widespread attention. This paper reviews the latest advancements in high-performance ERAMMs and their applications in the field of soft robot actuation, using ionic polymer-metal composites and dielectric elastomers as typical cases. Firstly, the definition, characteristics, and electro-driven working principles of high-performance ERAMMs are introduced. Then, the material design and synthesis, fabrication processes and optimization, as well as characterization and testing methods of the ERAMMs are summarized. Furthermore, various applications of two typical ERAMMs in the field of soft robot actuation are discussed in detail. Finally, the challenges and future directions in current research are analyzed and anticipated. This review paper aims to provide researchers with a reference for understanding the latest research progress in high-performance ERAMMs and to guide the development and application of soft robots.

Statement of significance

• •

  Inspired by the good performance of natural muscles, extensive attention has been paid to the study of artificial muscles. Based on the structure and properties of artificial muscles, the research progress of high-performance artificial muscle materials is systematically reviewed, the working principle of the device-driven deformation is comprehensively analyzed, and the material design, preparation process and characterization methods are deeply analyzed.

• •

  The opportunities and challenges of high-performance artificial muscle materials, especially ionic polymer-metal composites and dielectric elastomers, are discussed, and their future research directions are proposed, laying the foundation for further innovative research on artificial muscle materials and their application development in the field of soft robot actuation.

Hierarchical collagen fibers are the primary source of strength in tendons and ligaments; however, these fibers largely do not regenerate after injury or with repair, resulting in limited treatment options. We previously developed a static culture system that guides ACL fibroblasts to produce native-sized fibers and early fascicles by 6 weeks. These constructs are promising ligament replacements, but further maturation is needed. Mechanical cues are critical for development in vivo and in engineered tissues; however, the effect on larger fiber and fascicle formation is largely unknown. Our objective was to investigate whether intermittent cyclic stretch, mimicking rapid muscle activity, drives further maturation in our system to create stronger engineered replacements and to explore whether cyclic loading has differential effects on cells at different degrees of collagen organization to better inform engineered tissue maturation protocols. Constructs were loaded with an established intermittent cyclic loading regime at 5 or 10 % strain for up to 6 weeks and compared to static controls. Cyclic loading drove cells to increase hierarchical collagen organization, collagen crimp, and tissue tensile properties, ultimately producing constructs that matched or exceeded immature ACL properties. Further, the effect of loading on cells varied depending on degree of organization. Specifically, 10 % load drove early improvements in tensile properties and composition, while 5 % load was more beneficial later in culture, suggesting a shift in mechanotransduction. This study provides new insight into how cyclic loading affects cell-driven hierarchical fiber formation and maturation, which will help to develop better rehabilitation protocols and engineer stronger replacements.

Statement of significance

Collagen fibers are the primary source of strength and function in tendons and ligaments throughout the body. These fibers have limited regenerate after injury, with repair, and in engineered replacements, reducing treatment options. Cyclic load has been shown to improve fibril level alignment, but its effect at the larger fiber and fascicle length-scale is largely unknown. Here, we demonstrate intermittent cyclic loading increases cell-driven hierarchical fiber formation and tissue mechanics, producing engineered replacements with similar organization and mechanics as immature ACLs. This study provides new insight into how cyclic loading affects cell-driven fiber maturation. A better understanding of how mechanical cues regulate fiber formation will help to develop better engineered replacements and rehabilitation protocols to drive repair after injury.

The effectiveness of tumor treatment using reactive oxygen species as the primary therapeutic medium is hindered by limitations of tumor microenvironment (TME), such as intrinsic hypoxia in photodynamic therapy (PDT) and overproduction of reducing glutathione (GSH) in chemodynamic therapy (CDT). Herein, we fabricate metal-polyphenol self-assembled nanodots (Fe@BDP NDs) guided by second near-infrared (NIR-II) fluorescence imaging. The Fe@BDP NDs are designed for synergistic combination of type-I PDT and CDT-amplified ferroptosis. In a mildly acidic TME, Fe@BDP NDs demonstrate great Fenton activity, leading to the generation of highly toxic hydroxyl radicals from overproduced hydrogen peroxide in tumor cells. Furthermore, Fe@BDP NDs show favorable efficacy in type-I PDT, even in tolerating tumor hypoxia, generating active superoxide anion upon exposure to 808 nm laser irradiation. The significant efficiency in reactive oxygen species (ROS) products results in the oxidation of sensitive polyunsaturated fatty acids, accelerating lethal lipid peroxidation (LPO) bioprocess. Additionally, Fe@BDP NDs illustrate an outstanding capability for GSH depletion, causing the inactivation of glutathione peroxidase 4 and further promoting lethal LPO. The synergistic type-I photodynamic and chemodynamic cytotoxicity effectively trigger irreversible ferroptosis by disrupting the intracellular redox homeostasis. Moreover, Fe@BDP NDs demonstrate charming NIR-II fluorescence imaging capability and effectively accumulated at the tumor site, visualizing the distribution of Fe@BDP NDs and the treatment process. The chemo/photo-dynamic-amplified ferroptotic efficacy of Fe@BDP NDs was evidenced both in vitro and in vivo. This study presents a compelling approach to intensify ferroptosis via visualized CDT and PDT.

Statement of significance

In this study, we detailed the fabrication of metal-polyphenol self-assembled nanodots (Fe@BDP NDs) guided by second near-infrared (NIR-II) fluorescence imaging, aiming to intensify ferroptosis via the synergistic combination of type-I PDT and CDT. In a mildly acidic TME, Fe@BDP NDs exhibited significant Fenton activity, resulting in the generation of highly toxic •OH from overproduced H₂O₂ in tumor cells. Fe@BDP NDs possessed a remarkable capability for GSH depletion, resulting in the inactivation of glutathione peroxidase 4 (GPX4) and further accelerating lethal LPO. This study presented a compelling approach to intensify ferroptosis via visualized CDT and PDT.

The immune system plays an important role in fracture healing, by modulating the pro-inflammatory and anti-inflammatory responses occurring instantly upon injury. An imbalance in these responses can lead to adverse outcomes, such as non-union of fractures. Implants are used to support and stabilize complex fractures. Biodegradable metallic implants offer the potential to avoid a second surgery for implant removal, unlike non-degradable implants. However, considering our dynamic immune system it is important to conduct in-depth studies on the immune response to these implants in living systems. In this study, we investigated the immune response to Mg and Mg-10Gd in vivo in a rat femur fracture model with external fixation. In vivo imaging using liposomal formulations was used to monitor the fluorescence-related inflammation over time. We combine ex vivo methods with our in vivo study to evaluate and understand the systemic and local effects of the implants on the immune response. We observed no significant local or systemic effects in the Mg-10Gd implanted group compared to the SHAM and Mg implanted groups over time. Our findings suggest that Mg-10Gd is a more compatible implant material than Mg, with no adverse effects observed in the early phase of fracture healing during our 4-week study.

Statement of significance

Degradable metallic implants in form of Mg and Mg-10Gd intramedullary pins were assessed in a rat femur fracture model, alongside a non-implanted SHAM group with special respect to the potential to induce an inflammatory response. This pre-clinical study combines innovative non-invasive in vivo imaging techniques associated with multimodal, ex vivo cellular and molecular analytics. The study contributes to the development and evaluation of degradable biometals and their clinical application potential. The study results indicate that Mg-10Gd did not exhibit any significant harmful effects compared to the SHAM and Mg groups.

Biodegradable Zn alloys have significant application potential for hard-tissue implantation devices owing to their suitable degradation behavior and favorable biocompatibility. Nonetheless, pure Zn and its alloys in the as-cast state are mechanically instable and low in strength, which restricts their clinical applicability. Here, we report the exceptional mechanical, corrosion, and biocompatibility properties of hot-extruded Zn-5RE (wt.%, RE = rare earth of Y; or Ho; or Er) alloys intended for use in biodegradable bone substitutes. The microstructural characteristics, mechanical behavior, corrosion resistance, cytocompatibility, osteogenic differentiation, and capacity of osteogenesis in vivo of the Zn-5RE alloys are comparatively investigated. The Zn-5Y alloy demonstrates the best tensile properties, encompassing a 138 MPa tensile yield strength, a 302 MPa ultimate tensile strength, and 63% elongation, while the Zn-5Ho alloy shows the highest compression yield strength of 260 MPa and Vickers hardness of 104 HV. The Zn-5Er alloy shows a 126 MPa tensile yield strength, a 279 MPa ultimate tensile strength, 52% elongation, a 196 MPa compression yield strength, and a 101 HV Vickers microhardness. Further, the Zn-5Er alloy has a 130 µm per year corrosion rate in electrochemical tests and a 26 µm per year degradation rate in immersion tests, which is the lowest among the tested alloys. It also has the best in vitro osteogenic differentiation ability and capacity for osteogenesis and osteointegration in vivo after implantation in rat femurs among the Zn-5RE alloys, indicating promising potential in load-bearing biodegradable internal bone-fixation applications.

Statement of significance

This work reports the exceptional mechanical, corrosion, and biocompatibility properties of hot-extruded (HE) Zn-5 wt.%–rare earth (Zn-5RE) alloys using single yttrium (Y), holmium (Ho), and erbium (Er) alloying for biodegradable bone-implant applications. Our findings demonstrate that the HE Zn-5Er alloy showed σ_uts of 279 MPa, tensile yield strength of 126 MPa, elongation of 51.6%, compression yield strength of 196 MPa, and microhardness of 101.2 HV. Further, HE Zn-5Er showed the lowest electrochemical corrosion rate of 130 µm/y and lowest degradation rate of 26 µm/y, and the highest in vitro osteogenic differentiation ability, in vivo osteogenesis, and osteointegration ability after implantation in rat femurs among the Zn-5RE alloys, indicating promising potential in load-bearing biodegradable internal bone-fixation applications.