Journal Sciences News
Toxicology
September 2018
Engineered stem cell mimics to enhance stroke recovery
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Paul M. George, Byeongtaek Oh, Ruby Dewi, Thuy Hua, Lei Cai, Alexa Levinson, Xibin Liang, Brad A. Krajina, Tonya M. Bliss, Sarah C. Heilshorn, Gary K. Steinberg Currently, no medical therapies exist to augment stroke recovery. Stem cells are an intriguing treatment option being evaluated, but cell-based therapies have several challenges including developing a stable cell product with long term reproducibility. Since much of the improvement observed from cellular therapeutics is believed to result from trophic factors the stem cells release over time, biomaterials are well-positioned to deliver these important molecules in a similar fashion. Here we show that essential trophic factors secreted from stem cells can be effectively released from a multi-component hydrogel system into the post-stroke environment. Using our polymeric system to deliver VEGF-A and MMP-9, we improved recovery after stroke to an equivalent degree as observed with traditional stem cell treatment in a rodent model. While VEGF-A and MMP-9 have many unique mechanisms of action, connective tissue growth factor (CTGF) interacts with both VEGF-A and MMP-9. With our hydrogel system as well as with stem cell delivery, the CTGF pathway is shown to be downregulated with improved stroke recovery.
September 2018
Mussel-inspired catalytic selenocystamine-dopamine coatings for long-term generation of therapeutic gas on cardiovascular stents
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Zhilu Yang, Ying Yang, Li Zhang, Kaiqin Xiong, Xiangyang Li, Feng Zhang, Jin Wang, Xin Zhao, Nan Huang The development of a nitric oxide (NO)-generating surface with long-term, stable and controllable NO release improves the therapeutic efficacy of cardiovascular stents. In this work, we developed a ôone-potö method inspired by mussel adhesive proteins for copolymerization of selenocystamine (SeCA) and dopamine (Dopa) to form a NO-generating coating on a 316
September 2018
Multi-channel silk sponge mimicking bone marrow vascular niche for platelet production
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Lorenzo Tozzi, Pierre-Alexandre Laurent, Christian A. Di Buduo, Xuan Mu, Angelo Massaro, Ross Bretherton, Whitney Stoppel, David L. Kaplan, Alessandra Balduini In the bone marrow, the interaction of progenitor cells with the vasculature is fundamental for the release of blood cells into circulation. Silk fibroin, derived from Bombyx mori silkworm cocoons, is a promising protein biomaterial for bone marrow tissue engineering, because of its tunable architecture and mechanical properties, the capacity to incorporate labile compounds without loss of bioactivity and the demonstrated ability to support blood cell formation without premature activation. In this study, we fabricated a custom perfusion chamber to contain a multi-channel lyophilized silk sponge mimicking the vascular network in the bone marrow niche. The perfusion system consisted in an inlet and an outlet and 2 splitters that allowed funneling flow in each single channel of the silk sponge. Computational Fluid Dynamic analysis demonstrated that this design permitted confined flow inside the vascular channels. The silk channeled sponge supported efficient platelet release from megakaryocytes (Mks). After seeding, the Mks localized along SDF-1
September 2018
Promoting inávivo early angiogenesis with sub-micrometer strontium-contained bioactive microspheres through modulating macrophage phenotypes
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Fujian Zhao, Bo Lei, Xian Li, Yunfei Mo, Renxian Wang, Dafu Chen, Xiaofeng Chen Early vascularization capacity of biomaterials plays an essential role in efficient wound healing and tissue regeneration, especially in large tissue tension implanting position such as bone augmentation. Strontium-contained silica-based bioactive materials have shown the role of promoting angiogenesis by stimulating osteoblasts to secrete angiogenesis related cytokines. However, osteoblasts have little effect on early angiogenesis due to the inflammatory reaction of implantation site. Here, for the first time, we found that the monodispersed strontium-contained bioactive glasses microspheres (SrBGM) could significantly promote the early angiogenesis through regulating macrophage phenotypes. After being stimulated with SrBGM inávitro, RAW cells (macrophages) presented a trend towards to M2 phenotype and expressed high level of platelet-derived growth factor-BB (PDGF-BB). Moreover, the RAW conditioned medium of SrBGM significantly enhanced the angiogenic capacity of HUVECs. The inávivo early vascularization studies showed that significant new vessels were observed at the center of SrBGM-based scaffolds after implantation for 1 week in a bone defect model of rats, suggesting their enhanced early vascularization. Due to the efficient vascularization, the inávivo new bone formation was promoted significantly. Our study may provide a novel strategy to promote the early vascularization of biomaterials through modulating the microphage phenotypes, which has wide applications in various tissue regeneration and wound healing.

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September 2018
Biocompatible PEGylated Gold nanorods function As cytokinesis inhibitors to suppress angiogenesis
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Hongyuan Song, Ting Guo, Zichang Zhao, Youheng Wei, Haoyang Luo, Weizong Weng, Rui Zhang, Ming Zhong, Chunying Chen, Jiacan Su, Wei Shen Pathological angiogenesis is driven by uncontrolled growth of endothelial cells (ECs), which could lead to retinopathy, tumor and rheumatoid arthritis, etc. ECs must experience multiple cell division process to grow, and cytokinesis is the final step. The present study shows that PEGylated GNRs (PEG-GNRs) specifically target ECs cytokinesis process which results in high ratio of binucleated cells, and these binucleated ECs lose the ability to proliferate. Further data show that PEG-GNRs do not induce toxicity inávitro and inávivo. PEG-GNRs could inhibit ECs proliferation, migration, tube formation and inhibit angiogenesis in exávivo model. Oxygen induced retinopathy and tumor angiogenesis model further show that PEG-GNRs can inhibit angiogenesis inávivo. Gene expression profiles reveal that PEG-GNRs mainly affect ECs cell division process, and PEG-GNRs treated ECs are arrested in G2/M phase. The mechanism is that PEG-GNRs could disrupt TGF
September 2018
Multimode ultrasound viscoelastography for three-dimensional interrogation of microscale mechanical properties in heterogeneous biomaterials
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Xiaowei Hong, Ramkumar T. Annamalai, Tyler S. Kemerer, Cheri X. Deng, Jan P. Stegemann Both static and time-dependent mechanical factors can have a profound impact on cell and tissue function, but it is challenging to measure the mechanical properties of soft materials at the scale which cells sense. Multimode ultrasound viscoelastography (MUVE) uses focused ultrasound pulses to both generate and image deformations within soft hydrogels non-invasively, at sub-millimeter resolution, and in 3D. The deformation and strain over time data are used to extract quantitative parameters that describe both the elastic and viscoelastic properties of the material. MUVE was used in creep mode to characterize the viscoelastic properties of 3D agarose, collagen, and fibrin hydrogels. Quantitative comparisons were made by extracting characteristic viscoelastic parameters using Burger's lumped parameter constitutive model. Spatial resolution of the MUVE technique was found to be approximately 200
September 2018
Producing anti-inflammatory macrophages by nanoparticle-triggered clustering of mannose receptors
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Jingjing Gan, Yunyan Dou, Yurong Li, Zhenzhen Wang, Lintao Wang, Shang Liu, Qiu Li, Heran Yu, Chunyan Liu, Congwei Han, Zhen Huang, Junfeng Zhang, Chunming Wang, Lei Dong Macrophages are highly plastic cells that can either mediate or suppress inflammation, depending on their cellular phenotype and cytokine secretion. Inducing macrophages from an inflammatory (ĹM1ĺ) to anti-inflammatory (ĹM2ĺ) phenotype has significant implications for the treatment of inflammatory diseases and regeneration of injured tissues. Although certain cytokines, such as interleukin-4 and -13, are known to induce this phenotypic switch, their therapeutic use inávivo has both safety and efficacy concerns. Here, we demonstrate an alternative approach to change macrophage phenotype from M1 to M2, through inducing the clustering of mannose receptors (MR) on the cell surface, by using carbohydrate-presenting substrates. We prepared and screened glucomannan-decorated silicon oxide of different sizes ranging from 10 to 1000
September 2018
Integrin
September 2018
Nitroxide radical-containing nanoparticles attenuate tumorigenic potential of triple negative breast cancer
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Babita Shashni, Yukio Nagasaki The critical importance of reactive oxygen species (ROS) as oncogene activators and essential secondary messengers in cancer cell survival have been widely reported. Since oxidative stress has been implicated as being pivotal in various cancers, antioxidant therapy seems an apt strategy to abrogate ROS-mediated cellular processes to attenuate cancers. We therefore synthesized ROS scavenging nitroxide radical-containing nanoparticles (RNPs); pH insensitive RNPO and pH sensitive RNPN, to impede the proliferative and metastatic characteristics of the triple negative breast cancer cell line, MDA-MB-231, both inávitro and inávivo. RNPs significantly curtailed the proliferative and clonogenic potential of MDA-MB-231 and MCF-7
September 2018
CD4 T-cells regulate angiogenesis and myogenesis
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): Brian J. Kwee, Erica Budina, Alexander J. Najibi, David J. Mooney Ischemic diseases, such as peripheral artery disease, affect millions of people worldwide. While CD4+ T-cells regulate angiogenesis and myogenesis, it is not understood how the phenotype of these adaptive immune cells regulate these regenerative processes. The secreted factors from different types of CD4+ T-cells (Th1, Th2, Th17, and Treg) were utilized in a series of inávitro assays and delivered from an injectable alginate biomaterial into a murine model of ischemia to study their effects on vascular and skeletal muscle regeneration. Conditioned medium from Th2 and Th17
September 2018
Biomimetic O2-Evolving metal-organic framework nanoplatform for highly efficient photodynamic therapy against hypoxic tumor
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): 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
September 2018
Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa
Publication date: September 2018
Source:Biomaterials, Volume 178 Author(s): 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 Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are chronic inflammatory conditions often characterised by erosive and/or painful oral lesions that have a considerable impact on quality of life. Current treatment often necessitates the use of steroids in the form of mouthwashes, creams or ointments, but these are often ineffective due to inadequate drug contact times with the lesion. Here we evaluate the performance of novel mucoadhesive patches for targeted drug delivery. Electrospun polymeric mucoadhesive patches were produced and characterised for their physical properties and cytotoxicity before evaluation of residence time and acceptability in a human feasibility study. Clobetasol-17-propionate incorporated into the patches was released in a sustained manner in both tissue-engineered oral mucosa and exávivo porcine mucosa. Clobetasol-17 propionate-loaded patches were further evaluated for residence time and drug release in an inávivo animal model and demonstrated prolonged adhesion and drug release at therapeutic-relevant doses and time points. These data show that electrospun patches are adherent to mucosal tissue without causing tissue damage, and can be successfully loaded with and release clinically active drugs. These patches hold great promise for the treatment of oral conditions such as OLP and RAS, and potentially many other oral lesions.

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September 2018
Annealing novel nucleobase-lipids with oligonucleotides or plasmid DNA based on H-bonding or
September 2018
3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Joseph Candiello, Taraka Sai Pavan Grandhi, Saik Kia Goh, Vimal Vaidya, Maya Lemmon-Kishi, Kiarash Rahmani Eliato, Robert Ros, Prashant N. Kumta, Kaushal Rege, Ipsita Banerjee Organoids, which exhibit spontaneous organ specific organization, function, and multi-cellular complexity, are in essence the inávitro reproduction of specific inávivo organ systems. Recent work has demonstrated human pluripotent stem cells (hPSCs) as a viable regenerative cell source for tissue-specific organoid engineering. This is especially relevant for engineering islet organoids, due to the recent advances in generating functional beta-like cells from human pluripotent stem cells. In this study, we report specific engineering of regenerative islet organoids of precise size and cellular heterogeneity, using a novel hydrogel system, Amikagel. Amikagel facilitated controlled and spontaneous aggregation of human embryonic stem cell derived pancreatic progenitor cells (hESC-PP) into robust homogeneous spheroids. This platform further allowed fine control over the integration of multiple cell populations to produce heterogeneous spheroids, which is a necessity for complex organoid engineering. Amikagel induced hESC-PP spheroid formation enhanced pancreatic islet-specific Pdx-1 and NKX6.1 gene and protein expression, while also increasing the percentage of committed population. hESC-PP spheroids were further induced towards mature beta-like cells which demonstrated increased Beta-cell specific INS1 gene and C-peptide protein expression along with functional insulin production in response to inávitro glucose challenge. Further integration of hESC-PP with biologically relevant supporting endothelial cells resulted in multicellular organoids which demonstrated spontaneous maturation towards islet-specific INS1 gene and C-peptide protein expression along with a significantly developed extracellular matrix support system. These findings establish Amikagel ľfacilitated platform ideal for islet organoid engineering.
September 2018
Transfection of gene regulation nanoparticles complexed with pDNA and shRNA controls multilineage differentiation of hMSCs
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Hye Jin Kim, Se Won Yi, Hyun Jyung Oh, Jung Sun Lee, Ji Sun Park, Keun-Hong Park Overexpression and knockdown of specific proteins can control stem cell differentiation for therapeutic purposes. In this study, we fabricated RUNX2, SOX9, and C/EBP
September 2018
Reactive oxygen species scavenging with a biodegradable, thermally responsive hydrogel compatible with soft tissue injection
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Yang Zhu, Yasumoto Matsumura, Murugesan Velayutham, Lesley M. Foley, T. Kevin Hitchens, William R. Wagner Tissue damage and the impairment of regenerative processes by excessive reactive oxygen species (ROS) contributes to the pathogenesis of various diseases in soft tissues including diabetes, atherosclerosis, Parkinson's disease and myocardial ischemic/reperfusion injury. In this study, a thermally responsive injectable hydrogel poly(NIPAAm-co-VP-co-MAPLA-co-MATEMPO) (pNVMT, NIPAAm: N-isopropylacrylamide, VP: vinylpyrrolidone, MAPLA: methacrylate-polylactide, MATEMPO: methacrylate-TEMPO, TEMPO: 4-amino-TEMPO or 4-Amino-2,2,6,6-tetramethylpiperidine-1-oxyl) incorporating recyclable ROS scavenging nitroxide radicals on the polymer backbone was developed to locally control adverse tissue effects from free radical generation. In an inávitro oxidative environment, TEMPO Gel significantly preserved cell viability. In a rat myocardial infarction/reperfusion model, TEMPO Gel diffused through the infarcted myocardium, integrated with the tissue upon gelation, and remained for over one week as visualized by MRI. The TEMPO Gel reduced infarction/reperfusion injury and preserved left ventricle geometry. This thermally responsive hydrogel was demonstrated to have properties desirable for local application to soft tissue beds where oxidative damage by ROS is of concern in pathological mechanisms.
September 2018
Acellular vascular matrix grafts from human placenta chorion: Impact of ECM preservation on graft characteristics, protein composition and inávivo performance
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Karl H. Schneider, Marjan Enayati, Christian Grasl, Ingrid Walter, Lubos Budinsky, Gabriel Zebic, Christoph Kaun, Anja Wagner, Klaus Kratochwill, Heinz Redl, Andreas H. Teuschl, Bruno K. Podesser, Helga Bergmeister Small diameter vascular grafts from human placenta, decellularized with either Triton X-100 (Triton) or SDS and crosslinked with heparin were constructed and characterized. Graft biochemical properties, residual DNA, and protein composition were evaluated to compare the effect of the two detergents on graft matrix composition and structural alterations. Biocompatibility was tested inávitro by culturing the grafts with primary human macrophages and inávivo by subcutaneous implantation of graft conduits (n
September 2018
Transcutaneously refillable, 3D-printed biopolymeric encapsulation system for the transplantation of endocrine cells
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Marco Farina, Corrine Ying Xuan Chua, Andrea Ballerini, Usha Thekkedath, Jenolyn F. Alexander, Jessica R. Rhudy, Gianluca Torchio, Daniel Fraga, Ravi R. Pathak, Mariana Villanueva, Crystal S. Shin, Jean A. Niles, Raffaella Sesana, Danilo Demarchi, Andrew G. Sikora, Ghanashyam S. Acharya, A. Osama Gaber, Joan E. Nichols, Alessandro Grattoni Autologous cell transplantation holds enormous promise to restore organ and tissue functions in the treatment of various pathologies including endocrine, cardiovascular, and neurological diseases among others. Even though immune rejection is circumvented with autologous transplantation, clinical adoption remains limited due to poor cell retention and survival. Cell transplant success requires homing to vascularized environment, cell engraftment and importantly, maintenance of inherent cell function. To address this need, we developed a three dimensional (3D) printed cell encapsulation device created with polylactic acid (PLA), termed neovascularized implantable cell homing and encapsulation (NICHE). In this paper, we present the development and systematic evaluation of the NICHE inávitro, and the inávivo validation with encapsulated testosterone-secreting Leydig cells in Rag1
September 2018
Novel theranostic nanoplatform for complete mice tumor elimination via MR imaging-guided acid-enhanced photothermo-/chemo-therapy
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Bei Li, Jie Tang, Weiyu Chen, Guanyu Hao, Nyoman Kurniawan, Zi Gu, Zhi Ping Xu Non-invasive imaging-guided tumor therapy requires new-generation bio-nanomaterials to sensitively respond to the unique tumor microenvironment for precise diagnosis and efficient treatment. Here, we report such a theranostic nanoplatform by engineering defect-rich multifunctional Cu-doped layered double hydroxide (Cu-LDH) nanoparticles, which integrates pH-sensitive T1-magnetic resonance imaging (MRI), acid-enhanced photothermal therapy and heat-facilitated chemotherapy. As characterized with EXAFS and XPS, smaller Cu-LDH nanoparticles possess a considerable amount of defects around Cu cations, an advantageous microstructure that enables a high photothermal conversion of 808
September 2018
A novel bioscaffold with naturally-occurring extracellular matrix promotes hepatocyte survival and vessel patency in mouse models of heterologous transplantation
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Wei Yang, Quanyu Chen, Renpei Xia, Yujun Zhang, Ling Shuai, Jiejuan Lai, Xiaolin You, Yan Jiang, Ping Bie, Leida Zhang, Hongyu Zhang, Lianhua Bai Background Na
September 2018
Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Dongbo Guo, Shuting Xu, Yu Huang, Huangyong Jiang, Wumaier Yasen, Nan Wang, Yue Su, Jiwen Qian, Jing Li, Chuan Zhang, Xinyuan Zhu A combinatorial therapy that utilizes two or more therapeutic modalities is more effective in overcoming the limitations than each individual method used alone. Despite great advances have been achieved, the combination of chemotherapy and photodynamic therapy (PDT) still cannot satisfy the clinic requirements as the antitumor efficacy could be severely affected by tumor-associated hypoxia. Herein, for the first time, we reported a platinum(IV) complex-based polyprodrug that can in situ generate the highly toxic platinum(II) species as chemotherapeutics and simultaneously induce a high level of reactive oxygen species (ROS) in a PDT-like process without the use of photosensitizer and consumption of oxygen. By in situ polymerizing the platinum(IV) complex-based prodrug monomer (PPM) and 2-methacryloyloxy ethyl phosphorylcholine (MPC), nanosized hydrogel-like polyprodrug could be synthesized. Upon being exposed to light, Pt(IV) moieties in this photoactivable polyprodrug were reduced to generate Pt(II) species. At the meantime, a high level of ROS was generated without the presence of endogenous oxygen, which was confirmed by electron spin resonance (ESR) and fluorescence probes. With the unique nanosized architecture and photoresponsive feature, the as-synthesized polyprodrug exhibited the advantages of sustained drug release, long-term circulation, preferable tumor accumulation, and reversing drug resistance by downregulating the expression of multidrug resistance-associated protein 1 (MRP1) in the anticancer treatment.

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September 2018
A novel Lipidoid-MicroRNA formulation promotes calvarial bone regeneration
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Lei Sui, Ming Wang, Qianqian Han, Liming Yu, Lan Zhang, Leilei Zheng, Junxiang Lian, Jin Zhang, Paloma Valverde, Qiaobing Xu, Qisheng Tu, Jake Chen Specific microRNAs (miRs) and the Wnt signaling pathway play critical roles in regulating bone development and homeostasis. Our previous studies revealed the ability of miR-335-5p to promote osteogenic differentiation by downregulating Wnt antagonist Dickkopf-1 (DKK1). The purpose of this study was to use nano-materials to efficiently deliver miR-335-5p into osteogenic cells for tissue engineering applications. We synthesized and screened a library of 12 candidate nano-lipidoids
September 2018
Differentiating RNA from DNA by a molecular fluorescent probe based on the ôdoor-boltö mechanism biomaterials
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Qichao Yao, Haidong Li, Liman Xian, Feng Xu, Jing Xia, Jiangli Fan, Jianjun Du, Jingyun Wang, Xiaojun Peng Although excellent florescent probes have been developed for DNA, good probes for RNA remain lacking. The shortage of reported and commercial RNA probes is attributable to their severe interference from DNA. As DNA and RNA have similar structures but different functions, it has been an imperative challenge to develop RNA probes that differentiate from DNA. In this study, an NIR fluorescent probe, NBE, is described, which contains a bulky julolidine group that can fit in a spacious RNA pocket and emit intense fluorescence. However, NBE has no response to DNA, as it cannot intercalate into the double strands or even in the DNA minor groove. The sensing mechanism is similar to the effect of a door-bolt. NBE shows excellent performance in RNA sensing (outstanding photostability, high selectivity and fast response), whether in aqueous buffers, fixed cells or living cells. These findings might provide not only a potential imaging tool but also a new design strategy for the recognition of RNA while avoiding interference from DNA.

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September 2018
Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Christopher R. Rowland, Katherine A. Glass, Adarsh R. Ettyreddy, Catherine C. Gloss, Jared R.L. Matthews, Nguyen P.T. Huynh, Farshid Guilak Cartilage-derived matrix (CDM) has emerged as a promising scaffold material for tissue engineering of cartilage and bone due to its native chondroinductive capacity and its ability to support endochondral ossification. Because it consists of native tissue, CDM can undergo cellular remodeling, which can promote integration with host tissue and enables it to be degraded and replaced by neotissue over time. However, enzymatic degradation of decellularized tissues can occur unpredictably and may not allow sufficient time for mechanically competent tissue to form, especially in the harsh inflammatory environment of a diseased joint. The goal of the current study was to engineer cartilage and bone constructs with the ability to inhibit aberrant inflammatory processes caused by the cytokine interleukin-1 (IL-1), through scaffold-mediated delivery of lentiviral particles containing a doxycycline-inducible IL-1 receptor antagonist (IL-1Ra) transgene on anatomically-shaped CDM constructs. Additionally, scaffold-mediated lentiviral gene delivery was used to facilitate spatial organization of simultaneous chondrogenic and osteogenic differentiation via site-specific transduction of a single mesenchymal stem cell (MSC) population to overexpress either chondrogenic, transforming growth factor-beta 3 (TGF-
September 2018
Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Jordi Gonzalez-Molina, Xiaoli Zhang, Michela Borghesan, Joana Mendon
September 2018
Decellularized peripheral nerve supports Schwann cell transplants and axon growth following spinal cord injury
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Susana R. Cerqueira, Yee-Shuan Lee, Robert C. Cornelison, Michaela W. Mertz, Rebecca A. Wachs, Christine E. Schmidt, Mary Bartlett Bunge Schwann cell (SC) transplantation has been comprehensively studied as a strategy for spinal cord injury (SCI) repair. SCs are neuroprotective and promote axon regeneration and myelination. Nonetheless, substantial SC death occurs post-implantation, which limits therapeutic efficacy. The use of extracellular matrix (ECM)-derived matrices, such as Matrigel, supports transplanted SC survival and axon growth, resulting in improved motor function. Because appropriate matrices are needed for clinical translation, we test here the use of an acellular injectable peripheral nerve (iPN) matrix. Implantation of SCs in iPN into a contusion lesion did not alter immune cell infiltration compared to injury only controls. iPN implants were larger and contained twice as many SC-myelinated axons as Matrigel grafts. SC/iPN animals performed as well as the SC/Matrigel group in the BBB locomotor test, and made fewer errors on the grid walk at 4 weeks, equalizing at 8 weeks. The fact that this clinically relevant iPN matrix is immunologically tolerated and supports SC survival and axon growth within the graft offers a highly translational possibility for improving efficacy of SC treatment after SCI. To our knowledge, it is the first time that an injectable PN matrix is being evaluated to improve the efficacy of SC transplantation in SCI repair.
September 2018
Development and MPI tracking of novel hypoxia-targeted theranostic exosomes
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Kyung Oh Jung, Hunho Jo, Jung Ho Yu, Sanjiv Sam Gambhir, Guillem Pratx Treating the hypoxic region of the tumor remains a significant challenge. The goals of this study are to develop an exosome platform that can target regions of tumor hypoxia and that can be monitored inávivo using magnetic particle imaging (MPI). Four types of exosomes (generated under hypoxic or normoxic conditions, and with or without exposure to X-ray radiation) were isolated from MDA-MB-231 human breast cancer cells. Exosomes were labeled by DiO, a fluorescent lipophilic tracer, to quantify their uptake by hypoxic cancer cells. Subsequently, the exosomes were modified to carry SPIO (superparamagnetic iron oxide) nanoparticles and Olaparib (PARP inhibitor). FACS and fluorescence microscopy showed that hypoxic cells preferentially take up exosomes released by hypoxic cells, compared with other exosome formulations. In addition, the distribution of SPIO-labeled exosomes was successively imaged inávivo using MPI. Finally, the therapeutic efficacy of Olaparib-loaded exosomes was demonstrated by increased apoptosis and slower tumor growth inávivo. Our novel theranostic platform could be used as an effective strategy to monitor exosomes inávivo and deliver therapeutics to hypoxic tumors.
September 2018
Oxygen-boosted immunogenic photodynamic therapy with gold nanocages@manganese dioxide to inhibit tumor growth and metastases
Publication date: September 2018
Source:Biomaterials, Volume 177 Author(s): Ruijing Liang, Lanlan Liu, Huamei He, Zhikuan Chen, Zhiqun Han, Zhenyu Luo, Zhihao Wu, Mingbin Zheng, Yifan Ma, Lintao Cai Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease among women worldwide, characterized by high mortality and poor prognosis despite systemic therapy with radiation and chemotherapies. Photodynamic therapy (PDT) is an important strategy to eliminate the primary tumor, however its therapeutic efficacy against metastases and recurrence is still limited. Here, we employed a template method to develop the core-shell gold nanocage@manganese dioxide (AuNC@MnO2, AM) nanoparticles as tumor microenvironment responsive oxygen producers and near-infrared (NIR)-triggered reactive oxygen species (ROS) generators for oxygen-boosted immunogenic PDT against mTNBC. In this platform, MnO2 shell degrades in acidic tumor microenvironment pH/H2O2 conditions and generates massive oxygen to boost PDT effect of AM nanoparticles under laser irradiation. Fluorescence (FL)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging confirms the effective accumulation of AM nanoparticles with sufficient oxygenation in tumor site to ameliorate local hypoxia. Moreover, the oxygen-boosted PDT effect of AM not only destroys primary tumor effectively but also elicits immunogenic cell death (ICD) with damage-associated molecular patterns (DAMPs) release, which subsequently induces DC maturation and effector cells activation, thereby robustly evoking systematic antitumor immune responses against mTNBC. Hence, this oxygen-boosted immunogenic PDT nanosystem offers a promising approach to ablate primary tumor and simultaneously prevent tumor metastases via immunogenic abscopal effects.

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September 2018
Editorial Board
Publication date: September 2018
Source:Biomaterials, Volume 176

September 2018
Neighboring cells override 3D hydrogel matrix cues to drive human MSC quiescence
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Silvia A. Ferreira, Peter A. Faull, Alexis J. Seymour, Tracy T.L. Yu, Sandra Loaiza, Holger W. Auner, Ambrosius P. Snijders, Eileen Gentleman Physical properties of modifiable hydrogels can be tuned to direct stem cell differentiation in a role akin to that played by the extracellular matrix in native stem cell niches. However, stem cells do not respond to matrix cues in isolation, but rather integrate soluble and non-soluble signals to balance quiescence, self-renewal and differentiation. Here, we encapsulated single cell suspensions of human mesenchymal stem cells (hMSC) in hyaluronic acid-based hydrogels at high and low densities to unravel the contributions of matrix- and non-matrix-mediated cues in directing stem cell response. We show that in high-density (HD) cultures, hMSC do not rely on hydrogel cues to guide their fate. Instead, they take on characteristics of quiescent cells and secrete a glycoprotein-rich pericellular matrix (PCM) in response to signaling from neighboring cells. Preventing quiescence precluded the formation of a glycoprotein-rich PCM and forced HD cultures to differentiate in response to hydrogel composition. Our observations may have important implications for tissue engineering as neighboring cells may act counter to matrix cues provided by scaffolds. Moreover, as stem cells are most regenerative if activated from a quiescent state, our results suggest that exávivo native-like niches that incorporate signaling from neighboring cells may enable the production of clinically relevant, highly regenerative cells.
September 2018
Glycosylated superparamagnetic nanoparticle gradients for osteochondral tissue engineering
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Chunching Li, James PK. Armstrong, Isaac J. Pence, Worrapong Kit-Anan, Jennifer L. Puetzer, Sara Correia Carreira, Axel C. Moore, Molly M. Stevens In developmental biology, gradients of bioactive signals direct the formation of structural transitions in tissue that are key to physiological function. Failure to reproduce these native features in an inávitro setting can severely limit the success of bioengineered tissue constructs. In this report, we introduce a facile and rapid platform that uses magnetic field alignment of glycosylated superparamagnetic iron oxide nanoparticles, pre-loaded with growth factors, to pattern biochemical gradients into a range of biomaterial systems. Gradients of bone morphogenetic protein 2 in agarose hydrogels were used to spatially direct the osteogenesis of human mesenchymal stem cells and generate robust osteochondral tissue constructs exhibiting a clear mineral transition from bone to cartilage. Interestingly, the smooth gradients in growth factor concentration gave rise to biologically-relevant, emergent structural features, including a tidemark transition demarcating mineralized and non-mineralized tissue and an osteochondral interface rich in hypertrophic chondrocytes. This platform technology offers great versatility and provides an exciting new opportunity for overcoming a range of interfacial tissue engineering challenges.

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September 2018
Nanodiamonds as ôartificial proteinsö: Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Lukas Balek, Marcela Buchtova, Michaela Kunova Bosakova, Miroslav Varecha, Silvie Foldynova-Trantirkova, Iva Gudernova, Iva Vesela, Jan Havlik, Jitka Neburkova, Stuart Turner, Mateusz Adam Krzyscik, Malgorzata Zakrzewska, Lars Klimaschewski, Peter Claus, Lukas Trantirek, Petr Cigler, Pavel Krejci The blocking of specific protein-protein interactions using nanoparticles is an emerging alternative to small molecule-based therapeutic interventions. However, the nanoparticles designed as ôartificial proteinsö generally require modification of their surface with (bio)organic molecules and/or polymers to ensure their selectivity and specificity of action. Here, we show that nanosized diamond crystals (nanodiamonds, NDs) without any synthetically installed (bio)organic interface enable the specific and efficient targeting of the family of extracellular signalling molecules known as fibroblast growth factors (FGFs). We found that low nanomolar solutions of detonation NDs with positive
September 2018
Photo-excitable hybrid nanocomposites for image-guided photo/TRAIL synergistic cancer therapy
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Gan Lin, Yang Zhang, Congqing Zhu, Chengchao Chu, Yesi Shi, Xin Pang, En Ren, Yayun Wu, Peng Mi, Haiping Xia, Xiaoyuan Chen, Gang Liu Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without toxicity to normal cells. However, the efficiency is greatly limited by its short half-life and wild resistance in various cancer cells. In this study, we reported a micellar hybrid nanoparticle to carry TRAIL ligand (denoted as IPN@TRAIL) for a novel photo-excited TRAIL therapy. These IPN@TRAIL offered increased TRAIL stability, prolonged half-life and enhanced tumor accumulation, monitored by dual mode imaging. Furthermore, IPN@TRAIL nanocomposites enhanced wrapped TRAIL therapeutic efficiency greatly towards resistant cancer cells by TRAIL nanovectorization. More importantly, when upon external laser, these nanocomposites not only triggered tumor photothermal therapy (PTT), but also upregulated the expression of death receptors (DR4 and DR5), resulting in a greater apoptosis mediated by co-delivered TRAIL ligand. Such photo/TRAIL synergistic effect showed its great killing effects in a controllable manner on TRAIL-resistant A549 tumor model bearing mice. Finally, these nanocomposites exhibited rapid clearance without obvious systemic toxicity. All these features rendered our nanocomposites a promising theranostic platform in cancer therapy.
September 2018
Targeted reversal and phosphorescence lifetime imaging of cancer cell metabolism via a theranostic rhenium(I)-DCA conjugate
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Jing Yang, Qian Cao, Hang Zhang, Liang Hao, Danxia Zhou, Zhenji Gan, Zhiwei Li, Ye-Xiang Tong, Liang-Nian Ji, Zong-Wan Mao Cancer cell metabolism is quite different from normal cells. Targeting cancer metabolism and untuning the tumor metabolic machine has emerged as a promising strategy for cancer therapy. We have developed a multi-functional Re-dca conjugate (Re-dca 2) by conjugating the metabolic modulator dichloroacetate (DCA) to mitochondria-targeted rhenium(I) complex, allowing its efficient penetration into cancer cells and selective accumulation in mitochondria, thus achieving the cancer cell metabolism reversal from glycolysis to glucose oxidation at pharmacologically relevant DCA doses. Mechanism studies confirm the inhibition effect of Re-dca 2 on the activity of pyruvate dehydrogenase kinase (PDK) and capture the metabolic reversal window in Re-dca 2 treated NCI-1229
September 2018
NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Jun Yang, Shaodong Zhai, Huan Qin, He Yan, Da Xing, Xianglong Hu Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808
September 2018
Glycogen-nucleic acid constructs for gene silencing in multicellular tumor spheroids
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Marcin Wojnilowicz, Quinn A. Besford, Yun-Long Wu, Xian Jun Loh, Julia A. Braunger, Agata Glab, Christina Cortez-Jugo, Frank Caruso, Francesca Cavalieri The poor penetration of nanocarrier-siRNA constructs into tumor tissue is a major hurdle for the inávivo efficacy of siRNA therapeutics, where the ability of the constructs to permeate the 3D multicellular matrix is determined by their physicochemical properties. Herein, we optimized the use of soft glycogen nanoparticles for the engineering of glycogen-siRNA constructs that can efficiently penetrate multicellular tumor spheroids and exert a significant gene silencing effect. Glycogen nanoparticles from different bio-sources and with different structural features were investigated. We show that larger glycogen nanoparticles ranging from 50 to 80
September 2018
A bioactive implant in situ and long-term releases combined drugs for treatment of osteoarticular tuberculosis
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Chao-Xi Zhou, Litao Li, Yi-Guang Ma, Bing-Nan Li, Guang Li, Zhihang Zhou, Feng Shi, Jie Weng, Cong Zhang, Fenghua Wang, Xu Cui, Lei Wang, Hao Wang Anti-tuberculosis chemotherapy with a long duration and adequate dosing is the mainstay for treatment of osteoarticular tuberculosis (TB). However, it is difficult for systemic administration to reach adequate local drug concentrations and achieve effective treatment. Herein, a hydroxyapatite (HA) scaffold implant combined with a drug-releasing system was designed to achieve in situ and long-term anti-TB drug release and highly efficient therapeutic activity inávitro and inávivo. The clinical anti-TB drugs hydrophilic isoniazid (INH) and hydrophobic rifampicin (RFP) were molecularly dispersed into polyvinyl alcohol (PVA) through immersion-curing techniques and were steadily adhered onto the surfaces of HA scaffolds (HA-drug@PVA). The HA-drug@PVA scaffolds showed a long-term, sustained drug release profile and killed proliferating Mycobacterium inávitro. Inávivo experimental results revealed that the HA-drug@PVA scaffolds provided over 10- and 100-fold higher concentrations in muscles and bones, respectively, as well as a much lower concentration (<0.025) in blood. Furthermore, the HA-drug@PVA scaffold implanted in an osteoarticular TB rabbit model showed obvious bone regeneration and fusion due to the inhibition of TB-associated inflammatory changes. The excellent therapeutic effects indicate that in situ implant materials combined with a long-term drug release system are promising for the treatment of osteoarticular TB and other osteoarticular infections.
September 2018
Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Xintao Zhang, Ting He, Zheng Chai, R. Jude Samulski, Chengwen Li The adeno-associated virus (AAV) vector has been used in preclinical and clinical trials of gene therapy for central nervous system (CNS) diseases. One of the biggest challenges of effectively delivering AAV to the brain is to surmount the blood-brain barrier (BBB). Herein, we identified several potential BBB shuttle peptides that significantly enhanced AAV8 transduction in the brain after a systemic administration, the best of which was the THR peptide. The enhancement of AAV8 brain transduction by THR is dose-dependent, and neurons are the primary THR targets. Mechanism studies revealed that THR directly bound to the AAV8 virion, increasing its ability to cross the endothelial cell barrier. Further experiments showed that binding of THR to the AAV virion did not interfere with AAV8 infection biology, and that THR competitively blocked transferrin from binding to AAV8. Taken together, our results demonstrate, for the first time, that BBB shuttle peptides are able to directly interact with AAV and increase the ability of the AAV vectors to cross the BBB for transduction enhancement in the brain. These results will shed important light on the potential applications of BBB shuttle peptides for enhancing brain transduction with systemic administration of AAV vectors.

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September 2018
The study of relationships between pKa value and siRNA delivery efficiency based on tri-block copolymers
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Lili Du, Changrong Wang, Lingwei Meng, Qiang Cheng, Junhui Zhou, Xiaoxia Wang, Deyao Zhao, Jianhua Zhang, Liandong Deng, Zicai Liang, Anjie Dong, Huiqing Cao Tri-block copolymers have exhibited great potentials in small interfering RNA (siRNA) therapeutics. To reveal structure-activity relationships, we here synthesized a series of tri-block copolymers with different hydrophobic segments, PEG-PAMA-P(C6Ax-C7Ay-DPAz-DBAm) (EAAS) and PEG-PDAMAEMA-P(C6Ax-C7Ay-DPAz-DBAm) (EDAS), termed from EAASa to EAASh and EDASa to EDASh, with pKa ranging from 5.2 to 7.0. Our data showed that the better gene silencing efficiency was located in pKa of 5.8ľ6.2, which was contributed from higher endosomal escape observed with confocal images and hemolysis assay. EAASc, the leader polymer, showed excellent gene knockdown at w/w ratio of 14.5 on HepG2 (89.94%), MDA-MB-231 (92.45%), 293A (83.06%), and Hela cells (80.27%), all better than lipofectamine 2000. Besides, EAASc mediated effective gene silencing in tumor when performed peritumoral injection. This work found out that polymers with pKa ranging from 5.8 to 6.2 were efficient in siRNA delivery, which provided an optimization strategy for siRNA delivery systems, especially for tri-block copolymers.
August 2018
A ôtop-downö approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery
Publication date: September 2018
Source:Biomaterials, Volume 176 Author(s): Yuhang Jiang, Alice Gaudin, Junwei Zhang, Tushar Agarwal, Eric Song, Amy C. Kauffman, Gregory T. Tietjen, Yongheng Wang, Zhaozhong Jiang, Christopher J. Cheng, W. Mark Saltzman Gene delivery is known to be a complicated multi-step biological process. It has been observed that subtle differences in the structure and properties of polymeric materials used for gene delivery can lead to dramatic differences in transfection efficiency. Therefore, screening of properties is pivotal to optimizing the polymer. So far, most polymeric materials are built in a ôbottom-upö manner, i.e. synthesized from monomers that allow modification of polymer composition or structural factors. With this method, we previously synthesized and screened a library of biodegradable poly(amine-co-ester) (PACE) terpolymers for optimized DNA delivery. However, it can be tedious and time consuming to synthesize a polymer library for screening, particularly when small changes of a factor need to be tested, when multiple factors are involved, and when the effects of different factors are synergistic. In the present work, we evaluate the potential of PACE to deliver mRNA. After observing that mRNA transfection efficiency was highly dependent on both end group composition and molecular weight (MW) of PACE in a synergistic manner, we developed a ôtop-downö process we called actuation, to simultaneously vary these two factors. Some of the actuated PACE (aPACE) materials presented superior mRNA delivery properties compared to regular PACE, with up to a 106-fold-increase in mRNA transfection efficiency inávitro. Moreover, when aPACE was used to deliver mRNA coding for erythropoietin (EPO) inávivo, it produced high levels of EPO in the blood for up to 48
August 2018
Editorial Board
Publication date: August 2018
Source:Biomaterials, Volume 175

August 2018
Ingestible roasted barley for contrast-enhanced photoacoustic imaging in animal and human subjects
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Depeng Wang, Dong Hyeun Lee, Haoyuan Huang, Tri Vu, Rachel Su Ann Lim, Nikhila Nyayapathi, Upendra Chitgupi, Maggie Liu, Jumin Geng, Jun Xia, Jonathan F. Lovell Photoacoustic computed tomography (PACT) is an emerging imaging modality. While many contrast agents have been developed for PACT, these typically cannot immediately be used in humans due to the lengthy regulatory process. We screened two hundred types of ingestible foodstuff samples for photoacoustic contrast with 1064
August 2018
Decellularized and matured esophageal scaffold for circumferential esophagus replacement: Proof of concept in a pig model
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Guillaume Luc, Guillaume Charles, Caroline Gronnier, Magali Cabau, Charlotte Kalisky, Mallory Meulle, Reine Bareille, Samantha Roques, Lionel Couraud, Johanna Rannou, Laurence Bordenave, Denis Collet, Marl
August 2018
Gold and gold-silver alloy nanoparticles enhance the myogenic differentiation of myoblasts through p38 MAPK signaling pathway and promote inávivo skeletal muscle regeneration
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Juan Ge, Kai Liu, Wen Niu, Mi Chen, Min Wang, Yumeng Xue, Chuanbo Gao, Peter X. Ma, Bo Lei Under the severe trauma condition, the skeletal muscles regeneration process is inhibited by forming fibrous scar tissues. Understanding the interaction between bioactive nanomaterials and myoblasts perhaps has important effect on the enhanced skeletal muscle tissue regeneration. Herein, we investigate the effect of monodispersed gold and gold-silver nanoparticles (AuNPs and Au-AgNPs) on the proliferation, myogenic differentiation and associated molecular mechanism of myoblasts (C2C12), as well as the inávivo skeletal muscle tissue regeneration. Our results showed that AuNPs and Au-AgNPs could support myoblast attachment and proliferation with negligible cytotoxicity. Under various incubation conditions (normal and differentiation medium), AuNPs and Au-AuNPs significantly enhanced the myogenic differentiation of myoblasts by upregulating the expressions of myosin heavy chain (MHC) protein and myogenic genes (MyoD, MyoG and Tnnt-1). The further analysis demonstrated that AuNPs and Au-AgNPs could activate the p38
August 2018
Development of a centrally vascularized tissue engineering bone graft with the unique core-shell composite structure for large femoral bone defect treatment
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Le Wang, Li-xin Zhu, Zhao Wang, Ai-ju Lou, Yi-xi Yang, Yuan Guo, Song Liu, Chi Zhang, Zheng Zhang, Han-sheng Hu, Bo Yang, Ping Zhang, Hong-wei Ouyang, Zhi-yong Zhang Great effort has been spent to promote the vascularization of tissue engineering bone grafts (TEBG) for improved therapeutic outcome. However, the thorough vascularization especially in the central region still remained as a major challenge for the clinical translation of TEBG. Here, we developed a new strategy to construct a centrally vascularized TEBG (CV-TEBG) with unique core-shell composite structure, which is consisted of an angiogenic core and an osteogenic shell. The inávivo evaluation in rabbit critical sized femoral defect was conducted to meticulously compare CV-TEBG to other TEBG designs (TEBG with osteogenic shell alone, or angiogenic core alone or angiogenic core+shell). Microfil-enhanced micro-CT analysis has been shown that CV-TEBG could outperform TEBG with pure osteogenic or angiogenic component for neo-vascularization. CV-TEBG achieved a much higher and more homogenous vascularization throughout the whole scaffold (1.52ľ38.91 folds, pá<á0.01), and generated a unique burrito-like vascular network structure to perfuse both the central and peripheral regions of TEBG, indicating a potential synergistic effect between the osteogenic shell and angiogenic core in CV-TEBG to enhance neo-vascularization. Moreover, CV-TEBG has generated more new bone tissue than other groups (1.99ľ83.50 folds, pá<á0.01), achieved successful bridging defect with the formation of both cortical bone like tissue externally and cancellous bone like tissue internally, and restored approximately 80% of the stiffness of the defected femur (benchmarked to the intact femur). It has been further observed that different bone regeneration patterns occurred in different TEBG implants and closely related to their vascularization patterns, revealing the potential profound influence of vascularization patterns on the osteogenesis pattern during defect healing.
August 2018
Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Han Shao, Tingting Li, Rong Zhu, Xiaoting Xu, Jiandong Yu, Shengfeng Chen, Li Song, Seeram Ramakrishna, Zhigang Lei, Yiwen Ruan, Liumin He Carbon nanotubes (CNTs) have shown potential applications in neuroscience as growth substrates owing to their numerous unique properties. However, a key concern in the fabrication of homogeneous composites is the serious aggregation of CNTs during incorporation into the biomaterial matrix. Moreover, the regulation mechanism of CNT-based substrates on neural differentiation remains unclear. Here, a novel strategy was introduced for the construction of CNT nanocomposites via layer-by-layer assembly of negatively charged multi-walled CNTs and positively charged poly(dimethyldiallylammonium chloride). Results demonstrated that the CNT-multilayered nanocomposites provided a potent regulatory signal over neural stem cells (NSCs), including cell adhesion, viability, differentiation, neurite outgrowth, and electrophysiological maturation of NSC-derived neurons. Importantly, the dynamic molecular mechanisms in the NSC differentiation involved the integrin-mediated interactions between NSCs and CNT multilayers, thereby activating focal adhesion kinase, subsequently triggering downstream signaling events to regulate neuronal differentiation and synapse formation. This study provided insights for future applications of CNT-multilayered nanomaterials in neural fields as potent modulators of stem cell behavior.
August 2018
Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Bin Wang, Yanping Ding, Xiaozheng Zhao, Xuexiang Han, Na Yang, Yinlong Zhang, Ying Zhao, Xiao Zhao, Mohammad Taleb, Qing Robert Miao, Guangjun Nie Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid)2-poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics.
August 2018
A multifunctional nanotheranostic for the intelligent MRI diagnosis and synergistic treatment of hypoxic tumor
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Ruixue Song, Meng Zhang, Yanyan Liu, Zhaowen Cui, Hua Zhang, Zhongmin Tang, Xiaoyan Chen, Haihong Wu, Zhenwei Yao, Mingyuan He, Wenbo Bu Hypoxia, as an inevitable characteristic of solid tumors, has been regarded as a noticeably causative factor to therapeutic resistance and metastatic variants. Exploring novel theranostics to realize the accurate diagnosis of hypoxia and the simultaneous implementation of effective therapy is a promising prospect for the successful treatment of tumors. In the present study, we designed and synthesized a multifunctional rattle-structured nanotheranostic, with the inner core coated by hollow mesoporous silica for chemical drug Doxorubicin (DOX) storage and hypoxia-sensitive MnO2
August 2018
Ultra-small nanocluster mediated synthesis of Nd3+-doped core-shell nanocrystals with emission in the second near-infrared window for multimodal imaging of tumor vasculature
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Feng Ren, Lihua Ding, Hanghang Liu, Qian Huang, Hao Zhang, Lijuan Zhang, Jianfeng Zeng, Qiao Sun, Zhen Li, Mingyuan Gao In-vivo intravital short wavelength infrared (SWIR, 1000ľ2300

Perfluorohexane-cored nanodroplets for stimulations-responsive ultrasonography and O2-potentiated photodynamic therapy
Publication date: August 2018
Source:Biomaterials, Volume 175 Author(s): Meng Yu, Xiaolin Xu, Yujun Cai, Lingyun Zou, Xintao Shuai To achieve efficient ultrasonography-guided photodynamic therapy (PDT), two major obstacles need to be overcome. On the one hand, O2-dependent PDT produces limited effects on hypoxic solid tumors. On the other hand, small particles facilitate tumor accumulation whereas large ones strengthen ultrasound (US) imaging, which makes the development of an ultrasonographic probe showing effective tumor accumulation and high US sensitivity an intractable challenge. Therefore, an intelligent perfluorohexane (PFH)-based nanodroplet, PFH@Ce6@O2, was fabricated in order to simultaneously solve the above problems. The nanoscale PFH@Ce6@O2 particles were firstly delivered to elevate the local O2 level of tumors, which is critical for achieving excellent PDT effect under laser irradiation. Then, a spontaneous ôsmall-to-largeö growth of droplet at tumor acidic microenvironment resulted in an echo-contrast enhancement for high-performance US imaging of tumor. The inávitro and inávivo results manifested the advantage of PFH@Ce6@O2 in alleviating hypoxic status to inhibit tumor growth. Overall, PFH@Ce6@O2 integrating US/FL bimodal imaging and PDT effect appears to be a promising nanoplatform for ultrasonography-guided PDT of solid tumors.
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