Rational engineering of semiconductor QDs enabling remarkable 1O2 production for tumor-targeted photodynamic therapy Biomaterials (IF 8.402) Pub Date : 2017-09-20 Yizhong Shen, Yidan Sun, Runqi Yan, Erquan Chen, Huan Wang, Deju Ye, Jing-Juan Xu, Hong-Yuan Chen
Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation Biomaterials (IF 8.402) Pub Date : 2017-09-19 Sita M. Damaraju, Yueyang Shen, Ezinwa Elele, Boris Khusid, Ahmad Eshghinejad, Jiangyu Li, Michael Jaffe, Treena Livingston Arinzeh
The discovery of electric fields in biological tissues has led to efforts in developing technologies utilizing electrical stimulation for therapeutic applications. Native tissues, such as cartilage and bone, exhibit piezoelectric behavior, wherein electrical activity can be generated due to mechanical deformation. Yet, the use of piezoelectric materials have largely been unexplored as a potential strategy in tissue engineering, wherein a piezoelectric biomaterial acts as a scaffold to promote cell behavior and the formation of large tissues. Here we show, for the first time, that piezoelectric materials can be fabricated into flexible, three-dimensional fibrous scaffolds and can be used to stimulate human mesenchymal stem cell differentiation and corresponding extracellular matrix/tissue formation in physiological loading conditions. Piezoelectric scaffolds that exhibit low voltage output, or streaming potential, promoted chondrogenic differentiation and piezoelectric scaffolds with a high voltage output promoted osteogenic differentiation. Electromechanical stimulus promoted greater differentiation than mechanical loading alone. Results demonstrate the additive effect of electromechanical stimulus on stem cell differentiation, which is an important design consideration for tissue engineering scaffolds. Piezoelectric, smart materials are attractive as scaffolds for regenerative medicine strategies due to their inherent electrical properties without the need for external power sources for electrical stimulation.
Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering Biomaterials (IF 8.402) Pub Date : 2017-09-19 Jiesi Luo, Lingfeng Qin, Mehmet H. Kural, Jonas Schwan, Xia Li, Oscar Bartulos, Xiao-qiang Cong, Yongming Ren, Liqiong Gui, Guangxin Li, Matthew W. Ellis, Peining Li, Darrell N. Kotton, Alan Dardik, Jordan S. Pober, George Tellides, Marsha Rolle, Stuart Campbell, Robert J. Hawley, David H. Sachs, Laura E. Niklason, Yibing Qyang
Development of autologous tissue-engineered vascular constructs using vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (iPSCs) holds great potential in treating patients with vascular disease. However, preclinical, large animal iPSC-based cellular and tissue models are required to evaluate safety and efficacy prior to clinical application. Herein, swine iPSC (siPSC) lines were established by introducing doxycycline-inducible reprogramming factors into fetal fibroblasts from a line of inbred Massachusetts General Hospital miniature swine that accept tissue and organ transplants without immunosuppression within the line. Highly enriched, functional VSMCs were derived from siPSCs based on addition of ascorbic acid and inactivation of reprogramming factor via doxycycline withdrawal. Moreover, siPSC-VSMCs seeded onto biodegradable polyglycolic acid (PGA) scaffolds readily formed vascular tissues, which were implanted subcutaneously into immunodeficient mice and showed further maturation revealed by expression of the mature VSMC marker, smooth muscle myosin heavy chain. Finally, using a robust cellular self-assembly approach, we developed 3D scaffold-free tissue rings from siPSC-VSMCs that showed comparable mechanical properties and contractile function to those developed from swine primary VSMCs. These engineered vascular constructs, prepared from doxycycline-inducible inbred siPSCs, offer new opportunities for preclinical investigation of autologous human iPSC-based vascular tissues for patient treatment.
Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex Biomaterials (IF 8.402) Pub Date : 2017-09-18 Jooho Park, Jeong Uk Choi, Kwangmeyung Kim, Youngro Byun
Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry in vivo Biomaterials (IF 8.402) Pub Date : 2017-09-18 Sangmin Lee, Seulhee Jung, Heebeom Koo, Jin Hee Na, Hong Yeol Yoon, Man Kyu Shim, Jooho Park, Jong-Ho Kim, Seulki Lee, Martin G. Pomper, Ick Chan Kwon, Cheol-Hee Ahn, Kwangmeyung Kim
Bone regeneration with micro/nano hybrid-structured biphasic calcium phosphate bioceramics at segmental bone defect and the induced immunoregulation of MSCs Biomaterials (IF 8.402) Pub Date : 2017-09-18 Yu Zhu, Kun Zhang, Rui Zhao, Xingjiang Ye, Xuening Chen, Zhanwen Xiao, Xiao Yang, Xiangdong Zhu, Kai Zhang, Yujiang Fan, Xingdong Zhang
Adequate bone regeneration has been difficult to achieve at segmental bone defects caused by disease. The surface structure and phase composition of calcium phosphate bioceramic are crucial for its bioactivity and osteoinductivity. In the present study, biphasic calcium phosphate (BCP) bioceramics composed of micro-whiskers and nanoparticles hybrid-structured surface (hBCP) were fabricated via a hydrothermal reaction. The in vivo long bone defect model of beagle dogs implanted with hBCP bioceramics achieved a higher quality regenerated bone as compared to the traditional smooth-surface BCP control group. After a 12-week implantation period, more new bone formation within the implanted material and a higher fracture load were observed in the hBCP group (p < 0.05 vs. control). In addition, the local bone integration efficacy, as determined by nanoindentation, showed a significantly closer elastic modulus of the implanted hBCP bioceramics to that of the natural bone adjacent. Finally, in vitro gene microarray analysis of the mesenchymal stem cells (MSCs) co-cultured with two bioceramics showed that the hBCP group induced a drastic downregulation of the genes associated with inflammatory response, which was never documented in previous studies regarding biomaterials with a micro/nano hybrid structure. The tumor necrosis factor (TNF) signalling pathway was the most involved and preferentially inhibited by the hBCP material. Collectively, the findings suggested that the micro/nano hybrid-structured bioceramics augmented local bone regeneration at segmental bone defects and presented a potential alternative to autologous bone grafts.
Nanomaterials for Cancer Immunotherapy Biomaterials (IF 8.402) Pub Date : 2017-09-17 Wantong Song, Sara N. Musetti, Leaf Huang
Cancer immunotherapy is quickly growing to be the fourth most important cancer therapy, after surgery, radiation therapy, and chemotherapy. Immunotherapy is the most promising cancer management strategy because it orchestrates the body’s own immune system to target and eradicate cancer cells, which may result in durable antitumor responses and reduce metastasis and recurrence more than traditional treatments. Nanomaterials hold great promise in further improving the efficiency of cancer immunotherapy - in many cases, they are even necessary for effective delivery. In this review, we briefly summarize the basic principles of cancer immunotherapy and explain why and where to apply nanomaterials in cancer immunotherapy, with special emphasis on cancer vaccines and tumor microenvironment modulation.
A novel DOPA-albumin based tissue adhesive for internal medical applications Biomaterials (IF 8.402) Pub Date : 2017-09-14 Wenzhen Zhu, Yvonne Peck, Jabed Iqbal, Dong-An Wang
To date, existing tissue adhesives have various weak points in gluing kinetics and stability – particularly, in biocompatibility, which make most of them remain suboptimal for internal conditions. Herein, a novel mussel-inspired “BCD” tissue glue made of bovine serum albumin (BSA), citrate acid (CA) and dopamine was developed aiming at internal medical applications. BSA was employed as a natural and biocompatible macromolecular backbone; CA was introduced as a dual-functional intermediate to increase reactive carboxyl sites for engraftment of dopamine onto BSA backbone and also block the competing reactive amines from the proteinic backbone. Timely curing and stable adhesion were achieved between biological tissue substrates via instant chelation and gradual conjugation of DOPA-catechol groups in BCD glue. Within 30 min, this newly developed BCD tissue glue can provide over 10-fold greater adhesion stress than that of commercially available fibrin glue in wet environment. As a tissue adhesive for internal use, its superior properties also include ideal gelation kinetics and swelling behaviour, appropriate degradation rate, sound cytocompatibility in vitro, as well as fine biocompatibility in vivo. More importantly, successful animal experimentations in seroma prevention and instant hemostasis ultimately validated BCD tissue glue's preclinical efficacy as a tissue adhesive for various internal medical applications.
Multifunctional mesoporous ZrO2 encapsulated upconversion nanoparticles for mild NIR light activated synergistic cancer therapy Biomaterials (IF 8.402) Pub Date : 2017-09-13 Lili Feng, Shili Gai, Fei He, Yunlu Dai, Chongna Zhong, Piaoping Yang, Jun Lin
Desirable nanosystem that could not only deliver drugs safely and effectively into tumor sites, but also be expected to serve as photosensitizer to realize the photodynamic therapeutic function, would be of great significance in the synergistic cancer therapy. To perform this task, a multifunctional nanosystem has been developed for markedly enhanced cancer therapeutic efficacy by loading chemotherapy agent (doxorubicin hydrochloride, DOX) and photosensitive drug chlorin e6 (Ce6) into the channels of mesoporous zirconium dioxide (ZrO2) layer which coats on Nd3+-doped upconversion nanoparticles (UCNPs). As a temperature sensitive phase change material (PCM), the loaded tetradecanol was served as switch for control release of DOX and reactive oxygen species (ROS) in the condition of enhanced temperature triggered by the near infrared (NIR) light irradiation. The hyperthermia generated from the UCNPs cores exposed to NIR laser could raise the temperature of tumor location to 47.8 °C. The as-synthesized UCNPs@ZrO2-Ce6/DOX/PCM nanosystem demonstrates an excellent in vivo synergistic effect by administrating into U14 tumor-bearing mice via intravenous injection, under mild NIR laser irradiation (0.5 W cm−2, 5 min break after 5 min irradiation). In a word, our experimental results indicate that the finely designed UCNPs@ZrO2-Ce6/DOX/PCM may act as an ideal nanoplatform for multiple imaging guided tumor therapy.
Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma Biomaterials (IF 8.402) Pub Date : 2017-09-13 Chao Liang, Fangfei Li, Luyao Wang, Zong-Kang Zhang, Chao Wang, Bing He, Jie Li, Zhihao Chen, Atik Badshah Shaikh, Jin Liu, Xiaohao Wu, Songlin Peng, Lei Dang, Baosheng Guo, Xiaojuan He, D.W.T. Au, Cheng Lu, Hailong Zhu, Bao-Ting Zhang, Aiping Lu, Ge Zhang
Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment.
pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells Biomaterials (IF 8.402) Pub Date : 2017-09-10 Zhe Yang, Na Sun, Rui Cheng, Chenyang Zhao, Zerong Liu, Xian Li, Jie Liu, Zhongmin Tian
DNA nanotechnology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy Biomaterials (IF 8.402) Pub Date : 2017-09-09 Tomoya Yata, Yuki Takahashi, Mengmeng Tan, Hirotaka Nakatsuji, Shozo Ohtsuki, Tatsuya Murakami, Hiroshi Imahori, Yuka Umeki, Tomoki Shiomi, Yoshinobu Takakura, Makiya Nishikawa
Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory Biomaterials (IF 8.402) Pub Date : 2017-09-08 Samila Nasrollahi, Christopher Walter, Andrew J. Loza, Gregory V. Schimizzi, Gregory D. Longmore, Amit Pathak
Multifunctional superparamagnetic nanoparticles conjugated with fluorescein-labeled designed ankyrin repeat protein as an efficient HER2-targeted probe in breast cancer Biomaterials (IF 8.402) Pub Date : 2017-09-08 Dong-Li Li, Jian-Er Tan, Ying Tian, Shun Huang, Peng-Hui Sun, Meng Wang, Yan-Jiang Han, Hong-Sheng Li, Hu-Bing Wu, Xing-Mei Zhang, Yi-Kai Xu, Quan-Shi Wang
Based on the discordance of human epidermal growth factor receptor-2 (HER2) expression between primary and metastatic/recurrent breast cancer, HER2 molecular imaging, which had potential to systemically assess and dynamically monitor HER2 expression, might improve the selection of patients for anti-HER2 therapy. In this study, designed ankyrin repeat protein (DARPin) G3, a novel binding protein with picomolar affinity for HER2, was used and multifunctional superparamagnetic nanoparticles modified with fluorescein-5-maleimide-labeled DARPin G3 (SPIO-G3-5MF) were developed for HER2 imaging. Our results showed that SPIO-G3-5MF nanoparticles, which possessed uniform size of about 100 nm, favorable dispersity and low cytotoxicity, could selectively bind to HER2-positive breast cancer cells even in the presence of trastuzumab. Biodistribution assay demonstrated that abundant accumulation and long retention of SPIO-G3-5MF were observed in HER2-positive transplantation breast tumors although a portion of SPIO-G3-5MF nanoparticles were unavoidably captured by liver and spleen. Further MR imaging revealed that SPIO-G3-5MF could selectively image HER2-positive transplantation breast tumors, yielding remarkable T2 signal reduction (50.33±2.90% at 6 h and 47.29±9.36% at 24 h). Our study suggested that SPIO-G3-5MF might be a promising MR molecular probe for diagnosing and monitoring HER2 expression state of breast cancer in the future.
A hydrogel matrix prolongs persistence and promotes specific localization of an oncolytic adenovirus in a tumor by restricting nonspecific shedding and an antiviral immune response Biomaterials (IF 8.402) Pub Date : 2017-09-07 Bo-Kyeong Jung, Eonju Oh, JinWoo Hong, Yunki Lee, Ki Dong Park, Chae-Ok Yun
Currently, intratumoral injection of an oncolytic adenovirus (Ad) is the conventional administration route in clinical trials. Nonetheless, the locally administered Ad disseminates to the surrounding nontarget tissues and has short biological activity due to immunogenicity of Ad, thus necessitating multiple injections to achieve a sufficient therapeutic index. In the present study, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-expressing oncolytic Ad (oAd-TRAIL) was encapsulated in a gelatin hydrogel (oAd-TRAIL/gel) to enhance and prolong antitumor efficacy of the virus after a single intratumoral injection. oAd-TRAIL/gel showed greater antitumor efficacy than naked oAd-TRAIL did due to enhanced and prolonged intratumoral accumulation of Ad up to a 20-day period, showing potent induction of apoptosis and inhibition of tumor cell proliferation. Furthermore, the gel system effectively prevented shedding of oncolytic Ad from the injection site to hepatic and other healthy tissues. oAd-TRAIL/gel treatment resulted in a markedly weaker antiviral immune response against Ad relative to naked oAd-TRAIL, further contributing to prolonged persistence of the oncolytic Ad in tumor tissue. Moreover, the hydrogel matrix preserved oAd-TRAIL's ability to induce an antitumor immune response, resulting in higher intratumoral infiltration by CD4+/CD8+ T cells. Taken together, these findings show that single intratumoral administration of the Ad/hydrogel modality may prolong and potentiate the therapeutic efficacy of Ad, modulate the immune reaction in favor of the virotherapy, and enhance intratumoral localization of the virus, ultimately overcoming limitations of oncolytic virotherapy revealed in recent clinical trials.
Molecular insights for the biological interactions between polyethylene glycol and cells Biomaterials (IF 8.402) Pub Date : 2017-09-06 Li Xu, Jiapei Yang, Bai Xue, Chuan Zhang, Leilei Shi, Chenwei Wu, Yue Su, Xin Jin, Yumin Liu, Xinyuan Zhu
Co-coating of receptor-targeted drug nanocarriers with anti-phagocytic moieties enhances specific tissue uptake versus non-specific phagocytic clearance Biomaterials (IF 8.402) Pub Date : 2017-09-06 Joshua Kim, Saraudeep Sinha, Melani Solomon, Edgar Perez-Herrero, Janet Hsu, Zois Tsinas, Silvia Muro
Light-controlled drug release from singlet-oxygen sensitive nanoscale coordination polymers enabling cancer combination therapy Biomaterials (IF 8.402) Pub Date : 2017-09-06 Jingjing Liu, Guangbao Yang, Wenwen Zhu, Ziliang Dong, Yu Yang, Yu Chao, Zhuang Liu
The development of smart drug delivery systems to realize controlled drug release for highly specific cancer treatment has attracted tremendous attention. Herein, nanoscale coordination polymers (NCPs) constructed from hafnium ions and bis-(alkylthio) alkene (BATA), a singlet-oxygen responsive linker, are fabricated and applied as nanocarriers to realize light-controlled drug release under a rather low optical power density. In this system, NCPs synthesized through a solvothermal method are sequentially loaded with chlorin e6 (Ce6), a photosensitizer, and doxorubicin (DOX), a chemotherapeutic drug, and then coated with lipid bilayer to allow modification with polyethylene glycol (PEG) to acquire excellent colloidal stability. The singlet oxygen produced by such NCP-Ce6-DOX-PEG nanocomposite can be used not only for photodynamic therapy, but also to induce the break of BATA linker and thus the destruction of nanoparticle structures under light exposure, thereby triggering effective drug release. Notably, with efficient tumor accumulation after intravenous injection as revealed by CT imaging, those NCP-Ce6-DOX-PEG nanoparticles could be utilized for combined chemo-photodynamic therapy with great antitumor efficacy. Thus, this work presents a unique type of NCP-based drug delivery system with biodegradability, sensitive responses to light, as well as highly efficient tumor retention for effective cancer combinational treatment.
Bioreactor culture duration of engineered constructs influences bone formation by mesenchymal stem cells Biomaterials (IF 8.402) Pub Date : 2017-09-06 Debika Mitra, Jacklyn Whitehead, Osamu W. Yasui, J. Kent Leach
Perfusion culture of mesenchymal stem cells (MSCs) seeded in biomaterial scaffolds provides nutrients for cell survival, enhances extracellular matrix deposition, and increases osteogenic cell differentiation. However, there is no consensus on the appropriate perfusion duration of cellular constructs in vitro to boost their bone forming capacity in vivo. We investigated this phenomenon by culturing human MSCs in macroporous composite scaffolds in a direct perfusion bioreactor and compared their response to scaffolds in continuous dynamic culture conditions on an XYZ shaker. Cell seeding in continuous perfusion bioreactors resulted in more uniform MSC distribution than static seeding. We observed similar calcium deposition in all composite scaffolds over 21 days of bioreactor culture, regardless of pore size. Compared to scaffolds in dynamic culture, perfused scaffolds exhibited increased DNA content and expression of osteogenic markers up to 14 days in culture that plateaued thereafter. We then evaluated the effect of perfusion culture duration on bone formation when MSC-seeded scaffolds were implanted in a murine ectopic site. Human MSCs persisted in all scaffolds at 2 weeks in vivo, and we observed increased neovascularization in constructs cultured under perfusion for 7 days relative to those cultured for 1 day within each gender. At 8 weeks post-implantation, we observed greater bone volume fraction, bone mineral density, tissue ingrowth, collagen density, and osteoblastic markers in bioreactor constructs cultured for 14 days compared to those cultured for 1 or 7 days, and acellular constructs. Taken together, these data demonstrate that culturing MSCs under perfusion culture for at least 14 days in vitro improves the quantity and quality of bone formation in vivo. This study highlights the need for optimizing in vitro bioreactor culture duration of engineered constructs to achieve the desired level of bone formation.
Poly(2-ethyl-2-oxazoline) conjugates with doxorubicin for cancer therapy: In vitro and in vivo evaluation and direct comparison to poly[N-(2-hydroxypropyl)methacrylamide] analogues Biomaterials (IF 8.402) Pub Date : 2017-09-06 Ondrej Sedlacek, Bryn D. Monnery, Jana Mattova, Jan Kucka, Jiri Panek, Olga Janouskova, Anita Hocherl, Bart Verbraeken, Maarten Vergaelen, Marie Zadinova, Richard Hoogenboom, Martin Hruby
Amorphous liquid metal electrodes enabled conformable electrochemical therapy of tumors Biomaterials (IF 8.402) Pub Date : 2017-09-05 Xuyang Sun, Bo Yuan, Wei Rao, Jing Liu
Electrochemical treatment of tumors (EChT) has recently been identified as a very effective way for local tumor therapy. However, hindered by the limited effective area of a single rigid electrode, multiple electrodes are often recruited when tackling large tumors, where too many electrodes not only complicate the clinical procedures but also aggravate patients' pain. Here we present a new conceptual electric stimulation tumor therapy through introducing the injectable liquid metal electrodes, which can adapt to complex tumor shapes so as to achieve desired therapeutic performance. This approach can offer evident merits for dealing with the complex physiological situations, especially for those irregular body cavities like stomach, colon, rectum or even blood vessel etc., which are hard to tackle otherwise. As it was disclosed from the conceptual experiments that, Unlike traditional rigid and uncomfortable electrodes, liquid metal possesses high flexibility to attach to any crooked biological position to deliver and adjust targeted electric field to fulfill anticipated tumor destruction. And such amorphous electrodes exhibit rather enhanced treatment effect of tumors. Further, we also demonstrate that EChT with liquid metal electrodes produced more electrochemical products during electrolysis. Transformations with the shapes of liquid metal provided an easily regulatable strategy to improve EChT efficiency, which can conveniently aid to achieve better output compared to multiple electrodes. In vivo EChT of tumors further clarified the effect of liquid metal electrodes in retarding tumor growth and increasing life spans.
Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer Biomaterials (IF 8.402) Pub Date : 2017-09-05 Qiwei Yang, Ye Wang, Qing Yang, Yi Gao, Xiaopeng Duan, Qingcheng Fu, Chuanmin Chu, Xiuwu Pan, Xingang Cui, Yinghao Sun
AIEgens for biological process monitoring and disease theranostics Biomaterials (IF 8.402) Pub Date : 2017-09-04 Xinggui Gu, Ryan T.K. Kwok, Jacky W.Y. Lam, Ben Zhong Tang
Biological processes are of great significance for the normal physiological functions of living organisms and closely related to the health. Monitoring of biological processes and diagnosis of diseases based on fluorescent techniques would provide comprehensive insight into mechanism of life and pathogenesis of diseases, precisely guiding therapeutic effect in theranostics. It largely relied on fluorophores with the properties of excellent photostability, large Stokes shift, high signal-to-noise ratio and free of aggregation-caused quenching (ACQ) effect. Luminogens with aggregation-induced emission characteristic (AIEgens) could serve as superior agents for biological process monitoring and disease theranostics. Herein, we review the recent results in the aspects of monitoring biological processes such as autophagy, mitophagy, mitochondrion-related dynamics, cell mitotic, long-term cellular tracing and apoptosis as well as the diagnosis of related diseases based on AIEgens in real time. As part of AIEgens and AIEgen-based nanoparticles with the functionalities of drugs, photosensitizers and adjuvants accompanied with imaging, they exhibit huge potential in theranostic systems for image-guided chemotherapy, photodynamic therapy, radiotherapy and so on. Collectively, these examples show the potentials of AIEgens for understanding disease pathogenesis, for drug development and evaluation, and for clinical disease diagnosis and therapy. Future research efforts focused on developing long-wavelength excitable and phosphorescence-emissive AIEgens with improved depth-penetration and minimized background interference for fluorescence and photoacoustic imaging, will extend the potential applications of AIEgens in in vivo.
Nanomedicine for safe healing of bone trauma: Opportunities and challenges Biomaterials (IF 8.402) Pub Date : 2017-09-04 Shahed Behzadi, Gaurav A. Luther, Mitchel B. Harris, Omid C. Farokhzad, Morteza Mahmoudi
Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches.
Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria Biomaterials (IF 8.402) Pub Date : 2017-09-04 Minae An, Kihwan Kwon, Junbeom Park, Dong-Ryeol Ryu, Jung-A. Shin, Jihee Lee Kang, Ji Ha Choi, Eun-Mi Park, Kyung Eun Lee, Minna Woo, Minsuk Kim
Extracellular matrix (ECM) plays a critical role in the provision of the necessary microenvironment for the proper regeneration of the cardiac tissue. However, specific mechanisms that lead to ECM-mediated cardiac regeneration are not well understood. To elucidate the potential mechanisms, we investigated ultra-structures of the cardiac ECM using electron microscopy. Intriguingly, we observed large quantities of micro-vesicles from decellularized right atria. RNA and protein analyses revealed that these contained exosomal proteins and microRNAs (miRNAs), which we referred to herein as ECM-derived extracellular vesicles (ECM-EVs). One particular miRNA from ECM-EVs, miR-199a-3p, promoted cell growth of isolated neonatal cardiomyocytes and sinus nodal cells by repressing homeodomain-only protein (HOPX) expression and increasing GATA-binding 4 (Gata4) acetylation. To determine the mechanisms, we knocked down Gata4 and showed that miR-199a-3p actions required Gata4 for cell proliferation in isolated neonatal cardiomyocytes and sinus nodal cells. To further explore the role of this miRNA, we isolated neonatal cardiac cells and recellularized into atrial ECM, referred here has engineered atria. Remarkably, miR-199a-3p mediated the enrichment of cardiomyocyte and sinus nodal cell population, and enhanced electrocardiographic signal activity of sinus nodal cells in the engineered atria. Importantly, antisense of miRNA (antagomir) against miR-199a-3p was capable of abolishing these actions of miR-199a-3p in the engineered atria. We further showed in Ang II-infused animal model of sinus nodal dysfunction that miR-199-3p-treated cardiac cells remarkably ameliorated and restored the electrical activity as shown by normalization of the ECG, in contrast to untreated cells, which did not show electrical recovery. In conclusion, these results provide clear evidence of the critical role of ECM, in not only providing a scaffold for cardiac tissue growth, but also in promoting atrial electrical function through ECM-derived miR-199a-3p.
Live cell imaging of mouse intestinal organoids reveals heterogeneity in their oxygenation Biomaterials (IF 8.402) Pub Date : 2017-09-03 Irina A. Okkelman, Tara Foley, Dmitri B. Papkovsky, Ruslan I. Dmitriev
Polyglycerolated nanocarriers with increased ligand multivalency for enhanced In vivo therapeutic efficacy of paclitaxel Biomaterials (IF 8.402) Pub Date : 2017-08-29 Trang Huyen Le Kim, Jeong Heon Yu, Hwiseok Jun, Moon Young Yang, Mi-Jin Yang, Jae-Woo Cho, Jin Woong Kim, Jee Seon Kim, Yoon Sung Nam
Despite the excellent biocompatibility and antifouling effect of poly(ethylene glycol) (PEG), the high steric hindrance, limited chemical functionality, and low ligand multivalency of PEGylated nanocarriers often lead to inefficient cell targeting and intracellular trafficking. Hence, a new structure of hydrophilic corona allowing a higher ligand density without loss of excellent biocompatibility is highly desirable. Here we introduce tumor-targeted polyglycerolated (PGylated) nanocarriers that dramatically enhance the in vivo therapeutic efficacy of incorporated paclitaxel simply by increasing the surface density of hydrophobic tumor-targeting ligands. Linear polyglycerol-poly (ε-caprolactone) block copolymer (PG-b-PCL) is used to prepare PGylated lipiodol nanoemulsions, where PG serves as a corona conjugated with a large number of folic acid (FA) for efficient tumor targeting. Unlike FA-PEGylated nanoemulsions, FA-PGylated nanoemulsions can display a larger number of FA without structural destabilization. This property enables excellent anti-cancer activities and effective tumor regression in a cervical cancer xenograft murine model at a cumulative drug dose of ∼5 mg kg−1, which is about four fold smaller than that of commercial Taxol formulation. This study highlights the importance of surface chemistry of nanocarriers that enable multivalent ligand functionalization and high tolerance to the conjugation of hydrophobic ligands, which make PG as a very effective hydrophilic corona for in vivo drug delivery.
Tissue-engineered human 3D model of bladder cancer for invasion study and drug discovery Biomaterials (IF 8.402) Pub Date : 2017-08-29 Cassandra Ringuette Goulet, Geneviève Bernard, Stéphane Chabaud, Amélie Couture, Alexandre Langlois, Bertrand Neveu, Frédéric Pouliot, Stéphane Bolduc
The tumour microenvironment is critical to both the initiation and maintenance of tumorigenesis. Reconstitution of the microenvironment is a major challenge for in vitro cancer models. Indeed, conventional 2D culture systems cannot replicate the complexity, diversity and dynamic nature of the tumour microenvironment. In this study, we have developed a 3D endotheliazed vesical equivalent by using tissue engineering from primary human cells in which non-invasive or invasive bladder cancer (BCa) cell lines, cultured as compact spheroids, were incorporated. Invasive BCa cells cross the basement membrane and invade the stromal compartment whereas non-invasive BCa cells are confined to the urothelium. Our 3D BCa model could be used as a reliable model for assessing drug responses, potentially reducing or partially replacing animal experiments, and thus should have applications in the identification of novel targets as well as toxicological evaluation of anti-cancer therapies.
Hepatitis B surface antigen incorporated in dissolvable microneedle array patch is antigenic and thermostable Biomaterials (IF 8.402) Pub Date : 2017-08-29 Danielle Poirier, Frédéric Renaud, Vincent Dewar, Laurent Strodiot, Florence Wauters, Jim Janimak, Toshio Shimada, Tatsuya Nomura, Koki Kabata, Koji Kuruma, Takayuki Kusano, Masaki Sakai, Hideo Nagasaki, Takayoshi Oyamada
Alternatives to syringe-based administration are considered for vaccines. Intradermal vaccination with dissolvable microneedle arrays (MNA) appears promising in this respect, as an easy-to-use and painless method. In this work, we have developed an MNA patch (MNAP) made of hydroxyethyl starch (HES) and chondroitin sulphate (CS). In swines, hepatitis B surface antigen (HBsAg) formulated with the saponin QS-21 as adjuvant, both incorporated in HES-based MNAP, demonstrated the same level of immunogenicity as a commercially available aluminum-adjuvanted HBsAg vaccine, after two immunizations 28 days apart. MNAP application was associated with transient skin reactions (erythema, lump, scab), particularly evident when the antigen was delivered with the adjuvant. The thermostability of the adjuvanted antigen when incorporated in the HES-based matrix was also assessed by storing MNAP at 37, 45 or 50 °C for up to 6 months. We could demonstrate that antigenicity was retained at 37 and 45 °C and only a 10% loss was observed after 6 months at 50 °C. Our results are supportive of MNAP as an attractive alternative to classical syringe-based vaccination.
Graphene quantum dots suppress proinflammatory T cell responses via autophagy-dependent induction of tolerogenic dendritic cells Biomaterials (IF 8.402) Pub Date : 2017-08-29 Sergej Tomić, Kristina Janjetović, Dušan Mihajlović, Marina Milenković, Tamara Kravić-Stevović, Zoran Marković, Biljana Todorović-Marković, Zdenko Spitalsky, Matej Micusik, Dragana Vučević, Miodrag Čolić, Vladimir Trajković
Graphene quantum dots (GQD) are atom-thick nanodimensional carbon sheets with excellent physico-chemical and biological properties, making them attractive for application in theranostics. However, their immunoregulatory properties are insufficiently investigated, especially in human primary immune cells. We found that non-toxic doses of GQD inhibit the production of proinflammatory and T helper (Th)1 cytokines, and augment the production of anti-inflammatory and Th2 cytokines by human peripheral blood mononuclear cells. While unable to affect T cells directly, GQD impaired the differentiation and functions of monocyte-derived dendritic cells (DC), lowering their capacity to stimulate T cell proliferation, development of Th1 and Th17 cells, and T-cell mediated cytotoxicity. Additionally, GQD-treated DC potentiated Th2 polarization, and induced suppressive CD4+CD25highFoxp3+ regulatory T cells. After internalization in a dynamin-independent, cholesterol-dependent manner, GQD lowered the ROS generation and nuclear translocation of NF-κB in DC. The activity of mammalian target of rapamycin (mTOR) was reduced by GQD, which correlated with the increase in transcription of autophagy genes and autophagic flux in DC. Genetic suppression of autophagy impaired the pro-tolerogenic effects of GQD on DC. Our results suggest that GQD-triggered autophagy promotes tolerogenic functions in monocyte-derived DC, which could be beneficial in inflammatory T-cell mediated pathologies, but also harmful in GQD-based anti-cancer therapy.
Visual in vivo degradation of injectable hydrogel by real-time and non-invasive tracking using carbon nanodots as fluorescent indicator Biomaterials (IF 8.402) Pub Date : 2017-08-26 Lei Wang, Baoqiang Li, Feng Xu, Ying Li, Zheheng Xu, Daqing Wei, Yujie Feng, Yaming Wang, Dechang Jia, Yu Zhou
Amphiphilic semiconducting polymer as multifunctional nanocarrier for fluorescence/photoacoustic imaging guided chemo-photothermal therapy Biomaterials (IF 8.402) Pub Date : 2017-08-24 Yuyan Jiang, Dong Cui, Yuan Fang, Xu Zhen, Paul Kumar Upputuri, Manojit Pramanik, Dan Ding, Kanyi Pu
Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus Biomaterials (IF 8.402) Pub Date : 2017-08-23 Dayananda Kasala, Soo-Hwan Lee, Jin Woo Hong, Joung-Woo Choi, Kihoon Nam, Yoon Ho Chung, Sung Wan Kim, Chae-Ok Yun
Polymeric nanoparticles of siRNA prepared by a double-emulsion solvent-diffusion technique: Physicochemical properties, toxicity, biodistribution and efficacy in a mammary carcinoma mice model Biomaterials (IF 8.402) Pub Date : 2017-08-23 Meital Ben David-Naim, Etty Grad, Gil Aizik, Mirjam M. Nordling-David, Ofra Moshel, Zvi Granot, Gershon Golomb
siRNA-loaded nanoparticles (NPs) administered systemically can overcome the poor stability and rapid elimination of free double-stranded RNA in circulation, resulting in increased tumor accumulation and efficacy. siRNA against osteopontin (siOPN), a protein involved in breast cancer development, was encapsulated in poly(D,L-lactic-co-glycolic acid) NPs by a double emulsion solvent diffusion (DESD) technique. We also compared the effect of polyethylenimine (PEI) molecular weight (800 Da and 25 kDa), used as the counter-ion for siRNA complexation, on the physicochemical properties of the NPs, cytotoxicity, and cellular uptake.NPs prepared by the DESD technique were obtained at the desired size (∼170 nm) using both types of PEIs, and were characterized with a neutral surface charge, high encapsulation yield (up to ∼60%), siOPN concentration of 5.6–8.4 μg/mg, stability in physiologic conditions in vitro and in vivo, and long-term self-life stability (> 3 years). The NPs prepared using both PEIs exhibited no cytotoxicity in primary smooth muscle culture, and no detrimental effect on mice liver enzymes following their IV administration. Following cellular uptake and biodistribution studies, the therapeutic potential of the NPs was demonstrated by a significant decrease of tumor progression and size in an ectopic xenograft model of mammary carcinoma in mice.
Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials Biomaterials (IF 8.402) Pub Date : 2017-08-19 Michael A. Ramin, Laurent Latxague, Kotagudda Ranganath Sindhu, Olivier Chassande, Philippe Barthélémy
There is a critical need for soft materials in the field of regenerative medicine and tissue engineering. However, designing injectable hydrogel scaffolds encompassing both adequate mechanical and biological properties remains a key challenge for in vivo applications. Here we use a bottom-up approach for synthesizing supramolecular gels to generate novel biomaterial candidates. We evaluated the low molecular weight gels candidates in vivo and identified one urea-containing molecule, compound 16, that avoid foreign body reactions in mice. The self-assembly of bolaamphiphiles creates a unique hydrogel supramolecular structures featuring fast gelation kinetics, high elastic moduli, thixotropic, and thermal reversibility properties. This soft material, which inhibits recognition by macrophages and fibrous deposition, exhibits long-term stability after in vivo injection.
Prodrug-embedded angiogenic vessel-targeting nanoparticle: A positive feedback amplifier in hypoxia-induced chemo-photo therapy Biomaterials (IF 8.402) Pub Date : 2017-08-18 Dongbo Guo, Shuting Xu, Nan Wang, Huangyong Jiang, Yu Huang, Xin Jin, Bai Xue, Chuan Zhang, Xinyuan Zhu
Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis Biomaterials (IF 8.402) Pub Date : 2017-08-18 Jing Wei, Xiaoyu Shuai, Rui Wang, Xueling He, Yiwen Li, Mingming Ding, Jiehua Li, Hong Tan, Qiang Fu
Co-delivery of oxygen and erlotinib by aptamer-modified liposomal complexes to reverse hypoxia-induced drug resistance in lung cancer Biomaterials (IF 8.402) Pub Date : 2017-08-18 Fengqiao Li, Hao Mei, Yu Gao, Xiaodong Xie, Huifang Nie, Tao Li, Huijuan Zhang, Lee Jia
Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies Biomaterials (IF 8.402) Pub Date : 2017-08-17 Victoria M. Steffes, Meena M. Murali, Yoonsang Park, Bretton J. Fletcher, Kai K. Ewert, Cyrus R. Safinya
In situ depot comprising phase-change materials that can sustainably release a gasotransmitter H2S to treat diabetic wounds Biomaterials (IF 8.402) Pub Date : 2017-08-17 Wei-Chih Lin, Chieh-Cheng Huang, Shu-Jyuan Lin, Meng-Ju Li, Yen Chang, Yu-Jung Lin, Wei-Lin Wan, Po-Chien Shih, Hsing-Wen Sung
Patients with diabetes mellitus are prone to develop refractory wounds. They exhibit reduced synthesis and levels of circulating hydrogen sulfide (H2S), which is an ephemeral gaseous molecule. Physiologically, H2S is an endogenous gasotransmitter with multiple biological functions. An emulsion method is utilized to prepare a microparticle system that comprises phase-change materials with a nearly constant temperature of phase transitions to encapsulate sodium hydrosulfide (NaHS), a highly water-labile H2S donor. An emulsion technique that can minimize the loss of water-labile active compounds during emulsification must be developed. The as-prepared microparticles (NaHS@MPs) provide an in situ depot for the sustained release of exogenous H2S under physiological conditions. The sustained release of H2S promotes several cell behaviors, including epidermal/endothelial cell proliferation and migration, as well as angiogenesis, by extending the activation of cellular ERK1/2 and p38, accelerating the healing of full-thickness wounds in diabetic mice. These experimental results reveal the strong potential of NaHS@MPs for the sustained release of H2S for the treatment of diabetic wounds.
Overcoming resistance to cisplatin by inhibition of glutathione S-transferases (GSTs) with ethacraplatin micelles in vitro and in vivo Biomaterials (IF 8.402) Pub Date : 2017-08-17 Shuyi Li, Chan Li, Shubin Jin, Juan Liu, Xiangdong Xue, Ahmed Shaker Eltahan, Jiadong Sun, Jingjie Tan, Jinchen Dong, Xing-Jie Liang
Metal–carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA Biomaterials (IF 8.402) Pub Date : 2017-08-17 Fei Duan, Xiaochen Feng, Yan Jin, Dawei Liu, Xinjian Yang, Guoqiang Zhou, Dandan Liu, Zhenhua Li, Xing-Jie Liang, Jinchao Zhang
The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, β-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of β-lactam antibiotics and β-lactamase inhibitors co-delivery of nanoantibiotics based on metal–carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a β-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal–carbenicillin framework to block the pores of the MSN. Furthermore, these β-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these β-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.
Mechanically dynamic PDMS substrates to investigate changing cell environments Biomaterials (IF 8.402) Pub Date : 2017-08-17 Yi-Cheun Yeh, Elise A. Corbin, Steven R. Caliari, Liu Ouyang, Sebastián L. Vega, Rachel Truitt, Lin Han, Kenneth B. Margulies, Jason A. Burdick
Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ∼1300 to 1900 μm2 and from ∼2700 to 4600 μm2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ∼2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM.
The role of insulin growth factor-1 on the vascular regenerative effect of MAA coated disks and macrophage-endothelial cell crosstalk Biomaterials (IF 8.402) Pub Date : 2017-08-17 Ilana Talior-Volodarky, Redouan Mahou, David Zhang, Michael Sefton
The IGF-1 signaling pathway and IGF-1-dependent macrophage/endothelial cell crosstalk was found to be critical features of the vascular regenerative effect displayed by implanted methacrylic acid –co-isodecyl acrylate (MAA-co-IDA; 40% MAA) coated disks in CD1 mice. Inhibition of IGF-1 signaling using AG1024 an IGF1-R tyrosine kinase inhibitor abrogated vessel formation 14 days after disk implantation in a subcutaneous pocket. Explanted tissue had increased arginase 1 expression and reduced iNOS expression consistent with the greater shift from “M1” (“pro-inflammatory”) macrophages to “M2” (“pro-angiogenic”) macrophages for MAA coated disks relative to control MM (methyl methacrylate-co-IDA) disks; the latter did not generate a vascular response and the polarization shift was muted with AG1024. In vitro, medium conditioned by macrophages (both human dTHP1 cells and mouse bone marrow derived macrophages) had elevated IGF-1 mRNA and protein levels, while the cells had reduced IGF1-R but elevated IGFBP-3 mRNA levels. These cells also had reduced iNOS and elevated Arg1 expression, consistent with the in vivo polarization results, including the inhibitory effects of AG1024. On the other hand, HUVEC exposed to dTHP1 conditioned medium migrated and proliferated faster suggesting that the primary target of the macrophage released IGF-1 was endothelial cells. Although further investigation is warranted, IGF-1 appears to be a key feature underpinning the observed vascularization. Why MAA based materials have this effect remains to be defined, however.
State of Diagnosing Infectious Pathogens Using Colloidal Nanomaterials Biomaterials (IF 8.402) Pub Date : 2017-08-17 Jisung Kim, Mohamed A. Abdou Mohamed, Kyryl Zagorovsky, Warren C.W. Chan
Abstract Infectious diseases represent a major global threat accounting for one of the leading causes of global mortality and morbidity. Prompt diagnosis of infectious diseases is a crucial first step in the management of infectious threats, which aims to quarantine infected patients to avoid contacts with healthy individuals and deliver effective treatments prior to further spread of diseases. This review article discusses the current advances of diagnostic systems using colloidal nanomaterials (e.g., gold nanoparticles, quantum dots, magnetic nanoparticles) for identifying and differentiating infectious pathogens. The challenges involved in the clinical translation of these emerging nanotechnology based diagnostic devices will also be discussed.
RGD peptide-modified fluorescent gold nanoclusters as highly efficient tumor-targeted radiotherapy sensitizers Biomaterials (IF 8.402) Pub Date : 2017-08-16 Guohai Liang, Xudong Jin, Shuxu Zhang, Da Xing
Radiotherapy is a leading treatment approach of cancer therapy. While it is effective in killing tumor cells, it can also cause serious damage to surrounding normal tissue. Targeted radiotherapy with gold nanoparticle-based radiosensitizers is actively being investigated, and considered as a promising means to enhance the efficacy of radiotherapy against tumors under a relatively low and safe radiation dose. In this work, we report a green and one-step strategy to synthesize fluorescent gold nanoclusters by using a commercialized cyclic arginine-glycine-aspartic acid (c(RGDyC)) peptide as the template. The nanoclusters inherit special properties of both the Au core (red/NIR fluorescence emission and strong radiosensitizing effect) and c(RGDyC) shell (active cancer cell-targeting ability and good biocompatibility), and can be applied as fluorescent probes to stain αvβ3 integrin-positive cancer cells, as well as radiosensitizing agents to boost the killing efficacy of radiotherapy. Our data suggest that the as-designed gold nanoclusters have excellent biocompatibility, bright red/NIR fluorescence, active tumor targeting property, and strong radiosensitizing effect, making them highly promising towards potential clinical translation.
ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model Biomaterials (IF 8.402) Pub Date : 2017-08-15 Ernest Moles, Silvia Galiano, Ana Gomes, Miguel Quiliano, Cátia Teixeira, Ignacio Aldana, Paula Gomes, Xavier Fernàndez-Busquets
Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), indicating a potential for improvement of the proposed model.
Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir Biomaterials (IF 8.402) Pub Date : 2017-08-15 Muneeb Mohideen, Elias Quijano, Eric Song, Yang Deng, Gauri Panse, Wei Zhang, Meredith R. Clark, W. Mark Saltzman
New methods for long-lasting protection against sexually transmitted disease, such as the human immunodeficiency virus (HIV), are needed to help reduce the severity of STD epidemics, especially in developing countries. Intravaginal delivery of therapeutics has emerged as a promising means to provide women with local protection, but residence times of such agents are greatly reduced by the protective mucus layer, fluctuating hormone cycle, and complex anatomical structure of the reproductive tract. Polymeric nanoparticles (NPs) capable of encapsulating the desired cargo, penetrating through the mucosal surfaces, and delivering agents to the site of action have been explored. However, prolonged retention of polymer carriers and their enclosed materials may also be needed to ease adherence and confer longer-lasting protection against STDs. Here, we examined the fate of two poly (lactic acid)-hyperbranched polyglycerols (PLA-HPG) NP formulations – 1) nonadhesive PLA-HPG NPs (NNPs) and 2) surface-modified bioadhesive NPs (BNPs) – loaded with the antiretroviral elvitegravir (EVG) after intravaginal administration. BNP distribution was widespread throughout the reproductive tract, and retention was nearly 5 times higher than NNPs after 24 h. Moreover, BNPs were found to be highly associated with submucosal leukocytes and epithelial cell populations for up to 48 h after topical application, and EVG was retained significantly better in the vaginal lumen when delivered with BNPs as opposed to NNPs over a 24 h period. Our results suggest that bioadhesive PLA-HPG NPs can greatly improve and prolong intravaginal delivery of agents, which may hold potential in providing sustained protection over longer durations.
Multiscale design and synthesis of biomimetic gradient protein/biosilica composites for interfacial tissue engineering Biomaterials (IF 8.402) Pub Date : 2017-08-15 Jin Guo, Chunmei Li, Shengjie Ling, Wenwen Huang, Ying Chen, David L. Kaplan
Continuous gradients present at tissue interfaces such as osteochondral systems, reflect complex tissue functions and involve changes in extracellular matrix compositions, cell types and mechanical properties. New and versatile biomaterial strategies are needed to create suitable biomimetic engineered grafts for interfacial tissue engineering. Silk protein-based composites, coupled with selective peptides with mineralization domains, were utilized to mimic the soft-to-hard transition in osteochondral interfaces. The gradient composites supported tunable mineralization and mechanical properties corresponding to the spatial concentration gradient of the mineralization domains (R5 peptide). The composite system exhibited continuous transitions in terms of composition, structure and mechanical properties, as well as cytocompatibility and biodegradability. The gradient silicified silk/R5 composites promoted and regulated osteogenic differentiation of human mesenchymal stem cells in an osteoinductive environment in vitro. The cells differentiated along the composites in a manner consistent with the R5-gradient profile. This novel biomimetic gradient biomaterial design offers a useful approach to meet a broad range of needs in regenerative medicine.
Liposome-supported enzymatic peritoneal dialysis Biomaterials (IF 8.402) Pub Date : 2017-08-14 Anna Pratsinis, Stefanie Zuercher, Vincent Forster, Eric J. Fischer, Paola Luciani, Jean-Christophe Leroux
Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification Biomaterials (IF 8.402) Pub Date : 2017-08-14 Bin Jiang, Rachel Suen, Jiao-Jing Wang, Zheng J. Zhang, Jason A. Wertheim, Guillermo A. Ameer
Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent Biomaterials (IF 8.402) Pub Date : 2017-08-16 Mengchao Shi, Lunguo Xia, Zetao Chen, Fang Lv, Huiying Zhu, Fei Wei, Shengwei Han, Jiang Chang, Yin Xiao, Chengtie Wu
Self-assembled N-cadherin mimetic peptide hydrogels promote the chondrogenesis of mesenchymal stem cells through inhibition of canonical Wnt/β-catenin signaling Biomaterials (IF 8.402) Pub Date : 2017-08-16 Rui Li, Jianbin Xu, Dexter Siu Hong Wong, Jinming Li, Pengchao Zhao, Liming Bian
N-cadherin, a transmembrane protein and major component of adherens junction, mediates cell-cell interactions and intracellular signaling that are important to the regulation of cell behaviors and organ development. Previous studies have identified mimetic peptides that possess similar bioactivity as that of N-cadherin, which promotes chondrogenesis of human mesenchymal stem cells (hMSCs); however, the molecular mechanism remains unknown. In this study, we combined the N-cadherin mimetic peptide (HAVDI) with the self-assembling KLD-12 peptide: the resultant peptide is capable of self-assembling into hydrogels functionalized with N-cadherin peptide in phosphate-buffered saline (PBS) at 37 °C. Encapsulation of hMSCs in these hydrogels showed enhanced expression of chondrogenic marker genes and deposition of cartilage specific extracellular matrix rich in proteoglycan and Type II Collagen compared to control hydrogels, with a scrambled-sequence peptide after 14 days of chondrogenic culture. Furthermore, western blot showed a significantly higher expression of active glycogen synthase kinase-3β (GSK-3β), which phosphorylates β-catenin and facilitates ubiquitin-mediated degradation, as well as a lower expression of β-catenin and LEF1 in the N-cadherin peptide hydrogels versus controls. Immunofluorescence staining revealed significantly less nuclear localization of β-catenin in N-cadherin mimetic peptide hydrogels. Our findings suggest that N-cadherin peptide hydrogels suppress canonical Wnt signaling in hMSCs by reducing β-catenin nuclear translocation and the associated transcriptional activity of β-catenin/LEF-1/TCF complex, thereby enhancing the chondrogenesis of hMSCs. Our biomimetic self-assembled peptide hydrogels can serve as a tailorable and versatile three-dimensional culture platform to investigate the effect of biofunctionalization on stem cell behavior.
Design of a nanocomposite substrate inducing adult stem cell assembly and progression toward an Epiblast-like or primitive endoderm-like phenotype via mechanotransduction Biomaterials (IF 8.402) Pub Date : 2017-08-16 Francesco Morena, Ilaria Armentano, Pia Montanucci, Chiara Argentati, Elena Fortunati, Simona Montesano, Ilaria Bicchi, Teresa Pescara, Ilaria Pennoni, Samantha Mattioli, Luigi Torre, Loredana Latterini, Carla Emiliani, Giuseppe Basta, Riccardo Calafiore, Josè Maria Kenny, Sabata Martino
Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model Biomaterials (IF 8.402) Pub Date : 2017-08-16 Hongtao Yang, Cong Wang, Chaoqiang Liu, Houwen Chen, Yifan Wu, Jintao Han, Zichang Jia, Wenjiao Lin, Deyuan Zhang, Wenting Li, Wei Yuan, Hui Guo, Huafang Li, Guangxin Yang, Deling Kong, Donghui Zhu, Kazuki Takashima, Liqun Ruan, Jianfeng Nie, Xuan Li, Yufeng Zheng
In the present study, pure zinc stents were implanted into the abdominal aorta of rabbits for 12 months. Multiscale analysis including micro-CT, scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and histological stainings was performed to reveal the fundamental degradation mechanism of the pure zinc stent and its biocompatibility. The pure zinc stent was able to maintain mechanical integrity for 6 months and degraded 41.75 ± 29.72% of stent volume after 12 months implantation. No severe inflammation, platelet aggregation, thrombosis formation or obvious intimal hyperplasia was observed at all time points after implantation. The degradation of the zinc stent played a beneficial role in the artery remodeling and healing process. The evolution of the degradation mechanism of pure zinc stents with time was revealed as follows: Before endothelialization, dynamic blood flow dominated the degradation of pure zinc stent, creating a uniform corrosion mode; After endothelialization, the degradation of pure zinc stent depended on the diffusion of water molecules, hydrophilic solutes and ions which led to localized corrosion. Zinc phosphate generated in blood flow transformed into zinc oxide and small amounts of calcium phosphate during the conversion of degradation microenvironment. The favorable physiological degradation behavior makes zinc a promising candidate for future stent applications.
Deriving vascular smooth muscle cells from mesenchymal stromal cells: Evolving differentiation strategies and current understanding of their mechanisms Biomaterials (IF 8.402) Pub Date : 2017-08-15 Xiaoqing Zhang, Michelle P. Bendeck, Craig A. Simmons, J. Paul Santerre
Vascular smooth muscle cells (VSMCs) play essential roles in regulating blood vessel form and function. Regeneration of functional vascular smooth muscle tissue to repair vascular diseases is an area of intense research in tissue engineering and regenerative medicine. For functional vascular smooth muscle tissue regeneration to become a practical therapy over the next decade, the field will need to have access to VSMC sources that are effective, robust and safe. While pluripotent stem cells hold good future promise to this end, more immediate translation is expected to come from approaches that generate functional VSMCs from adult sources of multipotent adipose-derived and bone marrow-derived mesenchymal stromal cells (ASCs and BMSCs). The research to this end is extensive and is dominated by studies relating to classical biochemical signalling molecules used to induce differentiation of ASCs and BMSCs. However, prolonged use of the biochemical induction factors is costly and can cause potential endotoxin contamination in culture. Over recent years several non-traditional differentiation approaches have been devised to mimic defined aspects of the native micro-environment in which VSMCs reside to contribute to the differentiation of VSMC-like cells from ASCs and BMSCs. In this review, the promises and limitations of several non-traditional culture factors (e.g., co-culture, biomechanical, and biomaterial stimuli) targeting VSMC differentiation are discussed. The extensive crosstalk between the underlying signalling cascades are delineated and put into a translational context. It is expected that this review will not only provide significant insight into VSMC differentiation strategies for vascular smooth muscle tissue engineering applications, but will also highlight the fundamental importance of engineering the cellular microenvironment on multiple scales (with consideration of different combinatorial pathways) in order to direct cell differentiation fate and obtain cells of a desired and stable phenotype. These strategies may ultimately be applied to different sources of stem cells in the future for a range of biomaterial and tissue engineering disciplines.
Smart activatable and traceable dual-prodrug for image-guided combination photodynamic and chemotherapy Biomaterials (IF 8.402) Pub Date : 2017-08-14 Fang Hu, Ouyong Yuan, Duo Mao, Wenbo Wu, Bin Liu
Activatable photosensitizers (PSs) and chemo-prodrugs are highly desirable for anti-cancer therapy to reduce systemic toxicity. However, it is difficult to integrate both together into a molecular probe for combination therapy due to the complexity of introducing PS, singlet oxygen quencher, chemo-drug, chemo-drug inhibitor and active linker at the same time. To realize activatable PS and chemo-prodrug combination therapy, we develop a smart therapeutic platform in which the chemo-prodrug serves as the singlet oxygen quencher for the PS. Specifically, the photosensitizing activity and fluorescence of the PS (TPEPY-SH) are blocked by the chemo-prodrug (Mitomycin C, MMC) in the probe. Meanwhile, the cytotoxicity of MMC is also inhibited by the electron-withdrawing acyl at the nitrogen position next to the linker. Upon glutathione activation, TPEPY-S-MMC can simultaneously release active PS and MMC for combination therapy. The restored fluorescence of TPEPY-SH is also used to report the activation for both PS and MMC as well as to guide the photodynamic therapy.
Collagenase treatment enhances proteomic coverage of low-abundance proteins in decellularized matrix bioscaffolds Biomaterials (IF 8.402) Pub Date : 2017-08-13 Miljan Kuljanin, Cody F.C. Brown, Matthew J. Raleigh, Gilles A. Lajoie, Lauren E. Flynn
There is great interest in the application of advanced proteomic techniques to characterize decellularized tissues in order to develop a deeper understanding of the effects of the complex extracellular matrix (ECM) composition on the cellular response to these pro-regenerative bioscaffolds. However, the identification of proteins in ECM-derived bioscaffolds is hindered by the high abundance of collagen in the samples, which can interfere with the detection of lower-abundance constituents that may be important regulators of cell function. To address this limitation, we developed a novel multi-enzyme digestion approach using treatment with a highly-purified collagenase derived from Clostridium Histolyticum to selectively deplete collagen from ECM-derived protein extracts, reducing its relative abundance from up to 90% to below 10%. Moreover, we applied this new method to characterize the proteome of human decellularized adipose tissue (DAT), human decellularized cancellous bone (DCB), and commercially-available bovine tendon collagen (BTC). We successfully demonstrated with all three sources that collagenase treatment increased the depth of detection and enabled the identification of a variety of signaling proteins that were masked by collagen in standard digestion protocols with trypsin/LysC, increasing the number of proteins identified in the DAT by ∼2.2 fold, the DCB by ∼1.3 fold, and the BTC by ∼1.6 fold. In addition, quantitative proteomics using label-free quantification demonstrated that the DAT and DCB extracts were compositionally distinct, and identified a number of adipogenic and osteogenic proteins that were consistently more highly expressed in the DAT and DCB respectively. Overall, we have developed a new processing method that may be applied in advanced mass spectrometry studies to improve the high-throughput proteomic characterization of bioscaffolds derived from mammalian tissues. Further, our study provides new insight into the complex ECM composition of two human decellularized tissues of interest as cell-instructive platforms for regenerative medicine.
Application of three-dimensional collagen scaffolds to recapitulate and monitor the dynamics of epithelial-mesenchymal transition during tumor satellite formation of head and neck cancer Biomaterials (IF 8.402) Pub Date : 2017-08-13 Chun-Nan Chen, You-Tzung Chen, Tsung-Lin Yang
Head and neck squamous cell carcinoma (HNSCC) is a worldwide leading malignancy with poor prognoses. Aggressive HNSCC is manifested by forming tumor satellites in the invasive front, which is closely associated with epithelial-mesenchymal transition, local invasion, and metastasis. Limited by the pathological analyses of static cancer specimens conducted in most previous investigations, the dynamic processes and the decisive factors of tumor satellite formation in HNSCC cannot be monitored and studied. The establishment of a system to recapitulate the phenomenon in vitro may be instrumental to explicitly address the question. In this study, we explored the feasibility of establishing an in vitro system to induce tumor satellite formation of different HNSCC cells by applying a system composed of three-dimensional collagen scaffolds. The real-time dynamic process of tumor satellite formation could be monitored in detail, and the pivotal factors accounting for HNSCC tumor satellite formation were evaluated. E-cadherin remodeling, vimentin aggregation, invadopodia formation, and extracellular matrix degradation occurred in the HNSCC cells when they were cultured in an environment created with a low calcium concentration and steric collagen scaffolds, which altogether contributed to tumor satellite formation and spreading. The phenomena of HNSCC cell transition observed in the current system were confirmed in vivo with compatible findings in surgical specimens. Through the use of this system, we illustrated a novel method to study tumor satellite formation in HNSCC. It may serve as a platform for further investigation of underlying mechanisms for tumor satellites of cancer.
Highly absorbing multispectral near-infrared polymer nanoparticles from one conjugated backbone for photoacoustic imaging and photothermal therapy Biomaterials (IF 8.402) Pub Date : 2017-08-12 Haobin Chen, Jian Zhang, Kaiwen Chang, Xiaoju Men, Xiaofeng Fang, Libo Zhou, Dongliang Li, Duyang Gao, Shengyan Yin, Xuanjun Zhang, Zhen Yuan, Changfeng Wu
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