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    Weak magnetic fields alter stem cell-mediated growth. Van Huizen Alanna V,Morton Jacob M,Kinsey Luke J,Von Kannon Donald G,Saad Marwa A,Birkholz Taylor R,Czajka Jordan M,Cyrus Julian,Barnes Frank S,Beane Wendy S Science advances Biological systems are constantly exposed to electromagnetic fields (EMFs) in the form of natural geomagnetic fields and EMFs emitted from technology. While strong magnetic fields are known to change chemical reaction rates and free radical concentrations, the debate remains about whether static weak magnetic fields (WMFs; <1 mT) also produce biological effects. Using the planarian regeneration model, we show that WMFs altered stem cell proliferation and subsequent differentiation via changes in reactive oxygen species (ROS) accumulation and downstream heat shock protein 70 (Hsp70) expression. These data reveal that on the basis of field strength, WMF exposure can increase or decrease new tissue formation in vivo, suggesting WMFs as a potential therapeutic tool to manipulate mitotic activity. 10.1126/sciadv.aau7201
    Dextran-coated iron oxide nanoparticle-improved therapeutic effects of human mesenchymal stem cells in a mouse model of Parkinson's disease. Chung Tsai-Hua,Hsu Szu-Chun,Wu Shu-Hui,Hsiao Jong-Kai,Lin Chih-Peng,Yao Ming,Huang Dong-Ming Nanoscale Parkinson's disease (PD) is a prevalent neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons. With their migration capacity toward the sites of diseased DA neurons in the PD brain, mesenchymal stem cells (MSCs) have the potential to differentiate to DA neurons for the replacement of damaged neurons and to secrete neurotrophic factors for the protection and regeneration of diseased DA neurons; therefore MSCs show promise for the treatment of PD. In this study, for the first time, we demonstrate that dextran-coated iron oxide nanoparticles (Dex-IO NPs) can improve the therapeutic efficacy of human MSCs (hMSCs) in a mouse model of PD induced by a local injection of 6-hydroxydopamine (6-OHDA). In situ examinations not only show that Dex-IO NPs can improve the rescue effect of hMSCs on the loss of host DA neurons but also demonstrate that Dex-IO NPs can promote the migration capacity of hMSCs toward lesioned DA neurons and induce the differentiation of hMSCs to DA-like neurons at the diseased sites. We prove that in vitro Dex-IO NPs can enhance the migration of hMSCs toward 6-OHDA-damaged SH-SY5Y-derived DA-like cells, induce hMSCs to differentiate to DA-like neurons in the conditioned media derived from 6-OHDA-damaged SH-SY5Y-derived DA-like cells and promote the protection/regeneration effects of hMSCs on 6-OHDA-damaged SH-SY5Y-derived DA-like cells. We confirm the potential of MSCs for cell-based therapy for PD. Dex-IO NPs can be used as a tool to accelerate and optimize MSC therapeutics for PD applicable clinically. 10.1039/c7nr06976f
    Non-invasive monitoring of hydrogel degradation and cartilage regeneration by multiparametric MR imaging. Chen Zelong,Yan Chenggong,Yan Shina,Liu Qin,Hou Meirong,Xu Yikai,Guo Rui Theranostics Numerous biodegradable hydrogels for cartilage regeneration have been widely used in the field of tissue engineering. However, to non-invasively monitor hydrogel degradation and efficiently evaluate cartilage restoration in situ is still challenging. A ultrasmall superparamagnetic iron oxide (USPIO)-labeled cellulose nanocrystal (CNC)/silk fibroin (SF)-blended hydrogel system was developed to monitor hydrogel degradation during cartilage regeneration. The physicochemical characterization and biocompatibility of the hydrogel were evaluated . The hydrogel degradation and cartilage regeneration of different implants were assessed using multiparametric magnetic resonance imaging (MRI) and further confirmed by histological analysis in a rabbit cartilage defect model for 3 months. USPIO-labeled hydrogels showed sufficient MR contrast enhancement and retained stability without loss of the relaxation rate. Neither the mechanical properties of the hydrogels nor the proliferation of bone-marrow mesenchymal stem cells (BMSCs) were affected by USPIO labeling . CNC/SF hydrogels with BMSCs degraded more quickly than the acellular hydrogels as reflected by the MR relaxation rate trends . The morphology of neocartilage was noninvasively visualized by the three-dimensional water-selective cartilage MRI scan sequence, and the cartilage repair was further demonstrated by macroscopic and histological observations. This USPIO-labeled CNC/SF hydrogel system provides a new perspective on image-guided tissue engineering for cartilage regeneration. 10.7150/thno.22514
    Magnetically actuated mechanical stimuli on FeO/mineralized collagen coatings to enhance osteogenic differentiation of the MC3T3-E1 cells. Zhuang Junjun,Lin Suya,Dong Lingqing,Cheng Kui,Weng Wenjian Acta biomaterialia Mechanical stimuli at the bone-implant interface are considered to activate the mechanotransduction pathway of the cell to improve the initial osseointegration establishment and to guarantee clinical success of the implant. However, control of the mechanical stimuli at the bone-implant interface still remains a challenge. In this study, we have designed a strategy of a magnetically responsive coating on which the mechanical stimuli is controlled because of coating deformation under static magnetic field (SMF). The iron oxide nanoparticle/mineralized collagen (IOP-MC) coatings were electrochemically codeposited on titanium substrates in different quantities of IOPs and distributions; the resulting coatings were verified to possess swelling behavior with flexibility same as that of hydrogel. The relative quantity of IOP to collagen and the IOP distribution in the coatings were demonstrated to play a critical role in mediating cell behavior. The cells present on the outer layer of the distributed IOP-MC (O-IOP-MC) coating with a mass ratio of 0.67 revealed the most distinct osteogenic differentiation activity being promoted, which could be attributed to the maximized mechanical stimuli with exposure to SMF. Furthermore, the enhanced osteogenic differentiation of the stimulated MC3T3-E1 cells originated from magnetically actuated mechanotransduction signaling pathway, embodying the upregulated expression of osteogenic-related and mechanotransduction-related genes. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone-implant interface and thus to promote osseointegration. STATEMENT OF SIGNIFICANCE:The magnetically actuated coating is designed to produce mechanical stimuli to cells for promoting osteogenic differentiation based on the coating deformation. Iron oxide nanoparticles (IOPs) were incorporated into the mineralized collagen coatings (MC) forming the composite coatings (IOP-MC) with spatially distributed IOPs, and the IOP-MC coatings with outer distributed IOPs (O-IOPs-MC) shows the maximized mechanical stimuli to cells with enhanced osteogenic differentiation under static magnetic field. The upregulated expression of the associated genes reveals that the enabled mechanotransduction signaling pathway is responsible for the promoted cellular osteogenic differentiation. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone-implant interface to promote osseointegration. 10.1016/j.actbio.2018.03.009
    Temperature-Responsive Magnetic Nanoparticles for Enabling Affinity Separation of Extracellular Vesicles. Jauregui Ramon,Srinivasan Selvi,Vojtech Lucia N,Gammill Hilary S,Chiu Daniel T,Hladik Florian,Stayton Patrick S,Lai James J ACS applied materials & interfaces Small magnetic nanoparticles that have surfaces decorated with stimuli-responsive polymers can be reversibly aggregated via a stimulus, such as temperature, to enable efficient and rapid biomarker separation. To fully realize the potential of these particles, the synthesis needs to be highly reproducible and scalable to large quantity. We have developed a new synthesis for temperature-responsive magnetic nanoparticles via an in situ co-precipitation process of Fe/Fe salts at room temperature with poly(acrylic acid)- block-poly( N-isopropylacrylamide) diblock co-polymer template, synthesized via the reversible addition-fragmentation chain-transfer polymerization method. These particles were 56% polymer by weight with a 6.5:1 Fe/COOH ratio and demonstrated remarkable stability over a 2 month period. The hydrodynamic diameter remained constant at ∼28 nm with a consistent transition temperature of 34 °C, and the magnetic particle separation efficiency at 40 °C was ≥95% over the 2 month span. These properties were maintained for all large-scale synthesis batches. To demonstrate the practical utility of the stimuli-responsive magnetic nanoparticles, the particles were incorporated into a temperature-responsive binary reagent system and efficiently separated a model protein biomarker (mouse IgG) as well as purified extracellular vesicles derived from a human biofluid, seminal plasma. The ease of using these particles will prove beneficial for various biomedical applications. 10.1021/acsami.8b09751
    Remote Manipulation of Ligand Nano-Oscillations Regulates Adhesion and Polarization of Macrophages in Vivo. Kang Heemin,Kim Sungkyu,Wong Dexter Siu Hong,Jung Hee Joon,Lin Sien,Zou Kaijie,Li Rui,Li Gang,Dravid Vinayak P,Bian Liming Nano letters Macrophages play crucial roles in various immune-related responses, such as host defense, wound healing, disease progression, and tissue regeneration. Macrophages perform distinct and dynamic functions in vivo, depending on their polarization states, such as the pro-inflammatory M1 phenotype and pro-healing M2 phenotype. Remote manipulation of the adhesion of host macrophages to the implants and their subsequent polarization in vivo can be an attractive strategy to control macrophage polarization-specific functions but has rarely been achieved. In this study, we grafted RGD ligand-bearing superparamagnetic iron oxide nanoparticles (SPIONs) to a planar matrix via a long flexible linker. We characterized the nanoscale motion of the RGD-bearing SPIONs grafted to the matrix, in real time by in situ magnetic scanning transmission electron microscopy (STEM) and in situ atomic force microscopy. The magnetic field was applied at various oscillation frequencies to manipulate the frequency-dependent ligand nano-oscillation speeds of the RGD-bearing SPIONs. We demonstrate that a low oscillation frequency of the magnetic field stimulated the adhesion and M2 polarization of macrophages, whereas a high oscillation frequency suppressed the adhesion of macrophages but promoted their M1 polarization, both in vitro and in vivo. Macrophage adhesion was also temporally regulated by switching between the low and high frequencies of the oscillating magnetic field. To the best of our knowledge, this is the first demonstration of the remote manipulation of the adhesion and polarization phenotype of macrophages, both in vitro and in vivo. Our system offers the promising potential to manipulate host immune responses to implanted biomaterials, including inflammation or tissue reparative processes, by regulating macrophage adhesion and polarization. 10.1021/acs.nanolett.7b03405
    Magnetically Actuated Heterogeneous Microcapsule-Robot for the Construction of 3D Bioartificial Architectures. Liu Yang,Li Gen,Lu Haojian,Yang Yuanyuan,Liu Zeyang,Shang Wanfeng,Shen Yajing ACS applied materials & interfaces Core-shell microcapsules as one type of the most attractive carriers and reactors have been widely applied in the fields of drug screening and tissue engineering owing to their excellent biocompatibility and semi-permeability. Yet, the spatial organization of microcapsules with specific shapes into three-dimensional (3D) ordered architectures still remains a big challenge. Here, we present a method to assemble shape-controllable core-shell microcapsules using an untethered magnetic microcapsule-robot. The microcapsule-robot with the shape-matching design can grab the building components tightly during the transportation and assembly processes. The core-shell feature of the microcapsule effectively prevents the magnetic nanoparticles from interacting with bioactive materials. The assembly results of cell-loaded heterogeneous microcapsules reveal that this strategy not only allows the magnetic microcapsule-robot to work in different workspaces in vitro for the creation of 3D constructions but also offers a noninvasive and dynamical manipulation platform by remotely controlling the position and orientation of the soft and liquid-like microcapsule components individually. 10.1021/acsami.9b05517
    Magnetotherapy: The quest for tendon regeneration. Pesqueira Tamagno,Costa-Almeida Raquel,Gomes Manuela E Journal of cellular physiology Tendons are mechanosensitive tissues that connect and transmit the forces generated by muscles to bones by allowing the conversion of mechanical input into biochemical signals. These physical forces perform the fundamental work of preserving tendon homeostasis assuring body movements. However, overloading causes tissue injuries, which leads us to the field of tendon regeneration. Recently published reviews have broadly shown the use of biomaterials and different strategies to attain tendon regeneration. In this review, our focus is the use of magnetic fields as an alternative therapy, which has demonstrated clinical relevance in tendon medicine because of their ability to modulate cell fate. Yet the underlying cellular and molecular mechanisms still need to be elucidated. While providing a brief outlook about specific signalling pathways and intracellular messengers as framework in play by tendon cells, application of magnetic fields as a subcategory of physical forces is explored, opening up a compelling avenue to enhance tendon regeneration. We outline here useful insights on the effects of magnetic fields both at in vitro and in vivo levels, particularly on the expression of tendon genes and inflammatory cytokines, ultimately involved in tendon regeneration. Subsequently, the potential of using magnetically responsive biomaterials in tendon tissue engineering is highlighted and future directions in magnetotherapy are discussed. 10.1002/jcp.26637
    Chitosan modified FeO/KGN self-assembled nanoprobes for osteochondral MR diagnose and regeneration. Hong Yuping,Han Yaguang,Wu Jun,Zhao Xinxin,Cheng Jin,Gao Guo,Qian Qirong,Wang Xiuying,Cai Weidong,Zreiqat Hala,Feng Dagan,Xu Jianrong,Cui Daxiang Theranostics Chondral and osteochondral defects caused by trauma or pathological changes, commonly progress into total joint degradation, even resulting in disability. The cartilage restoration is a great challenge because of its avascularity and limited proliferative ability. Additionally, precise diagnosis using non-invasive detection techniques is challenging, which increases problems associated with chondral disease treatment. To achieve a theranostic goal, we used an integrated strategy that relies on exploiting a multifunctional nanoprobe based on chitosan-modified Fe3O4 nanoparticles, which spontaneously self-assemble with the oppositely charged small molecule growth factor, kartogenin (KGN). This nanoprobe was used to obtain distinctively brighter T-weighted magnetic resonance (MR) imaging, allowing its use as a positive contrast agent, and could be applied to obtain accurate diagnosis and osteochondral regeneration therapy. This nanoprobe was first investigated using adipose tissue-derived stem cells (ADSCs), and was found to be a novel positive contrast agent that also plays a significant role in stimulating ADSCs differentiation into chondrocytes. This self-assembled probe was not only biocompatible both and , contributing to cellular internalization, but was also used to successfully make distinction of normal/damaged tissue in T-weighted MR imaging. This novel combination was systematically shown to be biosafe via the decrement of apparent MR signals and elimination of ferroferric oxide over a 12-week regeneration period. Here, we established a novel method for osteochondral disease diagnosis and reconstruction. Using the FeO-CS/KGN nanoprobe, it is easy to distinguish the defect position, and it could act as a tool for dynamic observation as well as a stem cell-based therapy for directionally chondral differentiation. 10.7150/thno.43569
    Magnetically Actuated Manipulation and Its Applications for Cartilage Defects: Characteristics and Advanced Therapeutic Strategies. Zhang Chi,Cai You-Zhi,Lin Xiang-Jin,Wang Yue Frontiers in cell and developmental biology For the fact that articular cartilage is a highly organized and avascular tissue, cartilage defects are limited to spontaneously heal, which would subsequently progress to osteoarthritis. Many methods have been developed to enhance the ability for cartilage regeneration, among which magnetically actuated manipulation has attracted interests due to its biocompatibility and non-invasive manipulation. Magnetically actuated manipulation that can be achieved by introducing magnetic nanoparticles and magnetic field. This review summarizes the cutting-edge research on the chondrogenic enhancements via magnetically actuated manipulation, including cell labeling, cell targeting, cell assembly, magnetic seeding and tissue engineering strategies. 10.3389/fcell.2020.00526
    Fluorescent magnetic nanoparticles for modulating the level of intracellular Ca in motoneurons. Fedorenko Svetlana,Stepanov Alexey,Sibgatullina Gusel,Samigullin Dmitry,Mukhitov Alexander,Petrov Konstantin,Mendes Rafael,Rümmeli Mark,Giebeler Lars,Weise Bruno,Gemming Thomas,Nizameev Irek,Kholin Kirill,Mustafina Asiya Nanoscale This report introduces both synthesis and in vitro biological behaviour of dual magnetic-fluorescent silica nanoparticles. The amino group-decoration of 78 nm sized silica nanoparticles enables their efficient internalization into motoneurons, which is visualized by the red fluorescence arising from [Ru(dipy)3]2+ complexes encapsulated into a silica matrix. The internalized nanoparticles are predominantly located in the cell cytoplasm as revealed by confocal microscopy imaging. The magnetic function of the nanoparticles resulted from the incorporation of 17 nm sized superparamagnetic iron oxide cores into the silica matrix, enabling their responsivity to magnetic fields. Fluorescence analysis revealed the "on-off" switching of Ca2+ influx under the application and further removal of the permanent magnetic field. This result for the first time highlights the movement of the nanoparticles within the cell cytoplasm in the permanent magnetic field as a promising tool to enhance the neuronal activity of motoneurons. 10.1039/c9nr05071j
    Exploiting shape-selected iron oxide nanoparticles for the destruction of robust bacterial biofilms - active transport of biocides via surface charge and magnetic field control. Nickel Rachel,Kazemian Mohammad Reza,Wroczynskyj Yaroslav,Liu Song,van Lierop Johan Nanoscale Biofilms that form on reusable medical devices are a cause of hospital acquired infections; however, sanitization of biofilms is a challenge due to their dense extracellular matrix. This work presents an innovative strategy using biocide-loaded iron oxide nanoparticles transported within the matrix via a magnetic field to eradicate biofilms. Results show that the active delivery of the biocide to underlying cells effectively penetrates the extracellular matrix and inactivates Methicillin resistant Staphylococcus aureus (MRSA) biofilms (responsible for several difficult-to-treat infections in humans). To optimize this treatment, the loading of spherical, cubic and tetrapod-shaped nanoparticles with a model biocide, CTAB (cetyltrimethylammonium bromide) was studied. Biocide loading was determined to be dependent on the shapes' surface charge density instead of the surface area, meaning that biocide attachment is greater for nanoparticles with sharp edges (e.g. cubes and tetrapods). These results can be used to optimize treatment efficacy, and help further understanding of biofilm and nanoparticle surface zeta potentials, and the nanoparticle-biofilm interactions. 10.1039/c9nr09484a
    Applications of Iron Oxide-Based Magnetic Nanoparticles in the Diagnosis and Treatment of Bacterial Infections. Xu Chen,Akakuru Ozioma Udochukwu,Zheng Jianjun,Wu Aiguo Frontiers in bioengineering and biotechnology Diseases caused by bacterial infections, especially drug-resistant bacteria have seriously threatened human health throughout the world. It has been predicted that antimicrobial resistance alone will cause 10 million deaths per year and that early diagnosis and therapy will efficiently decrease the mortality rate caused by bacterial infections. Considering this severity, it is urgent to develop effective methods for the early detection, prevention and treatment of these infections. Until now, numerous efforts based on nanoparticles have been made to detect and kill pathogenic bacteria. Iron oxide-based magnetic nanoparticles (MNPs), as potential platforms for bacteria detection and therapy, have drawn great attention owing to their magnetic property. These MNPs have also been broadly used as bioimaging contrast agents and drug delivery and magnetic hyperthermia agents to diagnose and treat bacterial infections. This review therefore overviews the recent progress on MNPs for bacterial detection and therapy, including bacterial separation and enrichment , bacterial infection imaging , and their therapeutic activities on pathogenic bacteria. Furthermore, some bacterial-specific targeting agents, used to selectively target the pathogenic bacteria, are also introduced. In addition, the challenges and future perspective of MNPs for bacterial diagnosis and therapy are given at the end of this review. It is expected that this review will provide a better understanding toward the applications of MNPs in the detection and therapy of bacterial infections. 10.3389/fbioe.2019.00141