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  • Glucocorticoid-loaded liposomes induce a pro-resolution phenotype in human primary macrophages to support chronic wound healing
    Biomaterials (IF 8.806) Pub Date : 2018-04-05
    Anne Gauthier, Andreas Fisch, Klaus Seuwen, Birgit Baumgarten, Heinz Ruffner, Alexandra Aebi, Martin Rausch, Fabian Kiessling, Matthias Bartneck, Ralf Weiskirchen, Frank Tacke, Gert Storm, Twan Lammers, Marie-Gabrielle Ludwig

    Glucocorticoids are well established anti-inflammatory agents, however, their use to treat chronic inflammatory diseases is limited due to a number of serious side effects. For example, long-term local treatment of chronic wounds with glucocorticoids is prohibited by dysregulation of keratinocyte and fibroblast function, leading to skin thinning. Here, we developed and tested liposome formulations for local delivery of dexamethasone to primary human macrophages, to drive an anti-inflammatory/pro-resolution phenotype appropriate for tissue repair. The liposomes were loaded with the pro-drug dexamethasone-phosphate and surface-modified with either polyethylene glycol or phosphatidylserine. The latter was used to mimic phosphatidylserine-harboring apoptotic cells, which are substrates for efferocytosis, an essential pro-resolution function. Both formulations induced a dexamethasone-like gene expression signature in macrophages, decreased IL6 and TNFα release, increased secretion of thrombospondin 1 and increased efferocytosis activity. Phosphatidylserine-modified liposomes exhibited a faster uptake, a higher potency and a more robust phenotype induction than polyethylene glycol-modified liposomes. Fibroblast and keratinocyte cell cultures as well as a 3D skin equivalent model showed that liposomes applied locally to wounds are preferentially phagocytosed by macrophages. These findings indicate that liposomes, in particular upon shell modification with phosphatidylserine, promote dexamethasone delivery to macrophages and induce a phenotype suitable to support chronic wound healing.

    更新日期:2018-07-14
  • Advances in transformable drug delivery systems
    Biomaterials (IF 8.806) Pub Date : 2018-04-05
    Quanyin Hu, Qian Chen, Zhen Gu

    These years, transformable drug delivery systems (DDSs), which hold the capability of changing formulation morphology and subsequent functionality at the desired disease site, have shown great promise in control of spatio-temporal drug delivery/release manner and enhanced treatment efficacy. Equipped with controllability and design flexibility, the transformable DDSs are being increasingly pursued for the development of precision drug delivery platforms for biomedical applications. In this review, we describe the recently developed intracelluarly and extracellularly transformable DDSs, especially associated with assembly or disassociation of the original formulation units, for achieving various functionalities, including prolonged retention time, inhibited endocytosis and enhanced cytotoxicity. Furthermore, the different stimuli, such as pH, enzyme, light, temperature, redox and mechanical force that trigger the transformation process are also introduced. The future outlook and challenges are discussed in the end.

    更新日期:2018-07-14
  • Injectable polypeptide hydrogels via methionine modification for neural stem cell delivery
    Biomaterials (IF 8.806) Pub Date : 2018-04-05
    A.L. Wollenberg, T.M. O'Shea, J.H. Kim, A. Czechanski, L.G. Reinholdt, M.V. Sofroniew, T.J. Deming

    Injectable hydrogels with tunable physiochemical and biological properties are potential tools for improving neural stem/progenitor cell (NSPC) transplantation to treat central nervous system (CNS) injury and disease. Here, we developed injectable diblock copolypeptide hydrogels (DCH) for NSPC transplantation that contain hydrophilic segments of modified l-methionine (Met). Multiple Met-based DCH were fabricated by post-polymerization modification of Met to various functional derivatives, and incorporation of different amino acid comonomers into hydrophilic segments. Met-based DCH assembled into self-healing hydrogels with concentration and composition dependent mechanical properties. Mechanical properties of non-ionic Met-sulfoxide formulations (DCHMO) were stable across diverse aqueous media while cationic formulations showed salt ion dependent stiffness reduction. Murine NSPC survival in DCHMO was equivalent to that of standard culture conditions, and sulfoxide functionality imparted cell non-fouling character. Within serum rich environments in vitro, DCHMO was superior at preserving NSPC stemness and multipotency compared to cell adhesive materials. NSPC in DCHMO injected into uninjured forebrain remained local and, after 4 weeks, exhibited an immature astroglial phenotype that integrated with host neural tissue and acted as cellular substrates that supported growth of host-derived axons. These findings demonstrate that Met-based DCH are suitable vehicles for further study of NSPC transplantation in CNS injury and disease models.

    更新日期:2018-07-14
  • Degradation rate affords a dynamic cue to regulate stem cells beyond varied matrix stiffness
    Biomaterials (IF 8.806) Pub Date : 2018-04-12
    Yuanmeng Peng, Qiongjie Liu, Tianlei He, Kai Ye, Xiang Yao, Jiandong Ding

    While various static cues such as matrix stiffness have been known to regulate stem cell differentiation, it is unclear whether or not dynamic cues such as degradation rate along with the change of material chemistry can influence cell behaviors beyond simple integration of static cues such as decreased matrix stiffness. The present research is aimed at examining effects of degradation rates on adhesion and differentiation of mesenchymal stem cells (MSCs) in vitro on well-defined synthetic hydrogel surfaces. Therefore, we synthesized macromers by extending both ends of poly(ethylene glycol) (PEG) with oligo(lactic acid) and then acryloyl, and the corresponding hydrogels that were obtained after photopolymerization of the macromers were biodegradable. Combining the unique techniques of block copolymer micelle nanolithography with transfer lithography, we prepared a nanoarray of cell-adhesive arginine-glycine-aspartate peptides on this nonfouling biodegradable hydrogel. The biodegradation is caused by hydrolysis of the ester bonds, and different degradation rates in the cell culture medium were achieved by different stages of accelerated pre-hydrolysis in an acidic medium. For the following cell culture and induction, both the matrix stiffness and degradation rate varied among the examined groups. While adipogenic differentiation of MSCs can be understood by the lowered stiffness, the osteogenic differentiation was contradictory with common sense because we found enhanced osteogenesis on soft hydrogels. Higher degradation rates were suggested to account for this interesting phenomenon in the sole osteogenic/adipogenic induction and even more complicated trends in the co-induction. Hence, the degradation rate is a dynamic cue influencing cell behaviors, which should be paid attention to for degradable biomaterials.

    更新日期:2018-07-14
  • A targeting theranostics nanomedicine as an alternative approach for hyperthermia perfusion
    Biomaterials (IF 8.806) Pub Date : 2018-04-12
    Tao Sun, Guangping Zhang, Qingbing Wang, Qinjun Chen, Xinli Chen, Yifei Lu, Lisha Liu, Yu Zhang, Xi He, Chunhui Ruan, Yujie Zhang, Qin Guo, Chen Jiang

    Real-time monitoring drug-release is often regarded crucial in theranostics nanomedicine design, since it provides precise establishment of spatio-temporal activation of the drug-release in vitro and in vivo. A symmetrical self-immolative drug-dye conjugation (DDC) prodrug is developed in this study with disulfide bond as the trigger. The prodrug can be escorted by targeting PEG-PLGA micelles and hereby accumulated in the tumor by both active and passive targeting effect. Glutathione (GSH) with higher concentration in the tumor microenvironment can readily cleave the disulfide bond to initiate a subsequent decomposition of DDC, where the drug and dye can be released simultaneously in a strict one-to-one mode. Upon the disintegration, the “Turned-On” probe can emit near-infrared (NIR) fluorescence, with the aim of providing accurate and real-time information for the prodrugs' activation and biodistribution in vivo in a non-invasive way. Furthermore, the released dye can meanwhile act as a photothermic sensitizer, which can in-situ assist a deep penetration for the released drug in the tumor tissue with enhanced therapeutic efficiency. This “babysitting” strategy provides new reference for designing versatile theranostic nanomedicines for preclinical evaluations and an alternative approach for hyperthermia perfusion in clinic.

    更新日期:2018-07-14
  • Dendritic peptide bolaamphiphiles for siRNA delivery to primary adipocytes
    Biomaterials (IF 8.806) Pub Date : 2018-04-16
    Alexander C. Eldredge, Mark E. Johnson, Yang Cao, Lin Zhang, Can Zhao, Zhengxia Liu, Qin Yang, Zhibin Guan

    Obesity is a major risk factor for diabetes, heart disease and other health problems. Adipose tissue plays a central role in the development of obesity and obesity-associated diseases. Gene therapy targeting adipose tissue may provide a promising strategy for obesity treatment. However, nucleic acid delivery to adipose tissue or even cultured adipocytes is challenging due to low delivery efficacy and high toxicity of the current cationic lipid based delivery systems, or monoamphiphiles. Herein, we report using dendritic peptide bolaamphiphiles (bolas) to deliver siRNA to primary adipocytes and hepatocytes. The bola consists of two l-Lysine dendrons connected to a fluorocarbon core through disulfide linkages. The Lysine dendrons are functionalized with l-histidine and l-tryptophan to promote endosomal escape and cellular uptake. The bola exhibited over 70% knockdown of GAPDH gene in both primary adipocytes and hepatocytes. Importantly, different from Lipofectamine that significantly reduced genes involved in lipolysis, lipogenesis, fatty acid oxidation and ketogenesis, the bolas had little to no effect on these genes. These results demonstrate the bola as a promising new vector for clinical and experimental applications for delivery of siRNA to metabolic organs.

    更新日期:2018-07-14
  • Bioinspired supramolecular engineering of self-assembling immunofibers for high affinity binding of immunoglobulin G
    Biomaterials (IF 8.806) Pub Date : 2018-04-16
    Yi Li, Lye Lin Lock, Yuzhu Wang, Shih-Hao Ou, David Stern, Arne Schön, Ernesto Freire, Xuankuo Xu, Sanchayita Ghose, Zheng Jian Li, Honggang Cui

    Many one-dimensional (1D) nanostructures are constructed by self-assembly of peptides or peptide conjugates containing a short β-sheet sequence as the core building motif essential for the intermolecular hydrogen bonding that promotes directional, anisotropic growth of the resultant assemblies. While this molecular engineering strategy has led to the successful production of a plethora of bioactive filamentous β-sheet assemblies for interfacing with biomolecules and cells, concerns associated with effective presentation of α-helical epitopes and their function preservation have yet to be resolved. In this context, we report on the direct conjugation of the protein A mimicking peptide Z33, a motif containing two α-helices, to linear hydrocarbons to create self-assembling immuno-amphiphiles (IAs). Our results suggest that the resulting amphiphilic peptides can, despite lacking the essential β-sheet segment, effectively associate under physiological conditions into supramolecular immunofibers (IFs) while preserving their native α-helical conformation. Isothermal titration calorimetry (ITC) measurements confirmed that these self-assembling immunofibers can bind to the human immunoglobulin G class 1 (IgG1) with high specificity at pH 7.4, but with significantly weakened binding at pH 2.8. We further demonstrated the accessibility of Z33 ligand in the immunofibers using transmission electron microscopy (TEM) and confocal imaging. We believe these results shed important light into the supramolecular engineering of α-helical peptides into filamentous assemblies that may possess an important potential for antibody isolation.

    更新日期:2018-07-14
  • Near-infrared light-controlled regulation of intracellular calcium to modulate macrophage polarization
    Biomaterials (IF 8.806) Pub Date : 2018-04-21
    Heemin Kang, Kunyu Zhang, Dexter Siu Hong Wong, Fengxuan Han, Bin Li, Liming Bian

    Macrophages are multifunctional immune cells with diverse physiological functions such as fighting against infection, influencing progression of pathologies, maintaining homeostasis, and regenerating tissues. Macrophages can be induced to adopt distinct polarized phenotypes, such as classically activated pro-inflammatory (M1) phenotypes or alternatively activated anti-inflammatory and pro-healing (M2), to execute diverse and dynamic immune functions. However, unbalanced polarizations of macrophage can lead to various pathologies, such as atherosclerosis, obesity, tumor, and asthma. Thus, the capability to remotely control macrophage phenotypes is important to the success of treating many pathological conditions involving macrophages. In this study, we developed an upconversion nanoparticle (UCNP)-based photoresponsive nanocarrier for near-infrared (NIR) light-mediated control of intracellular calcium levels to regulate macrophage polarization. UCNP was coated with mesoporous silica (UCNP@mSiO2), into which loaded calcium regulators that can either supply or deplete calcium ions. UCNP@mSiO2 was chemically modified through serial coupling of photocleavable linker and Arg-Gly-Asp (RGD) peptide-bearing molecular cap via cyclodextrin-adamantine host-guest complexation. The RGD-bearing cap functioned as the photolabile gating structure to control the release of calcium regulators and facilitated the cellular uptake of UCNP@mSiO2 nanocarrier. The upconverted UV light emission from the UCNP@mSiO2 under NIR light excitation triggered the cleavage of cap and intracellular release of calcium regulators, thereby allowing temporal regulation on the intracellular calcium levels. Application of NIR light through skin tissue promoted M1 or M2 polarization of macrophages, by elevating or depleting intracellular calcium levels, respectively. To the best of our knowledge, this is the first demonstration of NIR light-mediated remote control on macrophage polarization. This photoresponsive nanocarrier offers the potential to remotely manipulate in vivo immune functions, such as inflammation or tissue regeneration, via NIR light-controlled macrophage polarization.

    更新日期:2018-07-14
  • 3D biomaterial matrix to support long term, full thickness, immuno-competent human skin equivalents with nervous system components
    Biomaterials (IF 8.806) Pub Date : 2018-04-24
    Sarah E. Lightfoot Vidal, Kasey A. Tamamoto, Hanh Nguyen, Rosalyn D. Abbott, Dana M. Cairns, David L. Kaplan

    Current commercially available human skin equivalents (HSEs) are used for relatively short term studies (∼1 week) due in part to the time-dependent contraction of the collagen gel-based matrix and the limited cell types and skin tissue components utilized. In contrast, here we describe a new matrix consisting of a silk-collagen composite system that provides long term, stable cultivation with reduced contraction and degradation over time. This matrix supports full thickness skin equivalents which include nerves. The unique silk-collagen composite system preserves cell-binding domains of collagen while maintaining the stability and mechanics of the skin system for long-term culture with silk. The utility of this new composite protein-based biomaterial was demonstrated by bioengineering full thickness human skin systems using primary cells, including nerves and immune cells to establish an HSE with a neuro-immuno-cutaneous system. The HSEs with neurons and hypodermis, compared to in vitro skin-only HSEs controls, demonstrated higher secretion of pro-inflammatory cytokines. Proteomics analysis confirmed the presence of several proteins associated with inflammation across all sample groups, but HSEs with neurons had the highest amount of detected protein due to the complexity of the model. This improved, in vitro full thickness HSE model system utilizes cross-linked silk-collagen as the biomaterial and allows reduced reliance on animal models and provides a new in vitro tissue system for the assessment of chronic responses related to skin diseases and drug discovery.

    更新日期:2018-07-14
  • Site-selective protein modification with polymers for advanced biomedical applications
    Biomaterials (IF 8.806) Pub Date : 2018-04-25
    Xinyu Liu, Jiawei Sun, Weiping Gao

    Protein modification with polymers has led to intriguing and new types of bioconjugates. They combine the tunable physicochemical properties of the polymers with the specific biological activity of the proteins. These unique attributes of protein-polymer conjugates render them interesting and useful in biomedicine. However, the application potential of protein-polymer conjugates is limited by the mostly non-selective protein modification with polymers due to the lack of site-selective protein modification technology. Recent advances in site-selective protein modification and controlled polymerization have made it possible to modify proteins with polymers in a site-selective and controlled manner. In this review, recent advances in site-selective protein modification with polymers are depicted in five parts as follows: site-selective protein modification; site-selective polymer modification; site-selective in situ growth of polymers from proteins; biosafety of polymers; and biomedical applications. Site-selective protein-polymer conjugates are superior to non-selective ones in precise control of structures and functions, which makes them more interesting for advanced biomedical applications ranging from protein delivery to diagnostics. Particularly, important examples in this regard are highlighted in this review. Additionally, major challenges and future directions in this emerging research field are also discussed in the perspective section of this review.

    更新日期:2018-07-14
  • 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes
    Biomaterials (IF 8.806) Pub Date : 2018-07-12
    Marco Campisi, Yoojin Shin, Tatsuya Osaki, Cynthia Hajal, Valeria Chiono, Roger D. Kamm

    The blood-brain barrier (BBB) regulates molecular trafficking, protects against pathogens, and prevents efficient drug delivery to the brain. Models to date failed to reproduce the human anatomical complexity of brain barriers, contributing to misleading results in clinical trials. To overcome these limitations, a novel 3-dimensional BBB microvascular network model was developed via vasculogenesis to accurately replicate the in vivo neurovascular organization. This microfluidic system includes human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled vascular networks in fibrin gel. Gene expression of membrane transporters, tight junction and extracellular matrix proteins, was consistent with computational analysis of geometrical structures and quantitative immunocytochemistry, indicating BBB maturation and microenvironment remodelling. Confocal microscopy validated microvessel-pericyte/astrocyte dynamic contact-interactions. The BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models, and similar to in vivo measurements in rat brain. This robust and physiologically relevant BBB microvascular model offers an innovative and valuable platform for drug discovery to predict neuro-therapeutic transport efficacy in pre-clinical applications as well as recapitulate patient-specific and pathological neurovascular functions in neurodegenerative disease.

    更新日期:2018-07-14
  • Fibronectin promotes elastin deposition, elasticity and mechanical strength in cellularised collagen-based scaffolds
    Biomaterials (IF 8.806) Pub Date : 2018-07-12
    Daniele Pezzoli, Joseph Di Paolo, Heena Kumra, Giulia Fois, Gabriele Candiani, Dieter P. Reinhardt, Diego Mantovani

    One of the tightest bottlenecks in vascular tissue engineering (vTE) is the lack of strength and elasticity of engineered vascular wall models caused by limited elastic fiber deposition. In this study, flat and tubular collagen gel-based scaffolds were cellularised with vascular smooth muscle cells (SMCs) and supplemented with human plasma fibronectin (FN), a known master organizer of several extracellular matrix (ECM) fiber systems. The consequences of FN on construct maturation was investigated in terms of geometrical contraction, viscoelastic mechanical properties and deposition of core elastic fiber proteins. FN was retained in the constructs and promoted deposition of elastin by SMCs as well as of several proteins required for elastogenesis such as fibrillin-1, lysyl oxidase, fibulin-4 and latent TGF-β binding protein-4. Notably, gel contraction, tensile equilibrium elastic modulus and elasticity were strongly improved in tubular engineered tissues, approaching the behaviour of native arteries. In conclusion, this study demonstrates that FN exerts pivotal roles in directing SMC-mediated remodeling of scaffolds toward the production of a physiological-like, elastin-containing ECM with excellent mechanical properties. The developed FN-supplemented systems are promising for tissue engineering applications where the generation of mature elastic tissue is desired and represent valuable advanced in vitro models to investigate elastogenesis.

    更新日期:2018-07-14
  • Large-scale Production of Stem Cells Utilizing Microcarriers: A Biomaterials Engineering Perspective from Academic Research to Commercialized Products
    Biomaterials (IF 8.806) Pub Date : 2018-07-11
    Hossein Tavassoli, Sanaz Naghavi Alhosseini, Andy Tay, Peggy P.Y. Chan, Steve Kah Weng Oh, Majid Ebrahimi Warkiani

    Human stem cells, including pluripotent, embryonic and mesenchymal, stem cells play pivotal roles in cell-based therapies. Over the past decades, various methods for expansion and differentiation of stem cells have been developed to satisfy the burgeoning clinical demands. One of the most widely endorsed technologies for producing large cell quantities is using microcarriers (MCs) in bioreactor culture systems. In this review, we focus on microcarriers properties that can manipulate the expansion and fate of stem cells. Here, we provide an overview of commercially available MCs and focus on novel stimulus responsive MCs controlled by temperature, pH and field changes. Different features of MCs including composition, surface coating, morphology, geometry/size, surface functionalization, charge and mechanical properties, and their cellular effects are also highlighted. We then conclude with current challenges and outlook on this promising technology.

    更新日期:2018-07-12
  • Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes
    Biomaterials (IF 8.806) Pub Date : 2018-07-11
    Meilu Dai, Baiyan Sui, Yang Xue, Xin Liu, Jiao Sun

    Cartilage lesions in degenerative osteoarthritis (OA) are involved with pathological microenvironmental alterations induced by inflammatory macrophages, and apoptotic and/or hypertrophic chondrocytes. However, current non-operative therapies for cartilage repair in OA can rarely achieve long-term and satisfactory outcomes. This study aims to evaluate a newly developed squid type II collagen (SCII) for repairing OA-induced cartilage lesions. Our in vitro data show that SCII induces M2 polarization of macrophages, and activates macrophages to express pro-chondrogenic genes (TGF-β and IGF), which greatly improves the microenvironment around chondrocytes to produce type II collagen and glycosaminoglycan. In addition, glycine in SCII activates glycine receptors on inflammatory chondrocytes to decrease intracellular calcium concentration, leading to effective inhibition of chondrocyte apoptosis and hypertrophy. The in vitro effects of SCII are further confirmed in vivo. In a rat model of OA, SCII increases the ratio of M2 macrophages, elevates the levels of pro-chondrogenic cytokines (TGF-β1 and TGF-β3) in synovial fluid, and inhibits chondrocyte apoptosis and MMP13 production. Our findings show that SCII immunomodulates M2 activation of macrophages to skew the local OA microenvironment towards a pro-chondrogenic atmosphere, and promotes cartilage repair under inflammatory condition. It shows great potential for SCII to be a novel biomaterial for cartilage repair in OA.

    更新日期:2018-07-12
  • Bone regeneration strategies: engineered scaffolds, bioactive molecules and stem cells Current stage and future perspectives
    Biomaterials (IF 8.806) Pub Date : 2018-07-11
    Antalya Ho-Shui-Ling, Johanna Bolander, Laurence E. Rustom, Amy Wagoner Johnson, Frank P. Luyten, Catherine Picart

    Bone fractures are the most common traumatic injuries in humans. The repair of bone fractures is a regenerative process that recapitulates many of the biological events of embryonic skeletal development. Most of the time it leads to successful healing and the recovery of the damaged bone. Unfortunately, about 5-10% of fractures will lead to delayed healing or non-union, more so in the case of co-morbidities such as diabetes. In this article, we review the different strategies to heal bone defects using synthetic bone graft substitutes and biologically active substances or stem cells. Our review is different from previous reviews, which focus on strategies that are still at the early stages of development and use mostly in vitro experiments with cell lines or stem cells. Here, we focus on what is already implemented in the clinics, what is currently in clinical trials, and what has been tested in animal models. Treatment approaches can be classified in three major categories: i) synthetic bone graft substitutes (BGS) whose architecture and surface can be optimized; ii) BGS combined with bioactive molecules such as growth factors, peptides or small molecules targeting bone precursor cells, bone formation and metabolism; iii) cell-based strategies with progenitor cells combined or not with active molecules that can be injected or seeded on BGS for improved delivery. We review the major types of adult stromal cells (bone marrow, adipose and periosteum derived) that have been used and compare their properties. Finally, we discuss the remaining challenges that need to be addressed to significantly improve the healing of bone defects.

    更新日期:2018-07-12
  • Receptor mediated transcytosis in biological barrier: The influence of receptor character and their ligand density on the transmembrane pathway of active-targeting nanocarriers
    Biomaterials (IF 8.806) Pub Date : 2018-07-05
    Xiaoning Song, Rui Li, Hailiang Deng, Ye Li, Yanan Cui, Hua Zhang, Wenbing Dai, Bing He, Ying Zheng, Xueqing Wang, Qiang Zhang

    Active-targeting nanocarriers can significantly improve the transcytosis of poorly water-soluble or bio-macromolecular drugs across biological barrier. However, reasons for the improvement are not understood enough, which hampered the reasonable design of active targeting nanocarriers. To illustrate how different factors influence the transport of active-targeting nanocarriers, we established ligand-decorated micelles targeting different receptors to study how the decorations influence the transcytosis of the micelles by comparing the endocytosis, transport pathway and exocytosis process.Three different kinds of receptors, Neonatal Fc receptor (FcRn), transferrin receptor (TfR) and αvβ3 receptor were selected. They presented three different transport pathways, mainly mediate transcytosis, recycling pathway and cell binding, respectively. Their corresponding ligand FcBP, 7pep and c(RGDfK) decorated micelles with different ligand densities were prepared first. Then the effects of receptor and ligand density on the transcytosis across biological barrier were investigated.The results showed that the uptake rate of active micelles was higher than passive micelles and an optimum ligand density with most endocytosis appeared in all functional micelles. Transport pathway study showed 7pep decorated micelles transferred into apical recycling endosome (ARE) and exocytosed to apical plasma membrane in a ligand depended way. c(RGDfK) decorated micelles transferred through common recycling endosome (CRE) and Golgi complex to basolateral plasma membrane instead of ARE. While FcBP decorated micelles took both the recycling pathway and transcytosis through CRE, but not Golgi complex. Proper ligand density, not the higher the better, led the most uptake. Also the apical to basolateral transcytosis ratio may not be in accordance with the uptake. Among all the itineraries, transcytosis through CRE is the best itinerary for transcytosis. So, in the design of active targeting nanocarriers to overcome biological barrier, receptor character should be considered priorly, and then ligand density should be optimized.

    更新日期:2018-07-08
  • A fluorescent chemical probe CDy9 selectively stains and enables the isolation of live naïve mouse embryonic stem cells
    Biomaterials (IF 8.806) Pub Date : 2018-07-05
    Seung-Ju Cho, Keun-Tae Kim, Jong-Soo Kim, Ok-Seon Kwon, Young-Hyun Go, Nam-Young Kang, Haejeong Heo, Mi-Rang Kim, Dong Wook Han, Sung-Hwan Moon, Young-Tae Chang, Hyuk-Jin Cha

    Human and mouse embryonic stem cells (ESCs) differ in terms of their pluripotency status, i.e., naïve vs. primed. This affects various biological properties and leads to several technical hurdles for future clinical applications, such as difficulties in chimera formation, single-cell passaging, and gene editing. In terms of generating functional human tissues and organs via mammalian interspecies chimerism, a fluorescent chemical probe that specifically labels naïve ESCs would help to isolate these cells and monitor their conversion. This study demonstrates that the fluorescent chemical probe compound of designation yellow 9 (CDy9) selectively stains naïve, but not primed, mouse ESCs (mESCs). CDy9 entered cells via Slc13a5, a highly expressed membrane transporter in naïve mESCs. Fluorescence-based cell sorting based on CDy9 staining successfully separated naïve mESCs from primed mESCs. Mice generated using CDy9+ cells isolated during the conversion of mouse epiblast stem cells into naïve mESCs exhibited coat color chimerism. Furthermore, CDy9 specifically stained cells in the inner cell mass of mouse embryos. These findings suggest that CDy9 is a useful tool to isolate functional naïve mESCs.

    更新日期:2018-07-08
  • Laminin-521 promotes quiescence in isolated stellate cells from rat liver
    Biomaterials (IF 8.806) Pub Date : 2018-07-07
    Friederike Rohn, Claus Kordes, Mirco Castoldi, Silke Götze, Gereon Poschmann, Kai Stühler, Diran Herebian, Amelie S. Benk, Fania Geiger, Tingyu Zhang, Joachim P. Spatz, Dieter Häussinger

    The laminin α5 protein chain is an element of basement membranes and important to maintain stem cells. Hepatic stellate cells (HSC) are liver-resident mesenchymal stem cells, which reside in a quiescent state on a basement membrane-like structure in the space of Dissé. In the present study, laminin α5 chain was detected in the space of Dissé of normal rat liver. Since HSC are critical for liver regeneration and can contribute to fibrosis in chronic liver diseases, the effect of laminins on HSC maintenance was investigated. Therefore, isolated rat HSC were seeded on uncoated polystyrene (PS) or PS coated with either laminin-521 (PS/LN-521) or laminin-211 (PS/LN-211). PS/LN-521 improved HSC adhesion and better preserved their retinoid stores as well as quiescence- and stem cell-associated phenotype, whereas HSC on PS/LN-211 or PS developed into myofibroblasts-like cells. To improve the homogeneity as well as the presentation of laminin molecules on the culture surface to HSC, laminin-functionalized, gold-nanostructured glass surfaces were generated. This approach further enhanced the expression of quiescence-associated genes in HSC. In conclusion, the results indicate that LN-521 supports the quiescent state of HSC and laminin α5 can be regarded as an important element of their niche in the space of Dissé.

    更新日期:2018-07-08
  • Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages
    Biomaterials (IF 8.806) Pub Date : 2018-07-07
    Minwoo Kih, Eun Jung Lee, Na Kyeong Lee, Yoon Kyoung Kim, Kyung Eun Lee, Cherlhyun Jeong, Yoosoo Yang, Dong-Hwee Kim, In-San Kim

    Presentation of an endogenous bioactive ligand in its native form is a key factor in controlling and determining its bioactivity, stability, and therapeutic efficacy. In this study, we developed a novel strategy for presenting trimeric ligands on nanocages by designing, optimizing and testing based on the rational design, high-resolution structural analysis and agonistic activity assays in vitro and in vivo. We successfully designed a nanocage that presents the TNF superfamily member, TRAIL (TNF-related apoptosis-inducing ligand) in its native-like trimeric structure. The native structure of TRAIL complexes was mimicked on the resulting TRAIL-presenting nanocages (TTPNs) by inserting sufficient spacing, determined from three-dimensional structural models, to provide optimal access to the corresponding receptors. The efficacy of TTPNs as an anti-tumor agent was confirmed in preclinical studies, which revealed up to 330-fold increased affinity, 62.5-fold enhanced apoptotic activity, and improved pharmacokinetic characteristics and stability compared with the monomeric form of TRAIL (mTRAIL). In this latter context, TTPNs exhibited greater than 90% stability over 1 mo, whereas ∼50% of mTRAIL aggregated within 2 d. Consistent with their enhanced stability and ultra-high affinity for the TRAIL receptor, TTPNs effectively induced apoptosis of tumor cells in vivo, leading to effective inhibition of tumor growth. Although TRAIL was used here as a proof-of-concept, all members of the TNF superfamily share the TNF homology domain (THD) and have similar distances between ecto-domain C-termini. Thus, other TNF superfamily ligands could be genetically substituted for the TRAIL ligand on the surface of this biomimetic delivery platform.

    更新日期:2018-07-08
  • Long-term monitoring of tumor-related autophagy in vivo by Fe3O4NO· nanoparticles
    Biomaterials (IF 8.806) Pub Date : 2018-07-04
    Chao Zhang, Jing Ren, Jian He, Yin Ding, Da Huo, Yong Hu

    In vivo read-out of autophagy is of great therapeutic and fundamental significance, and yet being conducted exclusively in high cost transgenic animal models. As an attempt to readily monitor the autophagy flux, we herein proposed an autophagy-responsive magnetic resonance imaging based on radical-conjugated magnetic nanoparticles. In principle, both the NO· radical and Fe3O4 nanoparticles are stable, and separately contributing to an observation of enhanced T1-and T2-weighted imaging, respectively. Meanwhile, the onset of autophagy concomitantly simulates the mass production of reactive species, and consequently quenches the T1-signal of NO·. On this basis, the content of autophagy flux is reflected by the ratio of T1-signal intensity to that of T2-signal, which is condition-insensitive, as a function of time. Assisted with such strategy, an unprecedented protection role autophagy played in respond to heat stress has been revealed, through which the killing effect of magneto-hyperthermia was greatly impeded. Furthermore, we noticed that the impairment of autophagy through the sequential chemotherapy, can markedly improve the therapeutic outcome, in a manner monitored and thoroughly analyzed using the strategy reported herein. We therefore believe that such a study offers a feasible method for in vivo read-out of autophagy and gives us insights how autophagy influences the therapeutic index of cancer treatments.

    更新日期:2018-07-05
  • Cellular interactions with hydrogel microfibers synthesized via interfacial tetrazine ligation
    Biomaterials (IF 8.806) Pub Date : 2018-07-04
    Shuang Liu, Axel C. Moore, Aidan B. Zerdoum, Han Zhang, Samuel L. Scinto, He Zhang, Liang Gong, David L. Burris, Ayyappan K. Rajasekaran, Joseph M. Fox, Xinqiao Jia

    Fibrous proteins found in the natural extracellular matrix (ECM) function as host substrates for migration and growth of endogenous cells during wound healing and tissue repair processes. Although various fibrous scaffolds have been developed to recapitulate the microstructures of the native ECM, facile synthesis of hydrogel microfibers that are mechanically robust and biologically active have been elusive. Described herein is the use of interfacial bioorthogonal polymerization to create hydrogel-based microfibrous scaffolds via tetrazine ligation. Combination of a trifunctional strained trans-cyclooctene monomer and a difunctional s-tetrazine monomer at the oil-water interface led to the formation of microfibers that were stable under cell culture conditions. The bioorthogonal nature of the synthesis allows for direct incorporation of tetrazine-conjugated peptides or proteins with site-selectively, genetically encoded tetrazines. The microfibers provide physical guidance and biochemical signals to promote the attachment, division and migration of fibroblasts. Mechanistic investigations revealed that fiber-guided cell migration was both F-actin and microtubule-dependent, confirming contact guidance by the microfibers. Prolonged culture of fibroblasts in the presence of an isolated microfiber resulted in the formation of a multilayered cell sheet wrapping around the fiber core. A fibrous mesh provided a 3D template to promote cell infiltration and tissue-like growth. Overall, the bioorthogonal approach led to the straightforward synthesis of crosslinked hydrogel microfibers that can potentially be used as instructive materials for tissue repair and regeneration.

    更新日期:2018-07-05
  • Double-sided effect of tumor microenvironment on platelets targeting nanoparticles
    Biomaterials (IF 8.806) Pub Date : 2018-07-04
    Xinli Chen, Qingbing Wang, Lisha Liu, Tao Sun, Wenxi Zhou, Qinjun Chen, Yifei Lu, Xi He, Yu Zhang, Yujie Zhang, Chunhui Ruan, Qin Guo, Chao Li, Chen Jiang

    The cancer cells and stromal cells in tumor microenvironment secrete cytokines and recruit “homing” cells (macrophage, lymphocytes, platelets, etc.). Platelets can interact with tumor microenvironment and specifically aggregate at tumor sites. Surprising, we observed different “homing” effects of activated platelets in breast cancer model and pancreatic cancer model which is highly related with the blood supply of tumors. Besides, platelets targeting magnetic nanoparticles (MNPs) can home to breast cancer but be repelled from pancreatic cancer. We observed the targeting effect of MNPs is highly related with the expressions of collagen Ⅰ (marker of extracellular matrix) and CD34 (marker of tumor neovascularization). The homing nanoparticles such as platelets targeting MNPs could realize the tumor targeting ability, photo-thermal effect and tumor immunotherapeutic ability in the accessible tumor (e.g. breast cancer) but not the hypovascular tumor (e.g. pancreatic cancer).

    更新日期:2018-07-05
  • Induced neuro-vascular interactions robustly enhance functional attributes of engineered neural implants
    Biomaterials (IF 8.806) Pub Date : 2018-07-04
    Erez Shor, Uri Merdler, Inbar Brosh, Shy Shoham, Shulamit Levenberg

    Engineered neural implants have a myriad of potential basic science and clinical neural repair applications. Although there are implants that are currently undergoing their first clinical investigations, optimizing their long-term viability and efficacy remain an open challenge. Functional implants with pre-vascularization of various engineered tissues have proven to enhance post-implantation host integration, and well-known synergistic neural-vascular interplays suggest that this strategy could also be promising for neural tissue engineering. Here, we report the development of a novel bio-engineered neuro-vascular co-culture construct, and demonstrate that it exhibits enhanced neurotrophic factor expression, and more complex neuronal morphology. Crucially, by introducing genetically encoded calcium indicators (GECIs) into the co-culture, we are able to monitor functional activity of the neural network, and demonstrate greater activity levels and complexity as a result of the introduction of endothelial cells in the construct. The presence of this enhanced activity could putatively lead to superior integration outcomes. Indeed, leveraging on the ability to monitor the construct's development post-implantation with GECIs, we observe improved integration phenotypes in the spinal cord of mice relative to non-vascularized controls. Our approach provides a new experimental system with functional neural feedback for studying the interplay between vascular and neural development while advancing the optimization of neural implants towards potential clinical applications.

    更新日期:2018-07-05
  • Engineered microenvironments and microdevices for modeling the pathophysiology of type 1 diabetes
    Biomaterials (IF 8.806) Pub Date : 2018-07-03
    Matthew W. Becker, Jennifer A. Simonovich, Edward A. Phelps

    The pathophysiology of type 1 diabetes is a complex process involving tightly controlled microenvironments, a number of highly specific immune cell – islet cell interactions, and the eventual breaking of immune tolerance leading to beta cell death. Modeling this process can provide researchers with powerful insights into how and when to best provide treatment, but has proven difficult to accurately model due to its complex nature and differences between animal models and humans. Much progress has been made in determining the genetic, molecular, and cellular mechanisms of type 1 diabetes, yet translating that knowledge to clinical treatments remains challenging. Thus, there exists a capabilities gap between understanding the disease pathophysiology and engineering effective clinical treatment strategies. Biomimetic modeling of human type 1 diabetes is a valuable tool to study and manipulate islet function and can be employed to address immunological aspects of type 1 diabetes. This article will review recent advances in this field, and will suggest ways to synergize systems to model and observe the pathophysiology of autoimmune diabetes with bioengineered therapeutic strategies.

    更新日期:2018-07-04
  • Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration
    Biomaterials (IF 8.806) Pub Date : 2018-07-03
    Xuzhu Wang, Jundong Shao, Mustafa Abd El Raouf, Hanhan Xie, Hao Huang, Huaiyu Wang, Paul K. Chu, Xue-Feng Yu, Yang Yang, AbdelBasit M. AbdEl-Aal, NefissaH.M. Mekkawy, Richard J. Miron, Yufeng Zhang

    A near-infrared (NIR) light-triggered drug delivery platform is produced by incorporating SrCl2 and BP nanosheets (BPs) into poly(lactic-co-glycolic acid) (PLGA) for bone regeneration. The fabricated BP-SrCl2/PLGA microspheres show efficient NIR absorption and photothermal effects due to the BPs. The NIR-triggered release behavior of Sr2+ by flawing the PLGA shells is investigated and the microspheres exhibit excellent cell viability and biodegradability. Implantation of the BP-SrCl2/PLGA microspheres into a rat femoral defect demonstrates good tissue compatibility and excellent bone regeneration capacity under NIR light irradiation. Our study indicates that local release of Sr2+ at optimal time periods controlled by NIR irradiation improves bone regeneration significantly and this NIR-triggered drug delivery system composed of BPs is suitable for therapies requiring precise control at specific time.

    更新日期:2018-07-04
  • In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis
    Biomaterials (IF 8.806) Pub Date : 2018-07-02
    Akihiro Nishiguchi, Michiya Matsusaki, Mitsunobu R. Kano, Hiroshi Nishihara, Daisuke Okano, Yoshiya Asano, Hiroshi Shimoda, Satoko Kishimoto, Soichi Iwai, Mitsuru Akashi
    更新日期:2018-07-03
  • Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H2O2-Activated bubble generating anti-inflammatory polymer particles
    Biomaterials (IF 8.806) Pub Date : 2018-07-02
    Eunkyeong Jung, Joungyoun Noh, Changsun Kang, Donghyuck Yoo, Chulgyu Song, Dongwon Lee
    更新日期:2018-07-03
  • Nanoengineering of nanorattles for tumor treatment by CT imaging-guided simultaneous enhanced microwave thermal therapy and managing inflammation
    Biomaterials (IF 8.806) Pub Date : 2018-06-30
    Qiong Wu, Jie Yu, Mei Li, Longfei Tan, Xiangling Ren, Changhui Fu, Zengzhen Chen, Feng Cao, Jun Ren, Laifeng Li, Ping Liang, Yu Zhang, Xianwei Meng

    Usually the tumor thermal therapy is accompanied with inflammatory reactions, which in turn promote tumor growth and metastasis meanwhile. Herein, we prepared novel trifunctional PEG-IL/ZrO2-Ag@SiO2 nanorattles, which can be used for CT imaging-guided simultaneous tumor microwave thermal therapy and resistance to bacterial infection. Under the microwave irradiation, the nanorattles present excellent microwave thermal properties. Simultaneously, the nanorattles have good antibacterial effect in vitro and in vivo, which can restrain bacterial growth effectively and reduce inflammation response during the microwave thermal therapy. In addition, the nanorattles also have the function of CT imaging, which can monitor the tumor therapy in real time. The strategy of simultaneous microwave thermal therapy and inflammation management effectively inhibits tumor growth in mice with a good anti-tumor effect (96.4%). This proof-of-concept investigation provides a simple and reliable strategy for tumor treatment and inhibiting inflammatory reaction using a multifunctional nanomaterial, indicating the great application prospect in tumor treatment by simultaneous eradicating tumor tissue and managing inflammation.

    更新日期:2018-07-01
  • pH-sensitive radiolabeled and superfluorinated ultra-small palladium nanosheet as a high-performance multimodal platform for tumor theranostics
    Biomaterials (IF 8.806) Pub Date : 2018-06-30
    Zhide Guo, Mei Chen, Chenyu Peng, Shiguang Mo, Changrong Shi, Guifeng Fu, Xuejun Wen, Rongqiang Zhuang, Xinhui Su, Ting Liu, Nanfeng Zheng, Xianzhong Zhang

    Radiolabeled nanomaterials, especially those with ultra-small structures, have been the research focus in recent years, and thus may open up new prospects for clinical diseases theranostics. Herein, fluorinated Pd nanosheets labeled with Gd or radionuclides are developed as multimodal platforms for tumor theranostics. These nanomaterials decorated by functional polyethylene glycol demonstrate ultrahigh 19F MRI signal, ultrasmall size and good dispersion. These ultrasmall materials exhibit good biocompatibility and easily to be modified for multimodal imaging (SPECT/MRI/PAI) by assembling the functional groups like building blocks. Furthermore, with high accumulation in tumor sites, under the guidance of multimodal imaging, combined photothermal therapy and radiotherapy are performed and synergistic effects are obtained. By comparing the in vivo behaviors of nanostructures labeled by different nuclides, the present study suggests the pH-sensitive radioiodinated Pd nanosheet which has unexpected T/NT ratio (>4-fold tumor-to-muscle ratio) in SPECT imaging and solves the critical high background issue of nanoprobes, could improve diagnostic accuracy and guide combination therapy. In summary, this functionalized nanoplatform with promising imaging and therapeutic efficacy has great potential for precision theranostic nanomedicines.

    更新日期:2018-07-01
  • Enzymatically degradable alginate hydrogel systems to deliver endothelial progenitor cells for potential revasculature applications
    Biomaterials (IF 8.806) Pub Date : 2018-06-27
    Kevin T. Campbell, Roberta S. Stilhano, Eduardo A. Silva

    The objective of this study was to design an injectable biomaterial system that becomes porous in situ to deliver and control vascular progenitor cell release. Alginate hydrogels were loaded with outgrowth endothelial cells (OECs) and alginate lyase, an enzyme which cleaves alginate polymer chains. We postulated and confirmed that higher alginate lyase concentrations mediated loss of hydrogel mechanical properties. Hydrogels incorporating 5 and 50 mU/mL of alginate lyase experienced approximately 28% and 57% loss of mass as well as 81% and 91% reduction in storage modulus respectively after a week. Additionally, computational methods and mechanical analysis revealed that hydrogels with alginate lyase significantly increased in mesh size over time. Furthermore, alginate lyase was not found to inhibit OEC proliferation, viability or sprouting potential. Finally, alginate hydrogels incorporating OECs and alginate lyase promoted up to nearly a 10 fold increase in OEC migration in vitro than nondegradable hydrogels over the course of a week and increased functional vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate lyase incorporated hydrogels can provide a simple and robust system to promote controlled outward cell migration into native tissue for potential therapeutic revascularization applications.

    更新日期:2018-06-28
  • Settable polymer/ceramic composite bone grafts stabilize weight-bearing tibial plateau slot defects and integrate with host bone in an ovine model
    Biomaterials (IF 8.806) Pub Date : 2018-06-26
    Sichang Lu, Madison A.P. McGough, Stefanie M. Shiels, Katarzyna J. Zienkiewicz, Alyssa R. Merkel, Joseph P. Vanderburgh, Jeffry S. Nyman, Julie A. Sterling, David J. Tennent, Joseph C. Wenke, Scott A. Guelcher

    Bone fractures at weight-bearing sites are challenging to treat due to the difficulty in maintaining articular congruency. An ideal biomaterial for fracture repair near articulating joints sets rapidly after implantation, stabilizes the fracture with minimal rigid implants, stimulates new bone formation, and remodels at a rate that maintains osseous integrity. Consequently, the design of biomaterials that mechanically stabilize fractures while remodeling to form new bone is an unmet challenge in bone tissue engineering. In this study, we investigated remodeling of resorbable bone cements in a stringent model of mechanically loaded tibial plateau defects in sheep. Nanocrystalline hydroxyapatite-poly(ester urethane) (nHA-PEUR) hybrid polymers were augmented with either ceramic granules (85% β-tricalcium phosphate/15% hydroxyapatite, CG) or a blend of CG and bioactive glass (BG) particles to form a settable bone cement. The initial compressive strength and fatigue properties of the cements were comparable to those of non-resorbable poly(methyl methacrylate) bone cement. In animals that tolerated the initial few weeks of early weight-bearing, CG/nHA-PEUR cements mechanically stabilized the tibial plateau defects and remodeled to form new bone at 16 weeks. In contrast, cements incorporating BG particles resorbed with fibrous tissue filling the defect. Furthermore, CG/nHA-PEUR cements remodeled significantly faster at the full weight-bearing tibial plateau site compared to the mechanically protected femoral condyle site in the same animal. These findings are the first to report a settable bone cement that remodels to form new bone while providing mechanical stability in a stringent large animal model of weight-bearing bone defects near an articulating joint.

    更新日期:2018-06-27
  • Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats
    Biomaterials (IF 8.806) Pub Date : 2018-06-26
    Liting Jiang, Wenjie Zhang, Li Wei, Qi Zhou, Guangzheng Yang, Niandong Qian, Yun Tang, Yiming Gao, Xinquan Jiang

    The decreased bone mass and impaired osteogenesis capacities that occur with aging may influence the outcome of dental implants. Parathyroid hormone (PTH) (1–34) is an anabolic agent for the treatment of osteoporosis. However, little is known about its effects and mechanisms on vascularized bone regeneration and implant osseointegration in aging. In current study, we adopted both in vivo and in vitro approaches to explore the mechanisms of early actions of PTH (1–34) on the angiogenic and osteogenic microenvironment to enhance implant osseointegration in aged rats. Daily subcutaneous injections of 30 μg/kg PTH (1–34) were given to female rats aged 20 months beginning on next day of implantation and lasting for 5 weeks. Radiological and histological analysis confirmed that PTH (1–34) improved new bone formation, angiogenesis and implant osseointegration in aged rats in the early stage. The osteogenic potential of aged bone mesenchymal stem cells (BMSCs) was enhanced, while their adipogenesis capacity was attenuated. Furthermore, PTH (1–34) was shown to promote angiogenesis directly via endothelial cell migration and blood vessel formation in vitro. Meanwhile, PTH (1–34) stimulated more osteoclasts participation in bone remodeling by secreting angiogenic and osteogenic growth factors to induce early vascularization and stimulate the migration or differentiation of BMSCs indirectly. Together, these results demonstrate mechanistic insight into how PTH (1–34) regulates the angiogenic and osteogenic microenvironment to result in more active bone remodeling and new bone formation, making it an excellent potential therapeutic agent for rapid vascularized bone regeneration and implant osseointegration in the aged population.

    更新日期:2018-06-27
  • 3D organizational mapping of collagen fibers elucidates matrix remodeling in a hormone-sensitive 3D breast tissue model
    Biomaterials (IF 8.806) Pub Date : 2018-06-26
    Zhiyi Liu, Lucia Speroni, Kyle P. Quinn, Carlo Alonzo, Dimitra Pouli, Yang Zhang, Emily Stuntz, Carlos Sonnenschein, Ana M. Soto, Irene Georgakoudi

    Hormones play an important role in normal and diseased breast tissue development. However, they can also disrupt cell-matrix interactions and their role in extracellular matrix reorganization during epithelial morphogenesis remains poorly understood, partly due to a lack of sensitive approaches for matrix characterization. Here, we assess the hormonal regulation of matrix reorganization in a three-dimensional (3D) breast tissue culture model using a novel metric, i.e., 3D directional variance, to characterize the 3D organization of collagen fibers visualized via high-resolution, second harmonic generation imaging. This metric enables resolving and quantifying patterns of spatial organization throughout the matrix surrounding epithelial structures treated with 17β-estradiol (E2) alone, and E2 in combination with either promegestone, a progestogen, or prolactin. Addition of promegestone results in the most disorganized fibers, while the E2 alone treatment leads to the most organized ones. Location-dependent organization mapping indicates that only the prolactin treatment leads to significant heterogeneities in the regional organization of collagen fibers, with higher levels of alignment observed at the end of the elongated epithelial structures. The observed collagen organization patterns for all groups persist for tens of micrometers. In addition, a comparison between 3D directional variance and typical 2D analysis approaches reveals an improved sensitivity of the 3D metric to identify organizational heterogeneities and differences among treatment groups. These results demonstrate that 3D directional variance is sensitive to subtle changes in the extracellular micro-environment and has the potential to elucidate reciprocal cell-matrix interactions in the context of numerous applications involving the study of normal and diseased tissue morphogenesis.

    更新日期:2018-06-27
  • Ex vivo synthetic immune tissues with T cell signals for differentiating antigen-specific, high affinity germinal center B cells
    Biomaterials (IF 8.806) Pub Date : 2018-06-26
    Alberto Purwada, Shivem B. Shah, Wendy Béguelin, Avery August, Ari M. Melnick, Ankur Singh

    Most antigen discovery and vaccine development aimed at driving functional B cell responses rely on mouse immunizations studies. To date, there is no 3D ex vivo immune tissues, which are capable of driving antigen-specific B cell responses to rapidly determine the humoral immunogenicity of antigens, understand the role of extracellular matrix in humoral immunity, and generate high affinity antibody responses. This can be attributed to the complexity of B cell differentiation and affinity maturation process in the germinal center (GC) reaction, which makes these highly specialized cells susceptible to rapid apoptosis ex vivo. We have previously reported immune tissues that show ex vivo GC-response, however in a non-antigen specific manner. Here, we report a maleimide (MAL)-functionalized polyethylene glycol (PEG)-based designer immune tissues that modulate B cell differentiation and enriches antigen-specific GC B cells in the presence of T-cell like signals. With the 3D synthetic immune tissue platform, we assessed various hydrogel design parameters to control ex vivo GC reaction. Using an Ezh2fl/fl Cγ1-cre transgenic mouse model, we demonstrated ex vivo IgG1 antibody class switching. Using immune tissues developed from a B1-8hi mutant mouse that represents a recombined antibody variable region derived from a 4-hydroxy-3-nitrophenylacetyl (NP) hapten binding antibody (B1-8), we demonstrate antigen specificity and selective enrichment of antigen-specific B cells with high affinity at both cell surface and secreted levels in integrin ligand-dependent manner. The ex vivo antigen-specific platform technology offers use in scientific understanding of immunobiology, matrix immunology, and in biotechnology applications, ranging from the antigen testing, vaccine development, and generation of antibodies against diseases.

    更新日期:2018-06-27
  • Mussel-inspired degradable antibacterial polydopamine/silica nanoparticle for rapid hemostasis
    Biomaterials (IF 8.806) Pub Date : 2018-06-26
    Chunyu Liu, Weihe Yao, Meng Tian, Junnan Wei, Qiling Song, Weihong Qiao
    更新日期:2018-06-27
  • Fabrication of injectable and superelastic nanofiber rectangle matrices (“peanuts”) and their potential applications in hemostasis
    Biomaterials (IF 8.806) Pub Date : 2018-06-22
    Shixuan Chen, Mark A. Carlson, Yu Shrike Zhang, Yong Hu, Jingwei Xie
    更新日期:2018-06-22
  • Cellular toxicity of silicon carbide nanomaterials as a function of morphology
    Biomaterials (IF 8.806) Pub Date : 2018-06-22
    Fang Chen, Gongyi Li, Eric Ruike Zhao, Jingting Li, Ghanim Hableel, Jeanne E. Lemaster, Yuting Bai, George L. Sen, Jesse V. Jokerst
    更新日期:2018-06-22
  • Pretargeting in nuclear imaging and radionuclide therapy: improving efficacy of theranostics and nanomedicines
    Biomaterials (IF 8.806) Pub Date : 2018-06-22
    E. Johanna L. Steen, Patricia E. Edem, Kamilla Nørregaard, Jesper T. Jørgensen, Vladimir Shalgunov, Andreas Kjaer, Matthias M. Herth
    更新日期:2018-06-22
  • Bone Marrow Mesenchymal Stem Cells: Aging and Tissue Engineering Applications to Enhance Bone Healing
    Biomaterials (IF 8.806) Pub Date : 2018-06-22
    Hang Lin, Jihee Sohn, He Shen, Mark T. Langhans, Rocky S. Tuan

    Bone has well documented natural healing capacity that normally is sufficient to repair fractures and other common injuries. However, the properties of bone change throughout life, and aging is accompanied by increased incidence of bone diseases and compromised fracture healing capacity, which necessitate effective therapies capable of enhancing bone regeneration. The therapeutic potential of adult mesenchymal stem cells (MSCs) for bone repair has been long proposed and examined. Actions of MSCs may include direct differentiation to become bone cells, attraction and recruitment of other cells, or creation of a regenerative environment via production of trophic growth factors. With systemic aging, MSCs also undergo functional decline, which has been well investigated in a number of recent studies. In this review, we first describe the changes in MSCs during aging and discuss how these alterations can affect bone regeneration. We next review current research findings on bone tissue engineering, which is considered a promising and viable therapeutic solution for structural and functional restoration of bone. In particular, the importance of MSCs and bioscaffolds is highlighted. Finally, potential approaches for the prevention of MSC aging and the rejuvenation of aged MSC are discussed.

    更新日期:2018-06-22
  • Studying biomineralization pathways in a 3D culture model of breast cancer microcalcifications
    Biomaterials (IF 8.806) Pub Date : 2018-06-22
    Netta Vidavsky, Jennie AMR. Kunitake, Aaron E. Chiou, Paul A. Northrup, Teresa Porri, Lu Ling, Claudia Fischbach, Lara A. Estroff

    Microcalcifications serve as diagnostic markers for breast cancer, yet their formation pathway(s) and role in cancer progression are debated due in part to a lack of relevant 3D culture models that allow studying the extent of cellular regulation over mineralization. Previous studies have suggested processes ranging from dystrophic mineralization associated with cell death to bone-like mineral deposition. Here, we evaluated microcalcification formation in 3D multicellular spheroids, generated from non-malignant, pre-cancer, and invasive cell lines from the MCF10A human breast tumor progression series. The spheroids with greater malignancy potential developed necrotic cores, thus recapitulating spatially distinct viable and non-viable areas known to regulate cellular behavior in tumors in vivo. The spatial distribution of the microcalcifications, as well as their compositions, were characterized using nanoCT, electron-microscopy, and X-ray spectroscopy. Apatite microcalcifications were primarily detected within the viable cell regions and their number and size increased with malignancy potential of the spheroids. Levels of alkaline phosphatase decreased with malignancy potential, whereas levels of osteopontin increased. These findings support a mineralization pathway in which cancer cells induce mineralization in a manner that is linked to their malignancy potential, but that is distinct from physiological osteogenic mineralization.

    更新日期:2018-06-22
  • Star polymer-based unimolecular micelles and their application in bio-imaging and diagnosis
    Biomaterials (IF 8.806) Pub Date : 2018-02-03
    Xin Jin, Pei Sun, Gangsheng Tong, Xinyuan Zhu
    更新日期:2018-06-22
  • Imaging γ-Glutamyltranspeptidase for tumor identification and resection guidance via enzyme-triggered fluorescent probe
    Biomaterials (IF 8.806) Pub Date : 2018-06-21
    Haidong Li, Qichao Yao, Feng Xu, Ning Xu, Ran Duan, Saran Long, Jiangli Fan, Jianjun Du, Jingyun Wang, Xiaojun Peng
    更新日期:2018-06-22
  • NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo
    Biomaterials (IF 8.806) Pub Date : 2018-06-21
    Gang Jia, Yong Han, Yanli An, Yinan Ding, Chen He, Xihui Wang, Qiusha Tang
    更新日期:2018-06-22
  • Mechanically cartilage-mimicking poly(PCL/PTHF urethane)/collagen nanofibers induce chondrogenesis by blocking NF–kappa B signaling pathway
    Biomaterials (IF 8.806) Pub Date : 2018-06-18
    Tongmeng Jiang, Dan Kai, Sijia Liu, Xianyuan Huang, Shujun Heng, Jinmin Zhao, Benjamin Qi Yu Chan, Xian Jun Loh, Ye Zhu, Chuanbin Mao, Li Zheng

    Cartilage cannot self-repair and thus regeneration is a promising approach to its repair. Here we developed new electrospun nanofibers, made of poly (ε-caprolactone)/polytetrahydrofuran (PCL-PTHF urethane) and collagen I from calf skin (termed PC), to trigger the chondrogenic differentiation of mesenchymal stem cells (MSCs) and the cartilage regeneration in vivo. We found that the PC nanofibers had a modulus (4.3 Mpa) lower than the PCL-PTHF urethane nanofibers without collagen I from calf skin (termed P) (6.8 Mpa) although both values are within the range of the modulus of natural cartilage (1–10 MPa). Both P and PC nanofibers did not show obvious difference in the morphology and size. Surprisingly, in the absence of the additional chondrogenesis inducers, the softer PC nanofibers could induce the chondrogenic differentiation in vitro and cartilage regeneration in vivo more efficiently than the stiffer P nanofibers. Using mRNA-sequence analysis, we found that the PC nanofibers outperformed P nanofibers in inducing chondrogenesis by specifically blocking the NF–kappa B signaling pathway to suppress inflammation. Our work shows that the PC nanofibers can serve as building blocks of new scaffolds for cartilage regeneration and provides new insights on the effect of the mechanical properties of the nanofibers on the cartilage regeneration.

    更新日期:2018-06-19
  • Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors
    Biomaterials (IF 8.806) Pub Date : 2018-06-18
    Evan M. Chen, Amanda R. Quijano, Young-Eun Seo, Christopher Jackson, Alexander D. Josowitz, Seth Noorbakhsh, Andrea Merlettini, Ranjini K. Sundaram, Maria Letizia Focarete, Zhaozhong Jiang, Ranjit S. Bindra, W. Mark Saltzman

    Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drug-loaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(ω-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co-DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rate and drug distribution profile. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors.

    更新日期:2018-06-19
  • A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters
    Biomaterials (IF 8.806) Pub Date : 2018-06-18
    Bowen Wang, Guojun Chen, Go Urabe, Ruosen Xie, Yuyuan Wang, Xudong Shi, Lian-Wang Guo, Shaoqin Gong, K. Craig Kent

    Drug-eluting stents are the most commonly employed method to control post-angioplasty restenosis. Unfortunately, they exacerbate life-threatening stent thrombosis because of endothelium damage caused by both drug and stenting. To solve this major medical problem, an endothelium-protective and stent-free anti-restenotic method is highly desirable. Here we have generated a biomimetic intravenous delivery system using dendritic polymer-based nanoclusters, which were coated with platelet membranes for targeting to the injured arterial wall where restenosis occurs. These nanoclusters were loaded with an endothelium-protective epigenetic inhibitor (JQ1) or an endothelium-toxic status quo drug (rapamycin), and compared for their ability to mitigate restenosis without hindering the process of re-endothelialization. Fluorescence imaging of Cy5-tagged biomimetic nanoclusters indicated their robust homing to injured, but not uninjured arteries. Two weeks after angioplasty, compared to no-drug control, both rapamycin- and JQ1-loaded biomimetic nanoclusters substantially reduced (by >60%) neointimal hyperplasia, the primary cause of restenosis. However, whereas the rapamycin formulation impaired the endothelial re-coverage of the denuded inner arterial wall, the JQ1 formulation preserved endothelial recovery. In summary, we have created an endothelium-protective anti-restenotic system with biomimetic nanoclusters containing an epigenetic inhibitor. This system warrants further development for a non-thrombogenic and stent-free method for clinical applications.

    更新日期:2018-06-19
  • Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis
    Biomaterials (IF 8.806) Pub Date : 2018-06-18
    Bao-Ping Tian, Fangyuan Li, Ruiqing Li, Xi Hu, Tian-Wen Lai, Jingxiong Lu, Yun Zhao, Yang Du, Zeyu Liang, Chen Zhu, Wei Shao, Wen Li, Zhi-Hua Chen, Xiaolian Sun, Xiaoyuan Chen, Songmin Ying, Daishun Ling, Huahao Shen

    Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma.

    更新日期:2018-06-19
  • Tissue-engineered submillimeter-diameter vascular grafts for free flap survival in rat model
    Biomaterials (IF 8.806) Pub Date : 2018-06-15
    Hiroki Yamanaka, Tetsuji Yamaoka, Atsushi Mahara, Naoki Morimoto, Shigehiko Suzuki

    Vascular grafts for free flap transfers should be of very small diameter and remain patent for approximately three weeks to supply blood until the revascularization from the surrounding tissue is established, with the autologous vein grafts acting as the gold standard. Artificial submillimeter-diameter vascular grafts with clinically useful size of 0.6 mm inner diameter and 5 cm length were prepared and evaluated by replacing the axial artery of free flap in rats. The rat tail artery, selected as a novel bioscaffold material, was decellularized using ultrahigh-hydrostatic pressure (UHP) method and compared with the detergent-based conventional method. To induce rapid endothelialization, the graft lumen was modified with synthesized peptides, having high affinity to the endothelial progenitor cells. The UHP method and peptide modification at 37 °C were found to preserve the extracellular matrix structure well, leading to the stable immobilization of the peptide at the luminal surface. These grafts showed the neointima formation, even at the center position far from the native vessels, remained patent for three weeks, and resulted in the flap survival in the rat free-flap model. The tissue-engineered vascular grafts with functionalized lumen have great future potential as an alternative to autologous vein grafts in free flap transfers.

    更新日期:2018-06-15
  • Elimination of melanoma by sortase A-generated TCR-like antibody-drug conjugates (TL-ADCs) targeting intracellular melanoma antigen MART-1
    Biomaterials (IF 8.806) Pub Date : 2018-06-15
    Jun Lai, Yun Wang, Shan-Shan Wu, Ding Ding, Ze-Yu Sun, Ying Zhang, Jie Zhou, Zhan Zhou, Ying-Chun Xu, Li-Qiang Pan, Shu-Qing Chen

    Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-126-35 peptide complex. Homogenous EA1 HL-vcMMAE (drug to antibody ratio of 4) efficiently eliminated melanoma cells in xenograft mouse models with no obvious toxicity at the therapeutic dosage. Trametinib, an MEK inhibitor serving as an HLA expression enhancing agent, augmented the TL-ADCs’ efficacy both in vitro and in vivo by upregulating MART-126-35 peptide presentation, thus providing a strategy for overcoming the limitation of antigen presentation level for TL-ADCs. Hence, our findings validate the strategy of using sortase A-generated TL-ADCs to target tumor-specific intracellular proteins, with or without agents present, to increase presenting TCR epitope peptides.

    更新日期:2018-06-15
  • Annealing novel nucleobase-lipids with oligonucleotides or plasmid DNA based on H-bonding or π-π interaction: Assemblies and transfections
    Biomaterials (IF 8.806) Pub Date : 2018-06-14
    Yuan Ma, Yuejie Zhu, Chao Wang, Delin Pan, Shuang Liu, Mengyi Yang, Zhangping Xiao, Xiantao Yang, Wenting Zhao, Xinyang Zhou, Yiding Li, Yufei Pan, Jing Sun, Shuhe Wang, Zhu Guan, Lihe Zhang, Zhenjun Yang
    更新日期:2018-06-14
  • Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa
    Biomaterials (IF 8.806) Pub Date : 2018-06-14
    H.E. Colley, Z. Said, M.E. Santocildes-Romero, S.R. Baker, K. D'Apice, J. Hansen, L. Siim Madsen, M.H. Thornhill, P.V. Hatton, C. Murdoch
    更新日期:2018-06-14
  • Correlating quantitative tumor accumulation and gene knockdown using SPECT/CT and bioluminescence imaging within an orthotopic ovarian cancer model
    Biomaterials (IF 8.806) Pub Date : 2018-06-13
    Steven K. Jones, Kirk Douglas, Anthony F. Shields, Olivia M. Merkel

    Using an orthotopic model of ovarian cancer, we studied the delivery of siRNA in nanoparticles of tri-block copolymers consisting of hyperbranched polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (hyPEI-g-PCL-b-PEG) with and without a folic acid targeting ligand. A SKOV-3/LUC FRα overexpressing cell line was employed to mimic the clinical manifestations of ovarian cancer. Both targeted and non-targeted micelleplexes were able to effectively deliver siRNA to the primary tumor and its metastases, as measured by gamma scintillation counting and confocal microscopy. Stability of the micelleplexes was demonstrated with a serum albumin binding study. Regarding biodistribution, intravenous (I.V.) administration showed a slight advantage of FRα targeted over non-targeted micelleplex accumulation within the tumor. However, both formulations displayed significant liver uptake. On the other hand, intraperitoneally (I.P.) injected mice showed a modest 6% of the injected dose per gram (ID/g) uptake within the primary and most interestingly also in the metastatic lesions which subsequently resulted in a 62% knockdown of firefly luciferase expression in the tumor after a single injection. While this is, to the best of our knowledge, the first paper that correlates quantitative tumor accumulation in an orthotopic tumor model with in vivo gene silencing, these data demonstrate that PEI-g-PCL-b-PEG-Fol conjugates are a promising option for gene knockdown in ovarian cancer.

    更新日期:2018-06-13
  • 更新日期:2018-06-13
  • Engineering innervated secretory epithelial organoids by magnetic three-dimensional bioprinting for stimulating epithelial growth in salivary glands
    Biomaterials (IF 8.806) Pub Date : 2018-06-12
    Christabella Adine, Kiaw K. Ng, Sasitorn Rungarunlert, Glauco R. Souza, João N. Ferreira
    更新日期:2018-06-12
  • From neutral to zwitterionic poly(α-amino acid) nonfouling surfaces: Effects of helical conformation and anchoring orientation
    Biomaterials (IF 8.806) Pub Date : 2018-02-03
    Chong Zhang, Jingsong Yuan, Jianhua Lu, Yingqin Hou, Wei Xiong, Hua Lu
    更新日期:2018-06-12
  • Promoting in vivo early angiogenesis with sub-micrometer strontium-contained bioactive microspheres through modulating macrophage phenotypes
    Biomaterials (IF 8.806) Pub Date : 2018-06-08
    Fujian Zhao, Bo Lei, Xian Li, Yunfei Mo, Renxian Wang, Dafu Chen, Xiaofeng Chen
    更新日期:2018-06-08
  • Mussel-inspired catalytic selenocystamine-dopamine coatings for long-term generation of therapeutic gas on cardiovascular stents
    Biomaterials (IF 8.806) Pub Date : 2018-06-07
    Zhilu Yang, Ying Yang, Li Zhang, Kaiqin Xiong, Xiangyang Li, Feng Zhang, Jin Wang, Xin Zhao, Nan Huang
    更新日期:2018-06-08
  • Biomimetic O2-Evolving metal-organic framework nanoplatform for highly efficient photodynamic therapy against hypoxic tumor
    Biomaterials (IF 8.806) Pub Date : 2018-06-07
    Shutao Gao, Pengli Zheng, Zhenhua Li, Xiaochen Feng, Weixiao Yan, Shizhu Chen, Weisheng Guo, Dandan Liu, Xinjian Yang, Shuxiang Wang, Xing-Jie Liang, Jinchao Zhang

    Improving the supply of O2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O2-evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen (1O2) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O2 from UiO-66. Subsequently, the generated O2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors.

    更新日期:2018-06-08
  • Biocompatible PEGylated Gold nanorods function As cytokinesis inhibitors to suppress angiogenesis
    Biomaterials (IF 8.806) Pub Date : 2018-06-07
    Hongyuan Song, Ting Guo, Zichang Zhao, Youheng Wei, Haoyang Luo, Weizong Weng, Rui Zhang, Ming Zhong, Chunying Chen, Jiacan Su, Wei Shen
    更新日期:2018-06-08
  • Noncovalent tagging of siRNA with steroids for transmembrane delivery
    Biomaterials (IF 8.806) Pub Date : 2018-02-03
    Wanyi Tai, Xiaohu Gao
    更新日期:2018-06-07
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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