显示样式:     当前期刊: Biomaterials    加入关注    导出
我的关注
我的收藏
您暂时未登录!
登录
  • Inhibition of intrinsic coagulation improves safety and tumor-targeted drug delivery of cationic solid lipid nanoparticles
    Biomaterials (IF 8.402) Pub Date : 2017-11-23
    Xuan Wu, Hongmei Chen, Chenxi Wu, Jialiang Wang, Shi Zhang, Jing Gao, Hongda Wang, Tianmeng Sun, Yong-Guang Yang

    Cationic solid lipid nanoparticles (cSLNs) are promising nanoparticles for controlled drug delivery. Increasing surface charge and/or reducing PEG density enhance cellular uptake of cSLNs in vitro, but for unknown reasons fail to improve drug delivery in vivo. Herein, we show that cSLNs present a risk for systemic platelet activation and aggregation in vivo, and this toxic effect can be significantly augmented by increasing the surface charge and reducing the PEG density. Furthermore, thrombotic toxicity significantly reduces blood circulation time and in vivo cellular uptake of cSLNs. Mechanistic studies revealed that the intrinsic coagulation pathway is responsible for cSLN-induced platelet activation. Importantly, pretreatment of the recipient mice with heparin, a clinically-approved intrinsic coagulation inhibitor, was highly effective in preventing toxicity, prolonging the circulation time of cSLNs, and improving cSLN-based antitumor drug delivery and therapeutic efficacy in tumor-bearing mice. This study offers a useful strategy for improving both the safety and efficacy of cSLN-based anticancer therapies.

    更新日期:2017-11-23
  • One-pot synthesis of pH-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy
    Biomaterials (IF 8.402) Pub Date : 2017-11-22
    Yu Yang, Ligeng Xu, Wenjun Zhu, Liangzhu Feng, Jingjing Liu, Qian Chen, Ziliang Dong, Jiayue Zhao, Zhuang Liu, Meiwan Chen

    Nanoscale coordination polymers (NCPs) are promising nanomedicine platforms featured with biodegradability and versatile functionalities. However, multi-step post-synthesis surface modification is usually required to functionalize as-made NCPs before their biomedical applications. Moreover, efforts are still required to design therapeutic NCPs responsive to the unique tumor microenvironment to achieve more specific and effective therapy. Herein, we uncover a simple yet general strategy to synthesize a series of polyethylene glycol (PEG) modified NCPs via a one-step method by adding poly-histidine-PEG co-polymer into the mixture of metal ions and organic ligands during NCPs formation. With NCPs consisting Ca2+/dicarboxylic cisplatin (IV) prodrug as the example, we show that such Ca/Pt(IV)@pHis-PEG NCPs are highly sensitive to pH changes. With slightly negative charges and compact structure under pH 7.4 during blood circulation, those NCPs exhibit efficient passive accumulation in the tumor, in which the reduced pH (c.a. 6.5) would trigger charge conversion and size expansion to enhance their tumor retention and cell internationalization. After cellular uptake, NCPs within cell endo-/lysosomes with further reduced pH would then lead to decomposition of those NCPs and thus drug release. Chemotherapy with Ca/Pt(IV)@pHis-PEG NCPs in our animal tumor model demonstrates great efficacy under low drug doses, and is found to be particularly effective towards solid tumors with reduced pH.

    更新日期:2017-11-22
  • Red blood cell-like particles with the ability to avoid lung and spleen accumulation for the treatment of liver fibrosis
    Biomaterials (IF 8.402) Pub Date : 2017-11-22
    Koichiro Hayashi, Shota Yamada, Hikaru Hayashi, Wataru Sakamoto, Toshinobu Yogo

    Micro-sized drug-carrier particles accumulate mainly in the lungs and nano-sized particles tend to accumulate in the liver and spleen. Here, we show that micro-particles designed to mimic red blood cells (RBCs) can overcome these limitations. The RBC-MPs created in this study have a unique intra-particle elasticity distribution (IED), enabling them to bend around the central axis of the RBC-like dent, enabling them to pass through pores smaller than their diameter, mechanically behaving as authentic RBCs. In contrast, spherical MPs (SPH-MPs) and RBC-MPs hardened by incorporating a siloxane network (SiO2-RBC-MPs), could not. In addition to the IED, we discovered that the deformability also depends on the shape and average particle elasticity. RBC-MPs did not accumulate in the lungs and the spleen, but were targeted specifically to the liver instead. In contrast, non-RBC-MPs such as SPH-MPs and SiO2-RBC-MPs showed heavy accumulation in the lungs and/or spleen, and were dispersed non-specifically in various organs. Thus, controlling the shape and mechanical properties of RBC-MPs is important for achieving the desired biodistribution. When RBC-MPs were loaded with a (TGF)-β receptor inhibitor, RBC-MPs could treat liver fibrosis without pneumotoxicity.

    更新日期:2017-11-22
  • Does soft really matter? Differentiation of induced pluripotent stem cells into mesenchymal stromal cells is not influenced by soft hydrogels
    Biomaterials (IF 8.402) Pub Date : 2017-11-22
    Roman Goetzke, Julia Franzen, Alina Ostrowska, Michael Vogt, Andreas Blaeser, Gerd Klein, Björn Rath, Horst Fischer, Martin Zenke, Wolfgang Wagner

    Induced pluripotent stem cells (iPSCs) can be differentiated toward mesenchymal stromal cells (MSCs), but this transition remains incomplete. It has been suggested that matrix elasticity directs cell-fate decisions. Therefore, we followed the hypothesis that differentiation of primary MSCs and generation of iPSC-derived MSCs (iMSCs) is supported by a soft matrix of human platelet lysate (hPL-gel). We demonstrate that this fibrin-based hydrogel supports growth of primary MSCs with pronounced deposition of extracellular matrix, albeit it hardly impacts on gene expression profiles or in vitro differentiation of MSCs. Furthermore, iPSCs can be effectively differentiated toward MSC-like cells on the hydrogel. Unexpectedly, this complex differentiation process is not affected by the substrate: iMSCs generated on tissue culture plastic (TCP) or hPL-gel have the same morphology, immunophenotype, differentiation potential, and gene expression profiles. Moreover, global DNA methylation patterns are essentially identical in iMSCs generated on TCP or hPL-gel, indicating that they are epigenetically alike. Taken together, hPL-gel provides a powerful matrix that supports growth and differentiation of primary MSCs and iMSCs – but this soft hydrogel does not impact on lineage-specific differentiation.

    更新日期:2017-11-22
  • Mechanistic insights into the role of glycosaminoglycans in delivery of polymeric nucleic acid nanoparticles by molecular dynamics simulations
    Biomaterials (IF 8.402) Pub Date : 2017-11-22
    Deniz Meneksedag-Erol, Tian Tang, Hasan Uludağ

    Delivery of polynucleotide-based therapeutics into target cells involves interactions with glycosaminoglycan chains that are located on cell membrane milieu. Mechanisms governing glycosaminoglycan-mediated changes in the nanoparticulate structures of polymer-polynucleotide complexes are unknown, and cannot be fully elucidated without atomistic level details of molecular interactions. We selected a representative nanoparticulate system consisting of a short interfering RNA (siRNA)-polyethylenimine complex, and performed all-atom molecular dynamics simulations with the prototypical glycosaminoglycan heparin. We monitored the binding between the complex constituents and the heparin, and identified key features contributing to the response of the siRNA nanoparticles to heparin. We observed three main metastable states that the siRNA nanoparticles might visit in the presence of heparin, which can be translated into different functional outcomes. By correlating our data with the widely different and seemingly contradictory roles previously assigned to glycosaminoglycans, this study provides unique insights into the discrepancies in the experimental literature concerning the role of glycosaminoglycans in the polymeric nanoparticle delivery.

    更新日期:2017-11-22
  • Matrix stiffness determines the phenotype of vascular smooth muscle cell in vitro and in vivo: Role of DNA methyltransferase 1
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Si-An Xie, Tao Zhang, Jin Wang, Feng Zhao, Yun-Peng Zhang, Wei-Juan Yao, Sung Sik Hur, Yi-Ting Yeh, Wei Pang, Li-Sha Zheng, Yu-Bo Fan, Wei Kong, Xian Wang, Jeng-Jiann Chiu, Jing Zhou

    Cells perceive the physical cues such as perturbations of extracellular matrix (ECM) stiffness, and translate these stimuli into biochemical signals controlling various aspects of cell behavior, which contribute to the physiological and pathological processes of multiple organs. In this study, we tested the hypothesis that during arterial stiffening, vascular smooth muscle cells (SMCs) sense the increase of ECM stiffness, which modulates the cellular phenotype through the regulation in DNA methyltransferases 1 (DNMT1) expression. Moreover, we hypothesized that the mechanisms involve intrinsic stiffening and deficiency in contractility of vascular SMCs. Substrate stiffening was mimicked in vitro with polyacrylamide gels. A contractile-to-synthetic phenotypic transition was induced by substrate stiffening in vascular SMCs through the down-regulation of DNMT1 expression. DNMT1 repression was also observed in the tunica media of mice aortas in an acute aortic injury model and a chronic kidney failure model, as well as in the tunica intima of human carotid arteries with calcified atherosclerotic lesions. DNMT1 inhibition facilitates arterial stiffening in vivo and promotes osteogenic transdifferentiation, calcification and cellular stiffening of vascular SMCs in vitro. These effects may be attributable, at least in part, to the role of DNMT1 in regulating the promoter activities of Transgelin (SM22α) and α-smooth muscle actin (SMA) and the functional contractility of SMCs. We conclude that DNMT1 is a critical regulator that negatively regulates arterial stiffening via maintaining the contractile phenotype of vascular SMCs. This research may facilitate elucidation of the complex crosstalk between vascular SMCs and their surrounding matrix in healthy and in pathological conditions and provide new insights into the implications for potential targeting of the phenotypic regulatory mechanisms in material-related therapeutic applications.

    更新日期:2017-11-22
  • Rerouting Mesenchymal Stem Cell Trajectory towards Epithelial Lineage by Engineering Cellular Niche
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Ananya Barui, Farhan Chowdhury, Abhay Pandit, Pallab Datta

    Mesenchymal stromal/stem cells (MSCs) are multipotent cells that offer a promising outcome in the field of regenerative medicine. MSCs are present in various tissues including bone marrow, fat, skin, and placenta. The interest in clinical application of these mesoderm-derived MSCs is primarily fueled by their high self-renewal capacity and multipotency. Although, early studies indicated limited differentiation capacity of MSCs into same cell lineages from which they were isolated, subsequent investigations showed differentiation potential into other cell types of mesoderm origin including osteoblasts, adipocytes, fibroblasts, cardiomyocytes, and chondrocytes. Furthermore, MSCs exhibit a remarkable feature of transdifferentiation into ectodermal, neuroectodermal, and endodermal cells, phenomena referred to as ‘stem cell plasticity’. This opened the possibility of clinical applications of MSCs in the regeneration of other tissues like corneal reconstruction, treatment of acute lung injury, oral mucosal regeneration, homing of MSCs for regeneration at sites of injury etc. Though several evidence have accrued demonstrating this phenomenon, there is still a gap in understanding the molecular mechanism of such transitions which will be important to efficiently control the process. Interestingly, the process can be drawn a parallel with the Mesenchymal to Epithelial Transitions (MET) that takes place inside the body during embryonic development or certain pathophysiological conditions. In this review, a brief attempt is first made to understand the evidence of MSC transdifferentiation based on the current knowledge about MET. We then specifically focus on systematic presentation and analysis of the microenvironment factors involved in MSC transdifferentiation to epithelial lineages which would have applications in regenerative medicine.

    更新日期:2017-11-22
  • Biomaterials-based 3D Cell Printing for Next-Generation Therapeutics and Diagnostics
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Jinah Jang, Ju Young Park, Ge Gao, Dong-Woo Cho

    Building human tissues via 3D cell printing technology has received particular attention due to its process flexibility and versatility. This technology enables the recapitulation of unique features of human tissues and the all-in-one manufacturing process through the design of smart and advanced biomaterials and proper polymerization techniques. For the optimal engineering of tissues, a higher-order assembly of physiological components, including cells, biomaterials, and biomolecules, should meet the critical requirements for tissue morphogenesis and vascularization. The convergence of 3D cell printing with a microfluidic approach has led to a significant leap in the vascularization of engineering tissues. In addition, recent cutting-edge technology in stem cells and genetic engineering can potentially be adapted to the 3D tissue fabrication technique, and it has great potential to shift the paradigm of disease modeling and the study of unknown disease mechanisms required for precision medicine. This review gives an overview of recent developments in 3D cell printing and bioinks and provides technical requirements for engineering human tissues. Finally, we propose suggestions on the development of next-generation therapeutics and diagnostics.

    更新日期:2017-11-22
  • Structure-based design for binding peptides in anti-cancer therapy
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Sheng-Hung Wang, John Yu

    The conventional anticancer therapeutics usually lack cancer specificity, leading to damage of normal tissues that patients find hard to tolerate. Ideally, anticancer therapeutics carrying payloads of drugs equipped with cancer targeting peptides can act like “guided missiles” with the capacity of targeted delivery toward many types of cancers. Peptides are amenable for conjugation to nano drugs for functionalization, thereby improving drug delivery and cellular uptake in cancer-targeting therapies. Peptide drugs are often more difficult to design through molecular docking and in silico analysis than small molecules, because peptide structures are more flexible, possess intricate molecular conformations, and undergo complex interactions. In this review, the development and application of strategies for structure-based design of cancer-targeting peptides against GRP78 are discussed. This Review also covers topics related to peptide pharmacokinetics and targeting delivery, including molecular docking studies, features that provide advantages for in vivo use, and properties that influence the cancer-targeting ability. Some advanced technologies and special peptides that can overcome the pharmacokinetic challenges have also been included.

    更新日期:2017-11-22
  • Strategies for MSC expansion and MSC-based microtissue for bone regeneration
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Varitsara Bunpetch, Zhi-Yong Zhang, Xiaoan Zhang, Shan Han, Pan Zongyou, Haoyu Wu, Ouyang Hongwei

    Mesenchymal stem cells (MSCs) have gained increasing attention as a potential approach for the treatment of bone injuries due to their multi-lineage differentiation potential and also their ability to recognize and home to damaged tissue sites, secreting bioactive factors that can modulate the immune system and enhance tissue repair. However, a wide gap between the number of MSCs obtainable from the donor site and the number required for implantation, as well as the lack of understanding of MSC functions under different in vitro and in vivo microenvironment, hinders the progression of MSCs toward clinical settings. The clinical translation of MSCs pre-requisites a scalable expansion process for the biomanufacturing of therapeutically qualified cells. This review briefly introduces the features of implanted MSCs to determine the best strategies to optimize their regenerative capacity, as well as the current MSC implantation for bone diseases. Current achievements for expansion of MSCs using various culturing methods, bioreactor technologies, biomaterial platforms, as well as microtissue-based expansion strategies are also discussed, providing new insights into future large-scale MSC expansion and clinical applications.

    更新日期:2017-11-21
  • Recent Progress on Semiconducting Polymer Nanoparticles for Molecular Imaging and Cancer Phototherapy
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Jingchao Li, Jianghong Rao, Kanyi Pu

    Abstract As a new class of organic optical nanomaterials, semiconducting polymer nanoparticles (SPNs) have the advantages of excellent optical properties, high photostability, facile surface functionalization, and are considered to possess good biocompatibility for biomedical applications. This review surveys recent progress made on the design and synthesis of SPNs for molecular imaging and cancer phototherapy. A variety of novel polymer design, chemical modification and nanoengineering strategies have been developed to precisely tune up optoelectronic properties of SPNs to enable fluorescence, chemiluminescence and photoacoustic (PA) imaging in living animals. With these imaging modalities, SPNs have been demonstrated not only to image tissues such as lymph nodes, vascular structure and tumors, but also to detect disease biomarkers such as reactive oxygen species (ROS) and protein sulfenic acid as well as physiological indexes such as pH and blood glucose concentration. The potentials of SPNs in cancer phototherapy including photodynamic and photothermal therapy are also highlighted with recent examples. Future efforts should further expand the use of SPNs in biomedical research and may even move them beyond pre-clinical studies.

    更新日期:2017-11-21
  • Targeted Drug Delivery for Tumor Therapy inside the Bone Marrow
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Chao-Feng Mu, Jianliang Shen, Jing Liang, Hang-Sheng Zheng, Yang Xiong, Ying-Hui Wei, Fanzhu Li

    Bone marrow is the primary hematopoietic organ, which is involved in multiple malignant diseases including acute and chronic leukemia, multiple myeloma, myelodysplastic syndromes, and bone metastases from solid tumors. These malignancies affect normal homeostasis and reshape the bone marrow microenvironment. There are limited treatment options for them because of their inevitable aggravation. The current systemic administration of anticancer agents is difficult to achieve ideal therapeutic dose to suppress tumor growth at bone marrow diseased sites, and is always associated with a high incidence of relapse and severe side effects. The limitations of current treatments urge scientists to develop bone marrow targeted drug delivery systems intended for the treatment of diseased bone marrow, which can improve the efficacy of therapeutic agents and reduce their dose-limiting systemic side effects on healthy tissues. In this review we first present the current opinions on bone marrow vasculature, as well as the molecular and structural interactions between tumor cells and the diseased bone marrow. In the second part, we highlight the different design rationales and strategies of bone marrow delivery systems and their therapeutic applications for the treatment of malignancies inside the bone marrow.

    更新日期:2017-11-21
  • MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity
    Biomaterials (IF 8.402) Pub Date : 2017-11-21
    Shipin Zhang, Shang Jiunn Chuah, Ruenn Chai Lai, James Hoi Po Hui, Sai Kiang Lim, Wei Seong Toh

    Mesenchymal stem cell (MSC) exosome was previously shown to be effective in repairing critical size osteochondral defects in an immunocompetent rat model. Here we investigate the cellular processes modulated by MSC exosomes and the mechanism of action underlying the exosome-mediated responses in cartilage repair. We observed that exosome-mediated repair of osteochondral defects was characterised by increased cellular proliferation and infiltration, enhanced matrix synthesis and a regenerative immune phenotype. Using chondrocyte cultures, we could attribute the rapid cellular proliferation and infiltration during exosome-mediated cartilage repair to exosomal CD73-mediated adenosine activation of AKT and ERK signalling. Inhibitors of AKT or ERK phosphorylation suppressed exosome-mediated increase in cell proliferation and migration but not matrix synthesis. The role of exosomal CD73 was confirmed by the attenuation of AKT and ERK signalling by AMPCP, a CD73 inhibitor and theophylline, an adenosine receptor antagonist. Exosome-treated defects also displayed a regenerative immune phenotype characterised by a higher infiltration of CD163+ regenerative M2 macrophages over CD86+ M1 macrophages, with a concomitant reduction in pro-inflammatory synovial cytokines IL-1β and TNF-α. Together, these observations demonstrated that the efficient osteochondral regeneration by MSC exosomes was effected through a coordinated mobilisation of multiple cell types and activation of several cellular processes.

    更新日期:2017-11-21
  • Rational incorporation of molecular adjuvants into a hybrid nanoparticle-based nicotine vaccine for immunotherapy against nicotine addiction
    Biomaterials (IF 8.402) Pub Date : 2017-11-20
    Zongmin Zhao, Brian Harris, Yun Hu, Theresa Harmon, Paul R. Pentel, Marion Ehrich, Chenming Zhang

    Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy due to their low immunogenicity. Achieving a sufficiently high immunogenicity is a necessity for establishing a clinically-viable nicotine vaccine. This study aims to facilitate the immunogenicity of a hybrid nanoparticle-based nicotine vaccine by rationally incorporating toll-like receptor (TLR)-based adjuvants, including monophosphoryl lipid A (MPLA), Resiquimod (R848), CpG oligodeoxynucleotide 1826 (CpG ODN 1826), and their combinations. The nanoparticle-delivered model adjuvant was found to be taken up more efficiently by dendritic cells than the free counterpart. Nanovaccine particles were transported to endosomal compartments upon cellular internalization. The incorporation of single or dual TLR adjuvants not only considerably increased total anti-nicotine IgG titers but also significantly affected IgG subtype distribution in mice. Particularly, the nanovaccines carrying MPLA+R848 or MPLA+ODN 1826 generated a much higher anti-nicotine antibody titer than those carrying none or one adjuvant. Meanwhile, the anti-nicotine antibody elicited by the nanovaccine adjuvanted with MPLA+R848 had a significantly higher affinity than that elicited by the nanovaccine carrying MPLA+ODN 1826. Moreover, the incorporation of all the selected TLR adjuvants (except MPLA) reduced the brain nicotine levels in mice after nicotine challenge. Particularly, the nanovaccine with MPLA+R848 exhibited the best ability to reduce the level of nicotine entering the brain. Collectively, rational incorporation of TLR adjuvants could enhance the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine, making it a promising next-generation immunotherapeutic candidate for treating nicotine addiction.

    更新日期:2017-11-21
  • Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation
    Biomaterials (IF 8.402) Pub Date : 2017-11-20
    Amit Sharma, Eun-Joong Kim, Hu Shi, Jin Yong Lee, Bong Geun Chung, Jong Seung Kim

    The high incidence of colorectal cancer worldwide is currently a major health concern. Although conventional chemotherapy and surgery are effective to some extent, there is always a risk of relapse due to associated side effects, including post-surgical complications and non-discrimination between cancer and normal cells. In this study, we developed a small molecule-based theranostic system, Gal-Dox, which is preferentially taken up by colon cancer cells through receptor-mediated endocytosis. After cancer-specific activation, the active drug Dox (doxorubicin) is released with a fluorescence turn-on response, allowing both drug localization and site of action to be monitored. The therapeutic potency of Gal-Dox was also evaluated, both in vivo and ex vivo, thus illustrating the potential of Gal-Dox as a colorectal cancer theranostic with great specificity.

    更新日期:2017-11-21
  • Manipulating human dendritic cell phenotype and function with targeted porous silicon nanoparticles
    Biomaterials (IF 8.402) Pub Date : 2017-11-20
    Sebastian O. Stead, Steven J.P. McInnes, Svjetlana Kireta, Peter D. Rose, Shilpanjali Jesudason, Darling Rojas-Canales, David Warther, Frédérique Cunin, Jean-Olivier Durand, Christopher J. Drogemuller, Robert P. Carroll, P. Toby Coates, Nicolas H. Voelcker

    Dendritic cells (DC) are the most potent antigen-presenting cells and are fundamental for the establishment of transplant tolerance. The Dendritic Cell-Specific Intracellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN; CD209) receptor provides a target for dendritic cell therapy. Biodegradable and high-surface area porous silicon (pSi) nanoparticles displaying anti-DC-SIGN antibodies and loaded with the immunosuppressant rapamycin (Sirolimus) serve as a fit-for-purpose platform to target and modify DC. Here, we describe the fabrication of rapamycin-loaded DC-SIGN displaying pSi nanoparticles, the uptake efficiency into DC and the extent of nanoparticle-induced modulation of phenotype and function. DC-SIGN antibody displaying pSi nanoparticles favourably targeted and were phagocytosed by monocyte-derived and myeloid DC in whole human blood in a time- and dose-dependent manner. DC preconditioning with rapamycin-loaded nanoparticles, resulted in a maturation resistant phenotype and significantly suppressed allogeneic T-cell proliferation.

    更新日期:2017-11-21
  • Co-delivery of human cancer-testis antigens with adjuvant in protein nanoparticles induces higher cell-mediated immune responses
    Biomaterials (IF 8.402) Pub Date : 2017-11-20
    Medea Neek, Jo Anne Tucker, Tae Il Kim, Nicholas M. Molino, Edward L. Nelson, Szu-Wen Wang

    Nanoparticles have attracted considerable interest as cancer vaccine delivery vehicles for inducing sufficient CD8+ T cell-mediated immune responses to overcome the low immunogenicity of tumor microenvironments. Our studies described here are the first to examine the effects of clinically-tested human cancer-testis (CT) peptide epitopes within a synthetic nanoparticle. Specifically, we focused on two significant clinical CT targets, the HLA-A2 restricted epitopes of NY-ESO-1 and MAGE-A3, using a viral-mimetic packaging strategy. Our data shows that simultaneous delivery of a NY-ESO-1 epitope (SLLMWITQV) and CpG using the E2 subunit assembly of pyruvate dehydrogenase (E2 nanoparticle), resulted in a 25-fold increase in specific IFN-γ secretion in HLA-A2 transgenic mice. This translated to a 15-fold increase in lytic activity toward target cancer cells expressing the antigen. Immunization with a MAGE-A3 epitope (FLWGPRALV) delivered with CpG in E2 nanoparticles yielded an increase in specific IFN-γ secretion and cell lysis by 6-fold and 9-fold, respectively. Furthermore, combined delivery of NY-ESO-1 and MAGE-A3 antigens in E2 nanoparticles yielded an additive effect that increased lytic activity towards cells bearing NY-ESO-1+ and MAGE-A3+. Our investigations demonstrate that formulation of CT antigens within a nanoparticle can significantly enhance antigen-specific cell-mediated responses, and the combination of the two antigens in a vaccine can preserve the increased individual responses that are observed for each antigen alone.

    更新日期:2017-11-21
  • Engineering detoxified pneumococcal pneumolysin derivative ΔA146PLY for self-biomineralization of calcium phosphate: Assessment of their protective efficacy in murine infection models
    Biomaterials (IF 8.402) Pub Date : 2017-11-20
    Jingwen Wu, Kaifeng Wu, Wenchun Xu, Taixian Yuan, Xiaofang Wang, Jinghui Zhang, Yajun Min, Yibing Yin, Xuemei Zhang

    Vaccine design ushered in the era of nanotechnology, as the vaccine is being developed toward particulate formulation. We have previously shown that the attenuated pneumolysin mutant (ΔA146PLY) was a safe and effective pneumococcal vaccine candidate. Here, to further optimize the formulation, we fused calcium phosphate (CaP) binding domains with ΔA146PLY so that the biocompatible CaP can mineralize with the protein automatically, allowing simple production of nanoparticle antigen during preparation. We fabricated four different nanoparticles, and then we compared the characteristics of different CaP-ΔA146PLY nanoparticles and demonstrated the influence of CaP binding domains on the size, shape and surface Ca/P ratio of the nanoparticles. It was found that these self-biomineralized CaP-ΔA146PLY nanoparticles varied in their capacity to induce BMDCs and splenocytes production of cytokines. We further demonstrated that, compared to free proteins, nanoparticle antigens induced more efficient humoral and cellular immune responses which was strong enough to protect mice from both pneumonia and sepsis infection. Also, the integration of CaP to protein has no significant impairment on body weight of animals, and subcutaneous infection of ΔA146PLY-peptides@CaP nanoparticles did not lead to the permanent formation of nodules in the skin relative to Alum adjuvant formulated antigens. Together, our data sufficiently suggest that soluble ΔA146PLY vaccine candidate could be processed into nanoparticles by self-biomineralization of CaP, the immunogenicity of which could be efficiently improved by the CaP binding domains.

    更新日期:2017-11-20
  • Rapid initiation of guided bone regeneration driven by spatiotemporal delivery of IL-8 and BMP-2 from hierarchical MBG-based scaffold
    Biomaterials (IF 8.402) Pub Date : 2017-11-17
    Dan Lin, Yanjun Chai, Yifan Ma, Duan Bing, Yuan Yuan, Changsheng Liu

    Initiation of endogenous repair mechanisms, including key steps of stem cell recruitment and cartilage intermediate formation in endochondral ossification, is vital to regeneration of large bone defects. To biomimetically promote a rapid initiation and ensuing osteogenic stimulation, exogenous chemokine IL-8 and growth factor BMP-2 were orchestrated in a mesoporous bioactive glass (MBG)-based spatiotemporal delivery system, to achieve a rapid release of IL-8 followed by a long-term sustained release of BMP-2. The synergistic effect of IL-8 and BMP-2 on initiation stage of bone healing and underlying mechanism were thoroughly investigated in vitro and in vivo. Intriguingly, apart from its superiority in stem cell recruitment to BMP-2, IL-8 not only endowed a histological “prep-state” of endochondral ossification by up-regulating chondrogenic genes and inducing the formation of extensive cartilage tissues, facilitating rapid bone transformation by BMP-2, but also triggered a cellular “prep-state” with high expression of BMP receptors, enhancing the osteoinductivity of BMP-2. With the spatiotemporal delivery system, orchestrated signal stimuli of IL-8 and BMP-2 induced a rapid initiation including efficient stem cell recruitment and a “chondrogenic/osteogenic balance” at the first stage of endochondral ossification, and the scaffold facilitated sufficient osteoconductivity, together resulting in early extensive bone mineralization and an advanced regeneration throughout the repair of large bone defect. We believe this new idea could provide insights toward designing bone-repairing biomaterials with higher regenerative efficiency.

    更新日期:2017-11-19
  • Epithelial-mesenchymal crosstalk influences cellular behavior in a 3D alveolus-fibroblast model system
    Biomaterials (IF 8.402) Pub Date : 2017-11-15
    Katherine J.R. Lewis, Jessica K. Hall, Emi A. Kiyotake, Tova Christensen, Vivek Balasubramaniam, Kristi S. Anseth

    Interactions between lung epithelium and interstitial fibroblasts are increasingly recognized as playing a major role in the progression of several lung pathologies, including cancer. Three-dimensional in vitro co-culture systems offer tissue-relevant platforms to study the signaling interplay between diseased and healthy cell types. Such systems provide a controlled environment in which to probe the mechanisms involved in epithelial-mesenchymal crosstalk. To recapitulate the native alveolar tissue architecture, we employed a cyst templating technique to culture alveolar epithelial cells on photodegradable microspheres and subsequently encapsulated the cell-laden spheres within poly (ethylene glycol) (PEG) hydrogels containing dispersed pulmonary fibroblasts. A fibroblast cell line (CCL-210) was co-cultured with either healthy mouse alveolar epithelial primary cells or a cancerous alveolar epithelial cell line (A549) to probe the influence of tumor-stromal interactions on proliferation, migration, and matrix remodeling. In 3D co-culture, cancerous epithelial cells and fibroblasts had higher proliferation rates. When examining fibroblast motility, the fibroblasts migrated faster when co-cultured with cancerous A549 cells. Finally, a fluorescent peptide reporter for matrix metalloproteinase (MMP) activity revealed increased MMP activity when A549s and fibroblasts were co-cultured. When MMP activity was inhibited or when cells were cultured in gels with a non-degradable crosslinker, fibroblast migration was dramatically suppressed, and the increase in cancer cell proliferation in co-culture was abrogated. Together, this evidence supports the idea that there is an exchange between the alveolar epithelium and surrounding fibroblasts during cancer progression that depends on MMP activity and points to potential signaling routes that merit further investigation to determine targets for cancer treatment.

    更新日期:2017-11-15
  • Improved heart repair upon myocardial infarction: Combination of magnetic nanoparticles and tailored magnets strongly increases engraftment of myocytes
    Biomaterials (IF 8.402) Pub Date : 2017-11-15
    Annika Ottersbach, Olga Mykhaylyk, Alexandra Heidsieck, Dietmar Eberbeck, Sarah Rieck, Katrin Zimmermann, Martin Breitbach, Britta Engelbrecht, T. Brügmann, Michael Hesse, Armin Welz, Philipp Sasse, Daniela Wenzel, Christian Plank, Bernhard Gleich, Michael Hölzel, Wilhelm Bloch, Alexander Pfeifer, Bernd K. Fleischmann, Wilhelm Roell

    Cell replacement in the heart is considered a promising strategy for the treatment of post-infarct heart failure. Direct intramyocardial injection of cells proved to be the most effective application route, however, engraftment rates are very low (<5%) strongly hampering its efficacy. Herein we combine magnetic nanoparticles (MNP) loading of fluorescent embryonic cardiomyocytes (eCM) and embryonic stem cell-derived cardiomyocytes (ES-CM) with application of custom designed magnets to enhance their short and long-term engraftment. To optimize cellular MNP uptake and magnetic force within the infarct area, first numerical simulations and experiments were performed in vitro. All tested cell types could be loaded efficiently with SOMag5-MNP (200 pg/cell) without toxic side effects. Application of a 1.3 T magnet at 5 mm distance from the heart for 10 min enhanced engraftment of both eCM and ES-CM by approximately 7 fold at 2 weeks and 3.4 fold (eCM) at 8 weeks after treatment respectively and also strongly improved left ventricular function at all time points. As underlying mechanisms we found that application of the magnetic field prevented the initial dramatic loss of cells via the injection channel. In addition, grafted eCM displayed higher proliferation and lower apoptosis rates. Electron microscopy revealed better differentiation of engrafted eCM, formation of cell to cell contacts and more physiological matrix formation in magnet-treated grafts. These results were corroborated by gene expression data. Thus, combination of MNP-loaded cells and magnet-application strongly increases long-term engraftment of cells addressing a major shortcoming of cardiomyoplasty.

    更新日期:2017-11-15
  • Targeted iron nanoparticles with platinum-(IV) prodrugs and anti-EZH2 siRNA show great synergy in combating drug resistance in vitro and in vivo
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Chang Yu, Binbin Ding, Xinyang Zhang, Xiaoran Deng, Kerong Deng, Ziyong Cheng, Bengang Xing, Dayong Jin, Ping'an Ma, Jun Lin

    Resistance to platinum agents is challenging in cancer treatment with platinum drugs. Such resistant cells prevent effective platinum accumulation intracellular and alter cellular adaptations to survive from cytotoxicity by regulating corresponding proteins expression. Ideal therapeutics should combine resolution to the pump and non-pump relevant resistance of cancer cells to achieve high efficacy and low side effect. Fe3O4 nanocarrier loaded with drugs could enter cells in a more efficient endocytosis manner which circumvents pump-relevant drug resistance. EZH2 protein which was previously found to be over-expressed in drug-resistant cancer cells was reported to be involved in platinum drug resistance and play a vital role in anti-apoptosis pathways. Here, we report Fe3O4 nanoparticles loaded with siEZH2 (siRNA), a platinum prodrug in +4 oxidation state (cis, cis, trans-diamminedichlorodisuccinato-platinum-(IV), namely Pt(IV)) and luteinizing hormone-releasing hormone (LHRH) targeting polypeptides which are over-expressed on the surface of various cancer cells. Results show that targeted nanoparticles loading with siEZH2 synergize with Pt(IV) and result in similar cell killing performance to A2780/DDP cells (cisplatin resistant) compared with non-siEZH2 loaded nanoparticles to A2780 cells (cisplatin sensitive). Thus, this Fe3O4@PEI-Pt(IV)-PEG-LHRH@siEZH2 nanoparticles reverse the cisplatin resistance from the pump and non-pump relevant aspects, fully taking advantage of nanocarrier system.

    更新日期:2017-11-15
  • Semiconducting polymer-based nanoparticles with strong absorbance in NIR-II window for in vivo photothermal therapy and photoacoustic imaging
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Ziyang Cao, Liangzhu Feng, Guobing Zhang, Junxia Wang, Song Shen, Dongdong Li, Xianzhu Yang

    Near-infrared (NIR) light-induced photothermal therapy (PTT) has attracted much interest in recent years. In the NIR region, tissue penetration ability of the second biological near-infrared window (1000–1350 nm) is recognized to be stronger than that of the first window (650–950 nm). However, NIR light absorbers in the second NIR region (NIR-II) have been scant even though various NIR light absorbers in the first NIR region (NIR-I) have been widely explored. In this work, a thieno-isoindigo derivative-based semiconducting polymer, PBTPBF-BT, were formulated into PEGylated nanoparticles. The obtained nanoparticle NPPBTPBF-BT exhibited strong absorption in NIR-II region, inherent high photothermal conversion efficacy, and excellent photostability. The in vitro and in vivo PTT study employing 1064 nm laser in NIR-II window revealed that NPPBTPBF-BT could efficiently ablate tumor cell at a power density of 0.42 W/cm2 (the skin tolerance threshold value). Moreover, NPPBTPBF-BT with excellent photostability exhibited enhanced photoacoustic (PA) imaging of tumor in living mice, suggesting the great probability of using NPPBTPBF-BT for in vivo PA imaging-guided PTT in the NIR-II window.

    更新日期:2017-11-15
  • Tracking and protection of transplanted stem cells using a ferrocenecarboxylic acid-conjugated peptide that mimics hTERT
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Hyun-Hee Park, Kyu-Yong Lee, Dong Woo Park, Na-Young Choi, Young Joo Lee, Jeong-Woo Son, Sangjae Kim, Chanil Moon, Hyun-Wook Kim, Im Joo Rhyu, Seong-Ho Koh

    In vivo tracking of transplanted stem cells has been a central aim of stem cell therapy. Although many tracking systems have been introduced, no method has yet been validated for clinical applications. We developed a novel sophisticated peptide (GV1001) that mimics hTERT (human telomerase reverse transcriptase) and analysed its ability to track and protect stem cells after transplantation. Ferrocenecarboxylic acid-conjugated GV1001 (Fe-GV1001) efficiently penetrated stem cells with no adverse effects. Moreover, Fe-GV1001 improved the viability, proliferation, and migration of stem cells under hypoxia. After Fe-GV1001-labelled stem cells were transplanted into the brains of rats after stroke, the labelled cells were easily tracked by MRI. Our findings indicate that Fe-GV1001 can be used for the in vivo tracking of stem cells after transplantation into the brain and can improve the efficacy of stem cell therapy by sustaining and enhancing stem cell characteristics under disease conditions.

    更新日期:2017-11-14
  • A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Yueyang Qu, Fan An, Yong Luo, Yao Lu, Tingjiao Liu, Weijie Zhao, Bingcheng Lin

    In this study, we developed a multilayer microfluidic device to simulate nephron, which was formed by “glomerulus”, “Bowman's capsule”, “proximal tubular lumen” and “peritubular capillary”. In this microdevice, artificial renal blood flow and glomerular filtrate flow were circulating simultaneously, mimicking the behavior of a nephron. . In this dynamic artificial nephron, we observed typical renal physiology, including the glomerular size-selective barrier, glomerular basement membrane charge-selective barrier, glucose reabsorption and para-aminohippuric acid secretion. To demonstrate the capability of our microdevice, we used it to investigate the pathophysiology of drug-induced acute kidney injury (AKI) and give assessment of drug-induced nephrotoxicity, with cisplatin and doxorubicin as model drugs. In the experiment, we loaded the doxorubicin or cisplatin in the “renal blood flow”, recorded the injury of primary glomerular endothelial cells, podocytes, tubular epithelial cells and peritubular endothelial cells by fluorescence imaging, and identified the time-dependence, dose-dependence and the death order of four types of renal cells. Then by measuring multiple biomarkers, including E-cadherin, VEGF, VCAM-1, Nephrin, and ZO-1, we studied the mechanism of cell injuries caused by doxorubicin or cisplatin. Also, we investigated the effect of BSA in the “renal blood flow” on doxorubicin-or-cisplatin-induced nephrotoxicity, and found that BSA enhanced the tight junctions between cells and eased cisplatin-induced nephrotoxicity. In addition, we compared the nephron model and traditional tubule models for assessment of drug-induced nephrotoxicity. And it can be inferred that our biomimetic microdevice simulated the complex, dynamic microenvironment of nephron, yielded abundant information about drug-induced-AKI at the preclinical stage, boosted the drug safety evaluation, and provided a reliable reference for clinical therapy.

    更新日期:2017-11-14
  • Nanoscaled red blood cells facilitate breast cancer treatment by combining photothermal/photodynamic therapy and chemotherapy
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Guoyun Wan, Bowei Chen, Ling Li, Dan Wang, Shurui Shi, Tao Zhang, Yue Wang, Lianyun Zhang, Yinsong Wang

    Red blood cells (RBCs)-based vesicles have been widely used for drug delivery due to their unique advantages. Intact RBCs contain a large amount of oxyhemoglobin (oxyHb), which can assist with photodynamic therapy (PDT). Indocyanine green (ICG), a photosensitizer both for photothermal therapy (PTT) and PDT, shows potent anticancer efficacy when combined with chemotherapeutic drug doxorubicin (DOX). In this study, we prepared nanoscaled RBCs (RAs) containing oxyHb and gas-generating agent ammonium bicarbonate (ABC) for co-loading and controlled release of ICG and DOX, thus hoping to achieve synergistic effects of PTT/PDT and chemotherapy against breast cancer. Compared to free ICG, ICG and DOX co-loaded RAs (DIRAs) exhibited nearly identical PTT efficiency both in vitro and in vivo, but meanwhile their PDT efficiency was enhanced significantly. In mouse breast cancer cells, DIRAs significantly inhibited cell growth and induced cell apoptosis after laser irradiation. In breast tumor-bearing mice, intratumoral injection of DIRAs and followed by local laser irradiation almost completely ablated breast tumor and further suppressed tumor recurrence and metastasis. In conclusion, this biomimetic multifunctional nanosystem can facilitate breast cancer treatment by combining PTT/PDT and chemotherapy.

    更新日期:2017-11-14
  • Theranostic 2D ultrathin MnO2 nanosheets with fast responsibility to endogenous tumor microenvironment and exogenous NIR irradiation
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Zhuang Liu, Shengjian Zhang, Han Lin, Menglong Zhao, Heliang Yao, Linlin Zhang, Weijun Peng, Yu Chen

    The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn2+ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T1-weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO2 nanosheets responsive to exogenous NIR irradiation have been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents.

    更新日期:2017-11-14
  • SnWO4-based nanohybrids with full energy transfer for largely enhanced photodynamic therapy and radiotherapy
    Biomaterials (IF 8.402) Pub Date : 2017-11-14
    Meng Zhang, Zhaowen Cui, Ruixue Song, Bin Lv, Zhongmin Tang, Xianfu Meng, Xiaoyan Chen, Xiangpeng Zheng, Jiawen Zhang, Zhenwei Yao, Wenbo Bu

    The “partial matching” between upconversion nanoparticle (UCNP) emission and absorption by photosensitizers (PSs) often leads to a theoretically reduced therapeutic efficiency in UC-based photodynamic therapy (PDT) strategies in which the chosen PSs have limited capabilities and are unable to utilize all the near-infrared-upconverted light. In this study, needle-like SnWO4 nanocrystals (SWs) with a broad UV–vis absorption region were synthesized to solve the problem. After covalent conjugation with UCNPs, all the UCNP-emitted light was effectively absorbed by SWs, triggering the type-I PDT process to activate ROS maxima. The unique nanostructure of the as-formed UCNP-SnWO4 nanohybrids (USWs) also enhanced the receiving light intensities of SW, which further boosted the antitumor efficacy. Meanwhile, the strong X-ray attenuation capacity of both tungsten and tin elements qualified the USWs as excellent radio-sensitizers for radiotherapy (RT) enhancement, which played a complementary role with PDT treatment because PDT-mediated induction arrested the cells in the G0-G1 cell cycle phase, and RT was more damaging toward cells in the G2/M phase. The remarkably enhanced UC-PDT/RT efficiency of USWs was next validated in vitro and in vivo, and the combined NIR light and ionizing irradiation treatment completely suppressed tumor growth, revealing its great potential as an efficient anticancer therapeutic agent against solid tumors.

    更新日期:2017-11-14
  • Syndecan-1 in mechanosensing of nanotopological cues in engineered materials
    Biomaterials (IF 8.402) Pub Date : 2017-11-09
    Victoria Le, Jason Lee, Somali Chaterji, Adrianne Spencer, Yen-Liang Liu, Peter Kim, Hsin-Chih Yeh, Deok-Ho Kim, Aaron B. Baker

    The cells of the vascular system are highly sensitive to biophysical cues from their local cellular microenvironment. To engineer improved materials for vascular devices and delivery of cell therapies, a key challenge is to understand the mechanisms that cells use to sense biophysical cues from their environment. Syndecans are heparan sulfate proteoglycans (HSPGs) that consist of a protein core modified with heparan sulfate glycosaminoglycan chains. Due to their presence on the cell surface and their interaction with cytoskeletal and focal adhesion associated molecules, cell surface proteoglycans are well poised to serve as mechanosensors of the cellular microenvironment. Nanotopological cues have become recognized as major regulators of cell growth, migration and phenotype. We hypothesized that syndecan-1 could serve as a mechanosensor for nanotopological cues and can mediate the responsiveness of vascular smooth muscle cells to nanoengineered materials. We created engineered substrates made of polyurethane acrylate with nanogrooves using ultraviolet-assisted capillary force lithography. We cultured vascular smooth muscle cells with knockout of syndecan-1 on engineered substrates with varying compliance and nanotopology. We found that knockout of syndecan-1 reduced alignment of vascular smooth muscle cells to the nanogrooves under inflammatory treatments. In addition, we found that loss of syndecan-1 increased nuclear localization of Yap/Taz and phospho-Smad2/3 in response to nanogrooves. Syndecan-1 knockout vascular smooth muscle cells also had elevated levels of Rho-associated protein kinase-1 (Rock1), leading to increased cell stiffness and an enhanced contractile state in the cells. Together, our findings support that syndecan-1 knockout leads to alterations in mechanosensing of nanotopographical cues through alterations of in rho-associated signaling pathways, cell mechanics and mediators of the Hippo and TGF-β signaling pathways.

    更新日期:2017-11-10
  • A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers
    Biomaterials (IF 8.402) Pub Date : 2017-11-09
    Wendong Ke, Wei Yin, Zengshi Zha, Jean Felix Mukerabigwi, Weijian Chen, Yuheng Wang, Chuanxin He, Zhishen Ge

    Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taken paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10−3 g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers.

    更新日期:2017-11-10
  • Spontaneous hair follicle germ (HFG) formation in vitro, enabling the large-scale production of HFGs for regenerative medicine
    Biomaterials (IF 8.402) Pub Date : 2017-11-06
    Tatsuto Kageyama, Chisa Yoshimura, Dina Myasnikova, Ken Kataoka, Tadashi Nittami, Junji Fukuda

    Hair follicle morphogenesis is triggered by reciprocal interactions between hair follicle germ (HFG) epithelial and mesenchymal layers. Here, we developed a method for large-scale preparation of HFGs in vitro via self-organization of cells. We mixed mouse epidermal and mouse/human mesenchymal cells in suspension and seeded them in microwells of a custom-designed array plate. Over a 3-day culture period, cells initially formed a randomly distributed single cell aggregate and then spatially separated from each other, exhibiting typical HFG morphological features. These self-sorted hair follicle germs (ssHFGs) were shown to be capable of efficient hair-follicle and shaft generation upon intracutaneous transplantation into the backs of nude mice. This finding facilitated the large-scale preparation of approximately 5000 ssHFGs in a microwell-array chip made of oxygen-permeable silicone. We demonstrated that the integrity of the oxygen supply through the bottom of the silicone chip was crucial to enabling both ssHFG formation and subsequent hair shaft generation. Finally, spatially aligned ssHFGs on the chip were encapsulated into a hydrogel and simultaneously transplanted into the back skin of nude mice to preserve their intervening spaces, resulting in spatially aligned hair follicle generation. This simple ssHFG preparation approach is a promising strategy for improving current hair-regenerative medicine techniques.

    更新日期:2017-11-10
  • Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture
    Biomaterials (IF 8.402) Pub Date : 2017-11-06
    Junzhe Lou, Ryan Stowers, Sungmin Nam, Yan Xia, Ovijit Chaudhuri

    The physical and architectural cues of the extracellular matrix (ECM) play a critical role in regulating important cellular functions such as spreading, migration, proliferation, and differentiation. Natural ECM is a complex viscoelastic scaffold composed of various distinct components that are often organized into a fibrillar microstructure. Hydrogels are frequently used as synthetic ECMs for 3D cell culture, but are typically elastic, due to covalent crosslinking, and non-fibrillar. Recent work has revealed the importance of stress relaxation in viscoelastic hydrogels in regulating biological processes such as spreading and differentiation, but these studies all utilize synthetic ECM hydrogels that are non-fibrillar. Key mechanotransduction events, such as focal adhesion formation, have only been observed in fibrillar networks in 3D culture to date. Here we present an interpenetrating network (IPN) hydrogel system based on HA crosslinked with dynamic covalent bonds and collagen I that captures the viscoelasticity and fibrillarity of ECM in tissues. The IPN hydrogels exhibit two distinct processes in stress relaxation, one from collagen and the other from HA crosslinking dynamics. Stress relaxation in the IPN hydrogels can be tuned by modulating HA crosslinker affinity, molecular weight of the HA, or HA concentration. Faster relaxation in the IPN hydrogels promotes cell spreading, fiber remodeling, and focal adhesion (FA) formation – behaviors often inhibited in other hydrogel-based materials in 3D culture. This study presents a new, broadly adaptable materials platform for mimicking key ECM features of viscoelasticity and fibrillarity in hydrogels for 3D cell culture and sheds light on how these mechanical and structural cues regulate cell behavior.

    更新日期:2017-11-10
  • In situ label-free monitoring of human adipose-derived mesenchymal stem cell differentiation into multiple lineages
    Biomaterials (IF 8.402) Pub Date : 2017-11-05
    Intan Rosalina Suhito, Yoojoong Han, Junhong Min, Hyungbin Son, Tae-Hyung Kim

    Precise characterizations of stem cell differentiation into specific lineages, especially in non-destructive and non-invasive manner, are extremely important for generating patient-specific cells without mass loss of differentiated cells. Here, we report a new method capable of in situ label-free quantification of stem cell differentiation into multiple lineages, even at a single cell level. The human adipose-derived mesenchymal stem cells (hADMSCs) were first differentiated into two different types of cells (osteoblasts and adipocytes) and these differentiated cells were then intensively analyzed by micro-Raman spectroscopy. Interestingly, the Raman peaks assigned to lipid droplets and hydroxyapatite were found to be highly specific to the adipocyte (fat cell) and osteoblast (bone cell) and were thus found to be useful for generating label-free single cell Raman images in combination with CH3 (2935 cm−1) peaks for visualizing cell shape. Remarkably, based on these Raman images, we found that the osteogenesis of hADMSCs could be determined and quantified after 9 days of differentiation, which is a week earlier than with the typical alizarin red staining method. In the case of adipogenesis, the increase of lipid droplets in the cytoplasm at the single cell level could be clearly visualized and detected during the entire period of adipogenesis, which is impossible using any other currently available methods such as Oil Red O and immunostaining. Hence, the new method reported in this study is highly promising as an analytical tool for precise in-situ monitoring of stem cell differentiation, and could facilitate the use of stem cell-based materials for the regenerative therapies.

    更新日期:2017-11-05
  • Shape-controlled magnetic mesoporous silica nanoparticles for magnetically-mediated suicide gene therapy of hepatocellular carcinoma
    Biomaterials (IF 8.402) Pub Date : 2017-11-04
    Zheng Wang, Zhimin Chang, Mengmeng Lu, Dan Shao, Yue Juan, Dian Yang, Xiao Zheng, Mingqiang Li, Kan He, Ming Zhang, Li Chen, Wen-fei Dong

    Magnetic nanoparticles (NPs) have emerged as a promising tool for suicide gene therapy. However, the separate delivery of the suicide gene and prodrug in current systems limits their clinical translation. Therefore, improving magnetically mediated suicide gene therapy by exploring higher performance magnetic NP-based hybrid nanoplatforms is an important challenge. In the current study, shape-controlled magnetic mesoporous silica nanoparticles (M-MSNs) were prepared, and their performance in magnetic resonance imaging (MRI)-guided, magnetically targeted and hyperthermia-enhanced suicide gene therapy of hepatocellular carcinoma (HCC) was investigated. Compared with sphere-like MSNs, rod-like MSNs exhibited higher loading capacity, faster prodrug release behavior, stronger magnetically enhanced gene delivery and better magnetic hyperthermia properties. Utilizing the improved magnetic properties of the M-MSNs allowed us to demonstrate highly effective dual magnetically enhanced suicide gene therapy in vivo with decreased systematic toxicity and with the ability to monitor therapeutic outcome by MRI. Because of their magnetic targeting abilities, magnetic hyperthermia performance and MRI properties, these M-MSNs might prove to be a potentially superior candidate for suicide gene therapy of HCC.

    更新日期:2017-11-05
  • Bone mesenchymal stem cell secretion of sRANKL/OPG/M-CSF in response to macrophage-mediated inflammatory response influences osteogenesis on nanostructured Ti surfaces
    Biomaterials (IF 8.402) Pub Date : 2017-11-04
    Qian-li Ma, Liang Fang, Nan Jiang, Liang Zhang, Ying Wang, Yu-mei Zhang, Li-hua Chen

    Although it has been well established that osteogenic differentiation of bone mesenchymal stem cells (bMSCs) as well as osteoclastic differentiation of macrophages can be manipulated by the nanostructure of biomaterial surfaces, the interactions among the effects of the surface on immune cells and bMSCs remained unknown. Therefore, in this study, the osteogenic behaviors and secretion of osteoclastogenesis-related cytokines of human bMSCs on TiO2 nanotubular (NT) surfaces in conditioned medium (CM) generated by macrophages cultured on the respective NT surfaces (NT-CM) were analyzed. Although bMSCs showed consistent osteogenic behaviors on the NT5 and NT20 surfaces in both standard culture medium and both types of NT-CM, collagen synthesis and extracellular matrix mineralization were partially impeded on the NT20 surface in NT20-CM and bMSC cytokine secretions on the NT20 surface in NT20-CM elicited remarkable multinuclear giant cell and osteoclast formation compared with that observed on the NT5 surface in NT5-CM. After implantation in vivo, mineralized bone formation was significantly delayed around the NT20 implant compared with the NT5 implant, but both surfaces contributed to good bone formation after 12 weeks. The results obtained in this study advance our understanding of the confounding influence of the implant surface nanostructure, macrophage inflammatory response, and osteogenic differentiation of bMSCs as well as the retro-regulative effects of bMSCs on the osteoclastic differentiation of macrophages, and the culture system based on different NT surfaces and CM generated on the respective surfaces may provide a systematic research model for evaluating the performance of endosseous implants as well as a prospective approach for improving implant osseointegration via immune-regulation.

    更新日期:2017-11-05
  • 更新日期:2017-11-05
  • Human embryonic stem cell-derived cardiovascular progenitor cells efficiently colonize in bFGF-tethered natural matrix to construct contracting humanized rat hearts
    Biomaterials (IF 8.402) Pub Date : 2017-11-01
    Sarah Rajabi, Sara Pahlavan, Mohammad Kazemi Ashtiani, Hassan Ansari, Saeed Abbasalizadeh, Forough Azam Sayahpour, Fahimeh Varzideh, Sawa Kostin, Nasser Aghdami, Thomas Braun, Hossein Baharvand
    更新日期:2017-11-02
  • An injectable, electrostatically interacting drug depot for the treatment of rheumatoid arthritis
    Biomaterials (IF 8.402) Pub Date : 2017-11-01
    Ji Hoon Park, Seung Hun Park, Hye Yun Lee, Jin Woo Lee, Bo Keun Lee, Bun Yeoul Lee, Jae Ho Kim, Moon Suk Kim

    To the best of our knowledge, no studies have yet examined the electrostatic interaction of polyelectrolytes with electrolyte drugs for the treatment of rheumatoid arthritis (RA). Here, an injectable, electrostatically interacting drug depot is described. We prepared methoxy polyethylene glycol-b-(poly(ε-caprolactone)-ran-poly(l-lactic acid) (MC) diblock copolymers with a carboxylic acid group (MC-C) at the pendant position. MC-C was polyelectrolytes that exhibited negative zeta potentials. Sulfasalazine [Sul(−)] and minocycline [Min(+)], electrolyte RA drugs, exhibited negative and positive zeta potentials, respectively. The electrolyte RA drugs were loaded into the polyelectrolyte MC-C solution to prepare injectable, electrostatically interacting depot formulations. The formulation with an attractive electrostatic interaction [Min(+)-MC-C] exhibited gradual release of Min(+) from the MC-C depot over an extended period and suppressed the growth of inflammatory RAW 264.7 cells without affecting synovial cells. Mature chondrocytes were observed after H&E and safranin O staining of the cartilage of Min(+)-MC-C intra-articularly injected RA-induced rats. In comparison with other formulations, Min(+)-MC-C induced the suppression of the expression of pro-inflammatory proteins TNF-α and IL-1β in the articular knee joint, which resulted in the amelioration of RA. In conclusion, an injectable, electrostatically interacting depot formulation administered through intra-articular injection successfully provided almost complete amelioration of RA.

    更新日期:2017-11-02
  • Tissue adhesive FK506–loaded polymeric nanoparticles for multi–layered nano–shielding of pancreatic islets to enhance xenograft survival in a diabetic mouse model
    Biomaterials (IF 8.402) Pub Date : 2017-11-01
    Tung Thanh Pham, Tiep Tien Nguyen, Shiva Pathak, Shobha Regmi, Hanh Thuy Nguyen, Tuan Hiep Tran, Chul Soon Yong, Jong Oh Kim, Pil–Hoon Park, Min Hui Park, Young Kyung Bae, Jeong Uk Choi, Youngro Byun, Cheol–Hee Ahn, Simmyung Yook, Jee–Heon Jeong

    This study aims to develop a novel surface modification technology to prolong the survival time of pancreatic islets in a xenogenic transplantation model, using 3,4–dihydroxyl–l–phenylalanine (DOPA) conjugated poly(lactide–co–glycolide)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (DOPA–NPs) carrying immunosuppressant FK506 (FK506/DOPA–NPs). The functionalized DOPA–NPs formed a versatile coating layer for antigen camouflage without interfering the viability and functionality of islets. The coating layer effectively preserved the morphology and viability of islets in a co–culture condition with xenogenic lymphocytes for 7 days. Interestingly, the mean survival time of islets coated with FK506/DOPA–NPs was significantly higher as compared with that of islets coated with DOPA–NPs (without FK506) and control. This study demonstrated that the combination of surface camouflage and localized low dose of immunosuppressant could be an effective approach in prolonging the survival of transplanted islets. This newly developed platform might be useful for immobilizing various types of small molecules on therapeutic cells and biomaterial surface to improve the therapeutic efficacy in cell therapy and regenerative medicine.

    更新日期:2017-11-01
  • Biological safety and tissue distribution of (16-mercaptohexadecyl)trimethylammonium bromide-modified cationic gold nanorods
    Biomaterials (IF 8.402) Pub Date : 2017-11-01
    Monika Zarska, Michal Sramek, Filip Novotny, Filip Havel, Andrea Babelova, Blanka Mrazkova, Oldrich Benada, Milan Reinis, Ivan Stepanek, Kamil Musilek, Jiri Bartek, Monika Ursinyova, Ondrej Novak, Rastislav Dzijak, Kamil Kuca, Jan Proska, Zdenek Hodny
    更新日期:2017-11-01
  • Multifunctional protein microparticles for medical applications
    Biomaterials (IF 8.402) Pub Date : 2017-10-31
    Hironori Yamazoe
    更新日期:2017-11-01
  • Guiding morphogenesis in cell-instructive microgels for therapeutic angiogenesis
    Biomaterials (IF 8.402) Pub Date : 2017-10-31
    A.L. Torres, S.J. Bidarra, M.T. Pinto, P.C. Aguiar, E.A. Silva, C.C. Barrias
    更新日期:2017-10-31
  • Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure
    Biomaterials (IF 8.402) Pub Date : 2017-10-31
    Yuki Ichihara, Masahiro Kaneko, Kenichi Yamahara, Marinos Koulouroudias, Nobuhiko Sato, Rakesh Uppal, Kenji Yamazaki, Satoshi Saito, Ken Suzuki

    Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix® (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly-produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce “instant” PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM-MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart.

    更新日期:2017-10-31
  • Development of PEGylated aspartic acid-modified liposome as a bone-targeting carrier for the delivery of paclitaxel and treatment of bone metastasis
    Biomaterials (IF 8.402) Pub Date : 2017-10-31
    Shugo Yamashita, Hidemasa Katsumi, Nozomi Hibino, Yugo Isobe, Yumiko Yagi, Yuka Tanaka, Saki Yamada, Chihiro Naito, Akira Yamamoto
    更新日期:2017-10-31
  • A biodegradable scaffold enhances differentiation of embryonic stem cells into a thick sheet of retinal cells
    Biomaterials (IF 8.402) Pub Date : 2017-10-31
    Deepti Singh, Shao-Bin Wang, Tina Xia, Laurel Tainsh, Maryam Ghiassi-Nejad, Tao Xu, Shaomin Peng, Ron Adelman, Lawrence Rizzolo

    Retinal degeneration is a leading cause of blindness in developed countries. Stem cells can be differentiated into retinal organoids to study mechanisms of retinal degeneration, develop therapeutic agents, and potentially serve as replacement tissues. The spherical nature of these retinoids limits their utility, because the investigator lacks ready access to both sides of the neo-tissue. For tissue-replacement, spherical retinoids are unable to interact simultaneously with the host retinal pigment epithelium and remaining neurosensory retina. To attempt making a planar retinoid, we developed a biodegradable scaffold that simulates the extracellular matrix of the neurosensory retina. Human embryonic stem cells were seeded on the scaffold. Differentiation into retinal cells was confirmed by quantitative RT-PCR, confocal immunocytochemistry, and immunoblotting. The scaffold favored differentiation into retinal cell types over other anterior forebrain cells, but retinal lamination was rudimentary. The cultures elicited a minimal immune response when implanted into the subretinal space of a mouse model of retinal degeneration. The implants survived for at least 12 weeks, but there was evidence of cytoplasmic transfer rather than implantation into the outer nuclear layer (photoreceptor layer). However, some implanted cells migrated to the inner layers of the retina and established elaborate arbors of neurites.

    更新日期:2017-10-31
  • Tumor targeted, stealthy and degradable bismuth nanoparticles for enhanced X-ray radiation therapy of breast cancer
    Biomaterials (IF 8.402) Pub Date : 2017-10-30
    Junjie Deng, Shandong Xu, Weike Hu, Xiaojie Xun, Liyuan Zheng, Ming Su
    更新日期:2017-10-31
  • Stem cell-based bone regeneration in diseased microenvironments: challenges and solutions
    Biomaterials (IF 8.402) Pub Date : 2017-10-30
    Bing-Dong Sui, Cheng-Hu Hu, An-Qi Liu, Chen-Xi Zheng, Kun Xuan, Yan Jin

    Restoration of extensive bone loss and defects remain as an unfulfilled challenge in modern medicine. Given the critical contributions to bone homeostasis and diseases, mesenchymal stem cells (MSCs) have shown great promise to jumpstart and facilitate bone healing, with immense regenerative potential in both pharmacology-based endogenous MSC rescue/mobilization in skeletal diseases and emerging application of MSC transplantation in bone tissue engineering and cytotherapy. However, efficacy of MSC-based bone regeneration was not always achieved; particularly, fulfillment of MSC-mediated bone healing in diseased microenvironments of host comorbidities remains as a major challenge. Indeed, impacts of diseased microenvironments on MSC function rely not only on the dynamic regulation of resident MSCs by surrounding niche to convoy pathological signals of bone, but also on the profound interplay between transplanted MSCs and recipient components that mediates and modulates therapeutic effects on skeletal conditions. Accordingly, novel solutions have recently been developed, including improving resistance of MSCs to diseased microenvironments, recreating beneficial microenvironments to guarantee MSC-based regeneration, and usage of subcellular vesicles of MSCs in cell-free therapies. In this review, we summarize state-of-the-art knowledge regarding applications and challenges of MSC-mediated bone healing, further offering principles and effective strategies to optimize MSC-based bone regeneration in aging and diseases.

    更新日期:2017-10-30
  • Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF1/insulin receptors
    Biomaterials (IF 8.402) Pub Date : 2017-10-29
    Tao Jia, Jungyoon Choi, Jéremy Ciccione, Maxime Henry, Ahmad Mehdi, Jean Martinez, Béatrice Eymin, Gilles Subra, Jean-Luc Coll
    更新日期:2017-10-30
  • An astrocyte derived extracellular matrix coating reduces astrogliosis surrounding chronically implanted microelectrode arrays in rat cortex
    Biomaterials (IF 8.402) Pub Date : 2017-10-29
    Robert S. Oakes, Michael D. Polei, John L. Skousen, Patrick A. Tresco

    Available evidence suggests that the magnitude of the foreign body response (FBR) to implants placed in cortical brain tissue is affected by the extent of vasculature damage following device insertion and the magnitude of the ensuing macrophage response. Since the extracellular matrix (ECM) serves as a natural hemostatic and immunomodulatory agent, we examined the ability of an FDA-approved neurosurgical hemostatic coating and an ECM coating derived from primary rat astrocytes to reduce the FBR surrounding a penetrating microelectrode array chronically implanted in rat cortex. Using quantitative methods, we examined various components of the FBR in vitro and after implantation. In vitro assays showed that both coatings accelerated coagulation in a similar fashion but only the astrocyte-derived material suppressed macrophage activation. In addition, the ECM coating derived from astrocytes, also decreased the astrogliotic response 8 weeks after implantation. Neither coating had a significant influence on the intensity or spatial distribution of FBR biomarkers 1 week after implantation or on degree of macrophage activation or neuronal survival at the later time point. The results show that microelectrode coatings with similar hemostatic properties but different immunomodulatory characteristics differentially affect the FBR to an anchored, single-shank, silicon microelectrode array. The results also support the concept that divergent biological pathways affect the various components of the FBR in the CNS and suggests that decreasing its impact will require a multifaceted approach.

    更新日期:2017-10-30
  • Gold nanostar-mediated neural activity control using plasmonic photothermal effects
    Biomaterials (IF 8.402) Pub Date : 2017-10-27
    Jee Woong Lee, Hyun Jun Jung, Hui Hun Cho, Jung Heon Lee, Yoonkey Nam

    Nanomaterials have emerged as an essential tool for the understanding of cellular level mechanism in the fields of biology and medical science. Recently, researchers have been studying the regulation of neuronal activity using plasmonic nanoparticles and light, and it has been reported that photothermal effects could lead to both excitation and inhibition of neuronal cells. So far, only a few photothermal transducers have been applied to modulate neural activity. In this paper, we synthesized biocompatible gold nanostars (AuNS) which generate heat by absorbing near-infrared (NIR) light. And we used the AuNS to inhibit the activity of neurons through light stimulation. We have demonstrated that AuNS inhibits the neural activity by NIR laser in both chip-attached mode and cell-attached mode. We also confirmed the suppression of single neuron signal by using digital micromirror device (DMD) set up. This approach is possible to inhibit the neural firing by controlling the intensity of light, and overcome the disadvantages of conventional electrochemical stimulation methods. This method of NIR-mediated stimulating neurons using light sensitive AuNS will be a powerful tool for neuromodulation researches and neuroscience studies.

    更新日期:2017-10-27
  • 更新日期:2017-10-27
  • Poly(N-isopropylacrylamide)-Based Thermoresponsive Surfaces Provide New Types of Biomedical Applications
    Biomaterials (IF 8.402) Pub Date : 2017-10-27
    Kenichi Nagase, Masayuki Yamato, Hideko Kanazawa, Teruo Okano
    更新日期:2017-10-27
  • A tumor-activatable particle with antimetastatic potential in breast cancer via inhibiting the autophagy-dependent disassembly of focal adhesion
    Biomaterials (IF 8.402) Pub Date : 2017-10-27
    Yang Wang, Sheng Yin, Li Zhang, Kairong Shi, Jiajing Tang, Zhirong Zhang, Qin He
    更新日期:2017-10-27
  • Near infrared dye-conjugated oxidative stress amplifying polymer micelles for dual imaging and synergistic anticancer phototherapy
    Biomaterials (IF 8.402) Pub Date : 2017-10-27
    Wonseok Yang, Joungyoun Noh, Hoyeon Park, Sian Gwon, Berwin Singh, Chulgyu Song, Dongwon Lee

    The recent advances in nanotechnology have led to the development of smart nanomaterials that combine diagnostic and therapeutic functions and provide synergistic anticancer effects through the combination of different treatment modalities. Here, we report a promising theranostic nanoconstruct that can translate into multiple functionalities: fluorescence/photoacoustic imaging, acid-triggered generation of ROS (reactive oxygen species), heat and singlet oxygen production under near infrared (NIR) laser irradiation, and coupling oxidative anticancer therapy to dual imaging-guided photothermal/photodynamic therapy. An NIR dye-conjugated hydroxyl radical generating biodegradable polymer (HRGP-IR) is employed as a theranostic nanoplatform. HRGP-IR could self-assemble to form micelles and elevate oxidative stress by generating hydrogen peroxide and hydroxyl radical. Under the NIR (808 nm) laser irradiation, HRGP-IR micelles also generate heat and singlet oxygen to induce cancer cell death. In mouse xenograft models, HRGP-IR micelles accumulated in tumors preferentially and the tumor could be detected by dual imaging. Effective tumor ablation was achieved by HRGP-IR micelles (5 mg/kg) combined with NIR laser irradiation, demonstrating the synergistic anticancer effects of oxidative stress with photothermal heating. Given their dual imaging capability, anticancer phototherapy and highly potent synergistic anticancer activity with NIR laser irradiation, HRGP-IR micelles hold great potential as a nanotheranostic agent for cancer treatment.

    更新日期:2017-10-27
  • Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells
    Biomaterials (IF 8.402) Pub Date : 2017-10-26
    Zhixiang Tong, Keir Martyn, Andy Yang, Xiaolei Yin, Benjamin E. Mead, Nitin Joshi, Nicholas E. Sherman, Robert S. Langer, Jeffrey M. Karp

    Current ISC culture systems face significant challenges such as animal-derived or undefined matrix compositions, batch-to-batch variability (e.g. Matrigel-based organoid culture), and complexity of assaying cell aggregates such as organoids which renders the research and clinical translation of ISCs challenging. Here, through screening for suitable ECM components, we report a defined, collagen based monolayer culture system that supports the growth of mouse and human intestinal epithelial cells (IECs) enriched for an Lgr5+ population comparable or higher to the levels found in a standard Matrigel-based organoid culture. The system, referred to as the Bolstering Lgr5 Transformational (BLT) Sandwich culture, comprises a collagen IV-coated porous substrate and a collagen I gel overlay which sandwich an IEC monolayer in between. The distinct collagen cues synergistically regulate IEC attachment, proliferation, and Lgr5 expression through maximizing the engagement of distinct cell surface adhesion receptors (i.e. integrin α2β1, integrin β4) and cell polarity. Further, we apply our BLT Sandwich system to identify that the addition of a bone morphogenetic protein (BMP) receptor inhibitor (LDN-193189) improves the expansion of Lgr5-GFP+ cells from mouse small intestinal crypts by nearly 2.5-fold. Notably, the BLT Sandwich culture is capable of expanding human-derived IECs with higher LGR5 mRNA levels than conventional Matrigel culture, providing superior expansion of human LGR5+ ISCs. Considering the key roles Lgr5+ ISCs play in intestinal epithelial homeostasis and regeneration, we envision that our BLT Sandwich culture system holds great potential for understanding and manipulating ISC biology in vitro (e.g. for modeling ISC-mediated gut diseases) or for expanding a large number of ISCs for clinical utility (e.g. for stem cell therapy).

    更新日期:2017-10-26
  • Functional differences between healthy and diabetic endothelial cells on topographical cues
    Biomaterials (IF 8.402) Pub Date : 2017-10-25
    Marie F.A. Cutiongco, Bryan M.X. Chua, Dawn J.H. Neo, Muhammad Rizwan, Evelyn K.F. Yim
    更新日期:2017-10-25
  • Porous composite scaffold incorporating osteogenic phytomolecule icariin for promoting skeletal regeneration in challenging osteonecrotic bone in rabbits
    Biomaterials (IF 8.402) Pub Date : 2017-10-23
    Yuxiao Lai, Huijuan Cao, Xinluan Wang, Shukui Chen, Ming Zhang, Nan Wang, Zhihong Yao, Yi Dai, Xinhui Xie, Peng Zhang, Xinsheng Yao, Ling Qin
    更新日期:2017-10-23
  • Mitochondrial specific photodynamic therapy by rare-earth nanoparticles mediated near-infrared graphene quantum dots
    Biomaterials (IF 8.402) Pub Date : 2017-10-23
    Dandan Zhang, Liewei Wen, Ru Huang, Huanhuan Wang, Xianglong Hu, Da Xing

    Photodynamic therapy (PDT) has been proposed in cancer treatment for decades, but its clinical translation is significantly impeded by the low yield of ROS, poor tissue penetration depth of most current photosensitizers, and short lifetime of ROS. These limitations directly affect the therapeutic effect of PDT in cancer therapy. Here we proposed a new strategy by collaboratively integrating rare-earth doped upconversion nanoparticles (UCNP) with graphene quantum dot (GQD) for highly efficacious PDT, based on the merits of UCNP, which can emit UV-vis light under near-infrared light (NIR) excitation, and GQD, which can produce 1O2 efficiently. For GQD-decorated UCNP nanoparticles (UCNP-GQD), the emission light from UCNP can further excite GQD with prominent 1O2 generation for NIR-triggered PDT. Furthermore, a hydrophilic rhodamine derivative, TRITC, is covalently tethered to afford the resultant UCNP-GQD/TRITC, possessing distinct mitochondrial targeting property. Thus mitochondrial specific PDT with in-situ1O2 burst in mitochondria induces sharp decrease of mitochondrial membrane potential, which initiates the tumor cell apoptosis irreversibly. Importantly, in vivo experiments demonstrate the tumor inhibition of mitochondrial targeting UCNP-GQD/TRITC with improved therapeutic efficiency compared with non-targeting UCNP-GQD. The proposed strategy highlights the advantages of precision organelles-specific PDT in cancer therapy.

    更新日期:2017-10-23
  • CD169+ macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair
    Biomaterials (IF 8.402) Pub Date : 2017-10-22
    Lena Batoon, Susan Marie Millard, Martin Eduard Wullschleger, Corina Preda, Andy Chiu-Ku Wu, Simranpreet Kaur, Hsu-Wen Tseng, David Arthur Hume, Jean-Pierre Levesque, Liza Jane Raggatt, Allison Robyn Pettit

    Osteal macrophages (osteomacs) contribute to bone homeostasis and regeneration. To further distinguish their functions from osteoclasts, which share many markers and growth factor requirements, we developed a rapid, enzyme-free osteomac enrichment protocol that permitted characterization of minimally manipulated osteomacs by flow cytometry. Osteomacs differ from osteoclasts in expression of Siglec1 (CD169). This distinction was confirmed using the CD169-diphtheria toxin (DT) receptor (DTR) knock-in model. DT treatment of naïve CD169-DTR mice resulted in selective and striking loss of osteomacs, whilst osteoclasts and trabecular bone area were unaffected. Consistent with a previously-reported trophic interaction, osteomac loss was accompanied by a concomitant and proportionately striking reduction in osteoblasts. The impact of CD169+ macrophage depletion was assessed in two models of bone injury that heal via either intramembranous (tibial injury) or endochondral (internally-plated femoral fracture model) ossification. In both models, CD169+ macrophage, including osteomac depletion compromised bone repair. Importantly, DT treatment in CD169-DTR mice did not affect osteoclast frequency in either model. In the femoral fracture model, the magnitude of callus formation correlated with the number of F4/80+ macrophages that persisted within the callus. Overall these observations provide compelling support that CD169+ osteomacs, independent of osteoclasts, provide vital pro-anabolic support to osteoblasts during both bone homeostasis and repair.

    更新日期:2017-10-23
  • Macrophages as a potential tumor-microenvironment target for noninvasive imaging of early response to anticancer therapy
    Biomaterials (IF 8.402) Pub Date : 2017-10-21
    Qizhen Cao, Xinrui Yan, Kai Chen, Qian Huang, Marites P. Melancon, Gabriel Lopez, Zhen Cheng, Chun Li

    As a result of therapy-induced apoptosis, peripheral blood monocytes are recruited to tumors, where they become tumor-associated macrophages (TAMs). To date, few studies have investigated noninvasive molecular imaging for assessment of macrophage infiltration in response to therapy-induced apoptosis. Here, noninvasive assessment of changes in tumor accumulation of TAMs was proposed as a new way to measure early tumor response to anticancer therapy. Three different nanoparticles, QD710-Dendron quantum dots (QD710-D), Ferumoxytol, and PG-Gd-NIR813, were used for near-infrared fluorescence imaging, T2-weighted magnetic resonance imaging, and dual optical/T1-weighted MR imaging, respectively, in the MDA-MB-435 tumor model. Treatment with Abraxane induced tumor apoptosis and infiltrating macrophages. In spite of markedly different physicochemical properties among the nanoparticles, in vivo imaging revealed increased uptake of all three nanoparticles in Abraxane-treated tumors compared with untreated tumors. Moreover, imaging visualized increased uptake of QD710-D in MDA-MB-435 tumors but not in drug-resistant MDA-MB-435R tumors grown in the mice treated with Abraxane. Our results suggest that infiltration of macrophages due to chemotherapy-induced apoptosis was partially responsible for increased nanoparticle uptake in treated tumors. Noninvasive imaging techniques in conjunction with systemic administration of imageable nanoparticles that are taken up by macrophages are a potentially useful tool for assessing early treatment response.

    更新日期:2017-10-21
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.
化学 • 材料 期刊列表