Journal Sciences News
Toxicology
July 2018
Suspended graphene oxide nanosheets maintain the self-renewal of mouse embryonic stem cells via down-regulating the expression of Vinculin
Publication date: July 2018
Source:Biomaterials, Volume 171 Author(s): Guoxin Jing, Zhaojie Wang, Xizhen Zhuang, Xiaolie He, Huijun Wu, Qingxiu Wang, Liming Cheng, Zhongmin Liu, Shilong Wang, Rongrong Zhu Graphene oxide (GO), with good hydrophilicity and biocompatibility, is widely explored as a carrier for various factors in the field of stem cell differentiation. However, its function of sustaining the stemness of mouse embryonic stem cells (mESCs) and the underlying mechanisms of this process remains undiscovered. Herein, we explored the biofunction of GO on mESCs and revealed the involved signaling pathways and key gene. The alkaline phosphatase activity detection, pluripotency genes quantification and the teratomas formation inávivo confirmed that GO nanosheets could sustain the self-renewal ability of mESCs instead of influencing its pluripotency. The underlying signaling pathways were uncovered by RNA-seq that integrin signaling pathway was involved in the biofunction of GO on mESCs and Vinculin turned to be a key gene for the effect of GO. Further experiments confirmed that the downregulation of Vinculin influenced the fate of mESCs through decreasing the expression of MEK1. Altogether, the study demonstrated for the first time that GOs hold the potential in sustaining the self-renewal of mESCs and clarified the mechanism of this function, which make it play a new role in stem cell research and regenerative medicine.
July 2018
Investigating the interplay between substrate stiffness and ligand chemistry in directing mesenchymal stem cell differentiation within 3D macro-porous substrates
Publication date: July 2018
Source:Biomaterials, Volume 171 Author(s): Matthew G. Haugh, Ted J. Vaughan, Christopher M. Madl, Rosanne M. Raftery, Laoise M. McNamara, Fergal J. O'Brien, Sarah C. Heilshorn Dimensionality can have a profound impact on stiffness-mediated differentiation of mesenchymal stem cells (MSCs). However, while we have begun to understand cellular response when encapsulated within 3D substrates, the behavior of cells within macro-porous substrates is relatively underexplored. The goal of this study was to determine the influence of macro-porous topographies on stiffness-mediated differentiation of MSCs. We developed macro-porous recombinant elastin-like protein (ELP) substrates that allow independent control of mechanical properties and ligand chemistry. We then used computational modeling to probe the impact of pore topography on the mechanical stimulus that cells are exposed to within these substrates, and finally we investigated stiffness induced biases towards adipogenic and osteogenic differentiation of MSCs within macro-porous substrates. Computational modeling revealed that there is significant heterogeneity in the mechanical stimuli that cells are exposed to within porous substrates and that this heterogeneity is predominantly due to the wide range of possible cellular orientations within the pores. Surprisingly, MSCs grown within 3D porous substrates respond to increasing substrate stiffness by up-regulating both osteogenesis and adipogenesis. These results demonstrate that within porous substrates the behavior of MSCs diverges from previously observed responses to substrate stiffness, emphasizing the importance of topography as a determinant of cellular behavior.
July 2018
Stable black phosphorus/Bi2O3 heterostructures for synergistic cancer radiotherapy
Publication date: July 2018
Source:Biomaterials, Volume 171 Author(s): Hao Huang, Lizhen He, Wenhua Zhou, Guangbo Qu, Jiahong Wang, Na Yang, Jie Gao, Tianfeng Chen, Paul K. Chu, Xue-Feng Yu X-ray induced photodynamic therapy (X-ray-PDT) is a promising approach for synergistic cancer radiotherapy and development of suitable radiosensitizers is highly desired. In this paper, we propose black phosphorus/Bi2O3 (BP/Bi2O3) heterostructures as efficient and biocompatible radiosensitizers for synergistic cancer radiotherapy. The heterostructures are synthesized by growth of ultrasmall Bi2O3 nanoparticles onto BP nanosheets. The Bi2O3 decoration inhibits the rapid degradation of BP nanosheets by occupation of the defect sites, and the synergistic effects of BP and Bi2O3 enable 1O2 overproduction under X-ray irradiation. This X-ray-PDT effect of the BP/Bi2O3 nanosheets enhances the radiotherapy activity towards cancer cells by inducing cell apoptosis and cycle arrest. Inávivo treatment of melanoma conducted on a clinical radiotherapeutic instrument demonstrates that the BP/Bi2O3 sensitized radiotherapy inhibits tumor growth efficiently. Furthermore, the BP/Bi2O3 nanosheets composed of biological friendly P, O, and Bi elements shows good biocompatibility inávitro and inávivo. This radiosensitizer thus has immense clinical potential for cancer therapy, and our findings reveal a general strategy to fabricate stable BP-based heterostructures for different applications.
July 2018
Multi-paratopic VEGF decoy receptor have superior anti-tumor effects through anti-EGFRs and targeted anti-angiogenic activities
Publication date: July 2018
Source:Biomaterials, Volume 171 Author(s): Dae Hee Lee, Myeong Youl Lee, Youngsuk Seo, Hyo Jeong Hong, Hyun Joo An, Jong Soon Kang, Ho Min Kim Limitation of current anti-Vascular Endothelial Growth Factor (VEGF) cancer therapy is transitory responses, inevitable relapses and its insufficient tumor-targeting. Thus, multifaceted approaches, including the development of bispecific antibodies and combination strategies targeting different pathways have been proposed as an alternative. Here, we developed a novel multi-paratopic VEGF decoy receptor, Cetuximab-VEGF-Grab and Trastuzumab-VEGF-Grab, by genetically fusing VEGF decoy receptor (VEGF-Grab) to a single chain Fv of anti-Epidermal Growth Factor Receptor (EGFR) antibody (Cetuximab and Trastuzumab). These multi-paratopic VEGF decoy receptor, which recognize VEGF and EGFR family (EGFR or HER2), effectively suppressed both VEGF and EGFR pathways inávitro, to levels similar to those of the parental VEGF-Grab and anti-EGFR antibodies. In addition, the concurrent binding of multi-paratopic VEGF decoy receptor to VEGF and EGFR family enabled their specific localization to EGFRá+átumor inávitro and inávivo. Furthermore, Cetuximab-VEGF-Grab and Trastuzumab-VEGF-Grab exhibited the enhanced anti-tumor activities compared to VEGF-Grab in EGFRá+átumor xenograft mouse model via anti-EGFR and the targeted anti-angiogenic activities. These results indicate that multi-paratopic VEGF decoy receptor can be a promising agent, combining tumor-targeted anti-angiogenic therapy with efficient blockade of proliferative signals mediated by EGFR family.
July 2018
Multifunctional hybrid nanoconstruct of zerovalent iron and carbon dots for magnetic resonance angiography and optical imaging: An Inávivo study
Publication date: July 2018
Source:Biomaterials, Volume 171 Author(s): N. Nimi, Ariya Saraswathy, Shaiju S. Nazeer, Nimmi Francis, Sachin J. Shenoy, Ramapurath S. Jayasree In magnetic resonance imaging (MRI), gadolinium (Gd) complexes are very often used as contrast agents to enhance the signal from soft tissue deformities and vascular anomalies, to improve the accuracy of diagnosis. The safety concern of using Gd complexes in renally compromised patients pose limitations on its application. To overcome this scenario, we introduce a nontoxic zerovalent iron based nanoparticle as a novel contrast agent for MR angiography and a hybrid version of the same to serve as a dual function contrast agent for targeted liver imaging. The synthesized zerovalent iron (ZVI) nanoparticles after citrate stabilization (C@ZVI) had an average size of 10
July 2018
In situ formation of interpenetrating polymer network using sequential thermal and click crosslinking for enhanced retention of transplanted cells
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Hamid Sadeghi Abandansari, Mohammad Hossein Ghanian, Fahimeh Varzideh, Elena Mahmoudi, Sarah Rajabi, Payam Taheri, Mohammad Reza Nabid, Hossein Baharvand Injectable hydrogels, which are used as scaffolds in cell therapy, provide a minimally invasive strategy to enhance cell retention and survival at injection site. However, till now, slow in situ gelation, undesired mechanical properties, and weak cell adhesion characteristics of reported hydrogels, have led to improper results. Here, we developed an injectable fully-interpenetrated polymer network (f-IPN) by integration of Diels-Alder (DA) crosslinked network and thermosensitive injectable hydrogel. The proposed DA hydrogels were formed in a slow manner showing robust mechanical properties. Interpenetration of thermosensitive network into DA hydrogel accelerated in situ gel-formation and masked the slow reaction rate of DA crosslinking while keeping its unique features. Two networks were formed by simple syringe injection without the need of any initiator, catalyst, or double barrel syringe. The DA and f-IPN hydrogels showed comparable viscoelastic properties along with outstanding load-bearing and shape-recovery even under high levels of compression. The subcutaneous administration of cardiomyocytes-laden f-IPN hydrogel into nude mice revealed high cell retention and survival after two weeks. Additionally, the cardiomyocyte's identity of retained cells was confirmed by detection of human and cardiac-related markers. Our results indicate that the thermosensitive-covalent networks can open a new horizon within the injection-based cell therapy applications.

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July 2018
Rapid and selective sampling of IgG from skin in less than 1
July 2018
Cytokine induced killer cells-assisted delivery of chlorin e6 mediated self-assembled gold nanoclusters to tumors for imaging and immuno-photodynamic therapy
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Fangfang Xia, Wenxiu Hou, Yanlei Liu, Wentao Wang, Yu Han, Meng Yang, Xiao Zhi, Chenlu Li, Daizong Qi, Tianliang Li, Jesus Martinez de la Fuente, Chunlei Zhang, Jie Song, Daxiang Cui The cytotoxicity and unique tumor-tropic properties of cytokine-induced killer (CIK) cells render them promising in the field of cancer immunotherapy and delivery systems. Here, we report a novel and facile approach to assemble gold nanoclusters (GNCs) into stable and monodispersed nanoparticles (NPs) using Chlorin e6 (Ce6) molecules. Notably, the fluorescence intensity of the GNCs-Ce6 NPs was about 4.5 folds stronger than the GNCs counterparts. The as-prepared GNCs-Ce6 NPs were conjugated with CD3 antibody (Ab) and further employed to label CIK cells to create a CIK cell-based drug delivery system (Ce6-GNCs-Ab-CIK). The Ce6-GNCs-Ab-CIK exhibited high tumor-targeting efficiency and excellent therapeutic efficacy toward MGC-803 tumor-bearing mice. Benefiting from the synergistic therapeutic effect between GNCs-Ce6-Ab NPs and CIK cells, the GNCs-Ce6-Ab-CIK strategy may present an ideal cancer theranostic platform for tumor targeted imaging and combination therapy.
July 2018
Stromal cell-laden 3D hydrogel microwell arrays as tumor microenvironment model for studying stiffness dependent stromal cell-cancer interactions
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Xiaoshan Yue, Trung Dung Nguyen, Victoria Zellmer, Siyuan Zhang, Pinar Zorlutuna Tumor properties such as growth and metastasis are dramatically dependent on the tumor microenvironment (TME). However, the diversity of the TME including the stiffness and the composition of the extracellular matrix (ECM), as well as the involvement of stromal cells, makes it extremely difficult to establish proper inávitro models for studying tumor growth and metastasis. In this research, we fabricated a stromal cell-laden microwell array system with tunable stiffness ranging from 200
July 2018
Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Jaydev R. Upponi, Kaushal Jerajani, Dattatri K. Nagesha, Praveen Kulkarni, Srinivas Sridhar, Craig Ferris, Vladimir P. Torchilin Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties inávitro. Inávivo, the resulting paclitaxel-SPION-co-loaded PEG-PE micelles retained their Magnetic Resonance contrast properties and apoptotic activity in breast and melanoma tumor mouse models. Such theranostic systems are likely to play a significant role in the combined diagnosis and therapy that leads to a more personalized and effective form of treatment.
July 2018
Comparison of osteointegration property between PEKK and PEEK: Effects of surface structure and chemistry
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Bo Yuan, Qinwen Cheng, Rui Zhao, Xiangdong Zhu, Xiao Yang, Xi Yang, Kai Zhang, Yueming Song, Xingdong Zhang Weak osteointegration affects the long-term stability of polyaryletherketone (PAEK) implants. Surface modification provides a potential solution to improve the osteointegration property of PAEKs. Polyetheretherketone (PEEK) and polyetherketoneketone (PEKK) are two representative PAEK materials, but the former has more ketone groups and better potential for surface chemical modification than the latter. In this work, porous PEKK (PEKK-P) and PEEK (PEEK-P) were fabricated by a porogen leaching method. The samples were treated with 80% sulfuric acid (PEKK-SP and PEEK-SP) and then simulated body fluid (SBF) incubation (PEKK-BSP and PEEK-BSP). More micropores and higher hydrophilic SO3H groups were found on PEKK-SP than PEEK-SP. Likely, more bone-like apatite crystals deposited on PEKK-BSP than PEEK-BSP. To evaluate their osteointegration properties, the samples were implanted in femoral condyle defects (
July 2018
Src activation decouples cell division orientation from cell geometry in mammalian cells
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Xiaoyan Sun, Hongsheng Qi, Xiuzhen Zhang, Li Li, Jiaping Zhang, Qunli Zeng, George S. Laszlo, Bo Wei, Tianhong Li, Jianxin Jiang, Alex Mogilner, Xiaobing Fu, Min Zhao Orientation of cell division plane plays a crucial role in morphogenesis and regeneration. Misoriented cell division underlies many important diseases, such as cancer. Studies with Drosophila and C. elegance models show that Src, a proto-oncogene tyrosine-protein kinase, is a critical regulator of this aspect of mitosis. However, the role for Src in controlling cell division orientation in mammalian cells is not well understood. Using genetic and pharmacological approaches and two extracellular signals to orient cell division, we demonstrated a critical role for Src. Either knockout or pharmacological inhibition of Src would retain the fidelity of cell division orientation with the long-axis orientation of mother cells. Conversely, re-expression of Src would decouple cell division orientation from the pre-division orientation of the long axis of mother cells. Cell division orientation in human breast and gastric cancer tissues showed that the Src activation level correlated with the degree of mitotic spindle misorientation relative to the apical surface. Examination of proteins associated with cortical actin revealed that Src activation regulated the accumulation and local density of adhesion proteins on the sites of cell-matrix attachment. By analyzing division patterns in the cells with or without Src activation and through use of a mathematical model, we further support our findings and provide evidence for a previously unknown role for Src in regulating cell division orientation in relation to the pre-division geometry of mother cells, which may contribute to the misoriented cell division.
July 2018
pH protective Y1 receptor ligand functionalized antiphagocytosis BPLP-WPU micelles for enhanced tumor imaging and therapy with prolonged survival time
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Zhenqi Jiang, Yuchen Tian, Dingying Shan, Yinjie Wang, Ethan Gerhard, Jianbi Xia, Rong Huang, Yan He, Aiguo Li, Jianchao Tang, Huimin Ruan, Yong Li, Juan Li, Jian Yang, Aiguo Wu Nanoparticle-based tumor therapies are extensively studied; however, few are capable of improving patient survival time due to premature drug leakage, off target effects, and poor tissue penetration. Previously, we successfully synthesized a novel family of Y1 receptor (Y1R) ligand modified, photoluminescent BPLP nanobubbles and nanoparticles for targeted breast cancer ultrasound imaging; however, increased accumulation could also be observed in the liver, kidney, and spleen, suggesting significant interaction of the particles with macrophages inávivo. Herein, for the first time, we imparted antiphagocytosis capability to Y1R ligand functionalized BPLP-WPU polymeric micelles through the incorporation of a CD47 human glycoprotein based self-peptide. Application of self-peptide modified, DOX loaded micelles inávivo resulted in a 100% survival rate and complete tumor necrosis over 100 days of treatment. Inávivo imaging of SPION loaded, self-peptide modified micelles revealed effective targeting to the tumor site while analysis of iron content demonstrated reduced particle accumulation in the liver and kidney, demonstrating reduced macrophage interaction, as well as a 2-fold increase of particles in the tumor. As these results demonstrate, Y1R ligand, self-peptide modified BPLP-WPU micelles are capable of target specific cancer treatment and imaging, making them ideal candidates to improve survival rate and tumor reduction clinically.

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July 2018
Zebrafish extracellular matrix improves neuronal viability and network formation in a 3-dimensional culture
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Sung-Min Kim, Daniel Ward Long, Michael Wai Kok Tsang, Yadong Wang Mammalian central nervous system (CNS) has limited capacity for regeneration. CNS injuries cause life-long debilitation and lead to $50 billion in healthcare costs in U.S. alone each year. Despite numerous efforts in the last few decades, CNS-related injuries remain as detrimental as they were 50 years ago. Some functional recovery can occur, but most regeneration are limited by an extracellular matrix (ECM) that actively inhibits axonal repair and promotes glial scarring. In most tissues, the ECM is an architectural foundation that plays an active role in supporting cellular development and regenerative response after injury. In mammalian CNS, however, this is not the case - its composition is not conducive for regeneration, with various molecules restricting plasticity and neuronal growth. In fact, the CNS ECM alters its composition dramatically following injury to restrict regeneration and to prioritize containment of injury as well as preservation of intact neural circuitry. This leads us to hypothesize that the inhibitory extracellular environment needs be modified or supplemented to be more regeneration-permissive for significant CNS regeneration. Mammalian nervous tissue cannot provide such ECM, and synthesizing it in a laboratory is beyond current technology. Evolutionarily lower species possess remarkably regenerative neural tissue. For example, small fresh-water dwelling zebrafish (Danio rerio) can regenerate severed spinal cord, re-gaining full motor function in a week. We believe their ECM contributes to its regenerative capability and that it can be harnessed to induce more regeneration in mammalian CNS. This study shows that ECM derived from zebrafish brains promotes more neuronal survival and axonal network formation than the widely studied and available ECM derived from mammalian tissues such as porcine brains, porcine urinary bladder, and rat brains. We believe its regenerative potential, combined with its affordability, easy handling, and fast reproduction, will make zebrafish an excellent candidate as a novel ECM source.
July 2018
Effective cancer immunotherapy in mice by polyIC-imiquimod complexes and engineered magnetic nanoparticles
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Ana Isabel Bocanegra Gondan, Ane Ruiz-de-Angulo, Aintzane Zabaleta, Nina G
July 2018
Detecting the functional complexities between high-density lipoprotein mimetics
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Yoshitaka J. Sei, Jungho Ahn, Taeyoung Kim, Eunjung Shin, Angel J. Santiago-Lopez, Seung Soon Jang, Noo Li Jeon, Young C. Jang, YongTae Kim High-density lipoprotein (HDL) is a key regulator of lipid homeostasis through its native roles like reverse cholesterol transport. The reconstitution of this natural nanoparticle (NP) has become a nexus between nanomedicine and multi-disease therapies, for which a major portion of HDL functionality is attributed to its primary scaffolding protein, apolipoprotein A1 (apoA1). ApoA1-mimetic peptides were formulated as cost-effective alternatives to apoA1-based therapies; reverse-4F (r4F) is one such peptide used as part of a nanoparticle platform. While similarities between r4F- and apoA1-based HDL-mimetic nanoparticles have been identified, key functional differences native to HDL have remained undetected. In the present study, we executed a multidisciplinary approach to uncover these differences by exploring the form, function, and medical applicability of engineered HDL-mimetic NPs (eHNPs) made from r4F (eHNP-r4F) and from apoA1 (eHNP-A1). Comparative analyses of the eHNPs through computational molecular dynamics (MD), advanced microfluidic NP synthesis and screening technologies, and inávivo animal model studies extracted distinguishable eHNP characteristics: the eHNPs share identical structural and compositional characteristics with distinct differences in NP stability and organization; eHNP-A1 could more significantly stimulate anti-inflammatory responses characteristic of the scavenger receptor class B type 1 (SR-B1) mediated pathways; and eHNP-A1 could outperform eHNP-r4F in the delivery of a model hydrophobic drug to an inávivo tumor. The biomimetic microfluidic technologies and MD simulations uniquely enabled our comparative analysis through which we determined that while eHNP-r4F is a capable NP with properties mimicking natural eHNP-A1, challenges remain in reconstituting the full functionality of NPs naturally derived from humans.
July 2018
Caffeine-catalyzed gels
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Angela M. DiCiccio, Young-Ah Lucy Lee, Dean L. Glettig, Elizabeth S.E. Walton, Eva L. de la Serna, Veronica A. Montgomery, Tyler M. Grant, Robert Langer, Giovanni Traverso Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.
July 2018
Corrigendum toôEffects of compatibility of deproteinized antler cancellous bone with various bioactive factors on their osteogenic potentialö [Biomaterials 34 (2013) 9103-9114]
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Xuehui Zhang, Mingming Xu, Lin Song, Yan Wei, Yuanhua Lin, Wentao Liu, Boon C. Heng, Hui Peng, Ying Wang, Xuliang Deng
July 2018
Photoinduced PEG deshielding from ROS-sensitive linkage-bridged block copolymer-based nanocarriers for on-demand drug delivery
Publication date: July 2018
Source:Biomaterials, Volume 170 Author(s): Jie Li, Chunyang Sun, Wei Tao, Ziyang Cao, Haisheng Qian, Xianzhu Yang, Jun Wang Controlling poly(ethylene glycol) (PEG) shielding/deshielding at the desired site of action exhibits great advantages for nanocarrier-based on-demand drug delivery inávivo. However, the current PEG deshielding strategies were mainly designed for anticancer drug delivery; even so, their applications are also limited by tumor heterogeneity. As a proof-of-concept, we explored a photoinduced PEG deshielding nanocarrier TK-NPCe6&PTX to circumvent the aforementioned challenge. The TK-NPCe6&PTX encapsulating chlorin e6 (Ce6) and paclitaxel (PTX) was self-assembled from an innovative thioketal (TK) linkage-bridged diblock copolymer of PEG with poly(d,l-lactic acid) (PEG-TK-PLA). We demonstrated that the high PEGylation of TK-NPCe6&PTX in blood helps the nanocarrier efficiently avoid rapid clearance and consequently prolongs its circulation time. At the desired site (tumor), 660-nm red light irradiation led to ROS generation in situ, which readily cleaved the TK linkage, resulting in PEG deshielding. Such photoinduced PEG deshielding at the desired site significantly enhances the cellular uptake of the nanocarriers, achieving on-demand drug delivery and superior therapeutic efficacy. More importantly, this strategy of photoinducing PEG deshielding of nanocarriers could potentially extend to a variety of therapeutic agents beyond anticancer drugs for on-demand delivery.

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July 2018
Editorial Board
Publication date: July 2018
Source:Biomaterials, Volume 169

July 2018
Ultra-thin, aligned, free-standing nanofiber membranes to recapitulate multi-layered blood vessel/tissue interface for leukocyte infiltration study
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Sang Min Park, HyeMi Kim, Kwang Hoon Song, Seongsu Eom, HyoungJun Park, Junsang Doh, Dong Sung Kim Leukocyte infiltration plays critical roles in tissue inflammation for pathogen clearance and tumor eradication. This process is regulated by complex microenvironments in blood vessels, including inflamed endothelium, blood flow, and perivascular components. The role of perivascular components in leukocyte infiltration has not been systematically investigated until recently mostly due to lack of technology. In this work, we developed a three-dimensional multi-layered blood vessel/tissue model with a nanofiber membrane, enabling real-time visualization of dynamic leukocyte infiltration and subsequent interaction with perivascular macrophages. We directly fabricated a highly aligned, free-standing nanofiber membrane with an ultra-thin thickness of
July 2018
Injectable hyaluronic acid based microrods provide local micromechanical and biochemical cues to attenuate cardiac fibrosis after myocardial infarction
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Long V. Le, Priya Mohindra, Qizhi Fang, Richard E. Sievers, Michael A. Mkrtschjan, Christopher Solis, Conrad W. Safranek, Brenda Russell, Randall J. Lee, Tejal A. Desai Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods inávitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct.
July 2018
Decellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Aaron H. Morris, Danielle K. Stamer, Britta Kunkemoeller, Julie Chang, Hao Xing, Themis R. Kyriakides Decellularized biologic scaffolds are gaining popularity over synthetic biomaterials as naturally derived materials capable of promoting improved healing. Nevertheless, the most widely used biologic material ľ acellular dermal matrix (ADM) ľ exhibits slow repopulation and remodeling, which prevents integration. Additionally, engineering control of these materials is limited because they require a natural source for their production. In the current report, we demonstrate the feasibility of using genetically engineered animals to create decellularized biologic scaffolds with favorable extracellular matrix (ECM) properties. Specifically, we utilized skin from thrombospondin (TSP)-2 KO mice to derive various decellularized products. Scanning electron microscopy and mechanical testing showed that TSP-2 KO ADM exhibited an altered structure and a reduction in elastic modulus and ultimate tensile strength, respectively. When a powdered form of KO ADM was implanted subcutaneously, it was able to promote enhanced vascularization over WT. Additionally, when implanted subcutaneously, intact slabs of KO ADM were populated by higher number of host cells when compared to WT. Inávitro studies confirmed the promigratory properties of KO ADM. Specifically, degradation products released by pepsin digestion of KO ADM induced greater cell migration than WT. Moreover, cell-derived ECM from TSP-2 null fibroblasts was more permissive to fibroblast migration. Finally, ADMs were implanted in a diabetic wound model to examine their ability to accelerate wound healing. KO ADM exhibited enhanced remodeling and vascular maturation, indicative of efficient integration. Overall, we demonstrate that genetic manipulation enables engineered ECM-based materials with increased regenerative potential.
July 2018
Programmed Ĺtriple-modeĺ anti-tumor therapy: Improving peritoneal retention, tumor penetration and activatable drug release properties for effective inhibition of peritoneal carcinomatosis
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Kondareddy Cherukula, Woo Kyun Bae, Jae Hyuk Lee, In-Kyu Park Peritoneal carcinomatosis (PC) is a fatal condition arising in the gastrointestinal tract. PC patients administered drugs locally in the tumor region, such as in intraperitoneal chemotherapy (IPCh), suffer from low drug retention time and tumor penetration. Herein, we synthesized a lithocholic acid (LCA)-conjugated disulfide-linked polyethyleneimine (ssPEI) micelle (LAPMi) nanoconstruct by covalently conjugating ssPEI and LCA, thereby forming positive charged nanomicellar structures loaded with paclitaxel (PTX) (LAPMi-PTX) for IPCh. The incorporation of a positive surface charge aided in prolonging the peritoneal retention time, presumably via ascites-induced protein corona formation, and the subsequent size expansion caused resistance against undesired clearance through lymphatic openings. Furthermore, preferential tumor penetration by LAPMi-PTX is attributable to the permeation-enhancing properties of LCA, and the subsequent tumor activatable drug release was induced by the presence of disulfide linkages. By integrating these properties, LAPMi exhibited prolonged peritoneal residence time, enhanced tumor permeation and chemotherapeutic effect evidenced by inávitro, tumor spheroid and inávivo studies. Importantly, our strategy enabled significant PC inhibition and increased the overall survival rate of tumor-bearing mice. In conclusion, we provided a new paradigm of intractable PC treatment by enabling the prolonged residence time of the nanoconstruct, thereby enhancing tumor penetration and anti-tumor therapy.
July 2018
Photoactivatable substrates for systematic study of the impact of an extracellular matrix ligand on appearance of leader cells in collective cell migration
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Shimaa A. Abdellatef, Jun Nakanishi Epithelial cells migrate as multicellular units. The directionality and speed of these units are determined by actively moving leader cells. It is important to understand how external cues affect the appearance of these leader cells in physiological and pathological processes. However, the impact of extracellular matrices (ECMs) is still controversial, because physically-adsorbed ECM proteins are amenable to protein remodeling, and uncontrolled cluster geometry can vary migration phenotypes. Here, we demonstrate a photoactivatable substrate, which we used to study the impact of a cyclic Arg-Gly-Asp (cRGD) ligand on leader cell formation in MDCK cells. This robust platform allowed us to investigate the effect of cRGD density on leader cell formation, in any given cluster geometry, with minimized ECM remodeling. Our results show a biphasic response of leader cell appearance upon reducing the surface cRGD density. The increase, in leader cell appearance, within the higher density range, is not only associated with the weakening of circumferential actomyosin belts, but also reduction of cellular mechanical tension and intercellular junctional E-cadherin. These results indicate that cRGD-mediated cell-ECM interactions positively regulate mechanical and biochemical coupling within cell clusters; both are critical for the coordination of cell collectives and eventual reduction in the appearance of leader cells.

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July 2018
Second near-infrared emissive lanthanide complex for fast renal-clearable inávivo optical bioimaging and tiny tumor detection
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Youbin Li, Xiaolong Li, Zhenluan Xue, Mingyang Jiang, Songjun Zeng, Jianhua Hao Inávivo optical imaging by using a new imaging window located at short-wavelength infrared region (1000ľ1700
June 2018
Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models
Publication date: July 2018
Source:Biomaterials, Volume 169 Author(s): Maofan Zhang, C. Tilden Hagan, Yuangzeng Min, Hayley Foley, Xi Tian, Feifei Yang, Yu Mi, Kin Man Au, Yusra Medik, Kyle Roche, Kyle Wagner, Zachary Rodgers, Andrew Z. Wang Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.
June 2018
Editorial Board
Publication date: June 2018
Source:Biomaterials, Volume 168

June 2018
Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Rui Li, Yiyang Li, Yanqing Wu, Yingzheng Zhao, Huanwen Chen, Yuan Yuan, Ke Xu, Hongyu Zhang, Yingfeng Lu, Jian Wang, Xiaokun Li, Xiaofeng Jia, Jian Xiao Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation inávitro. Inávivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p
June 2018
3D cell printing of inávitro stabilized skin model and inávivo pre-vascularized skin patch using tissue-specific extracellular matrixábioink: A step towards advanced skin tissue engineering
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Byoung Soo Kim, Yang Woo Kwon, Jeong-Sik Kong, Gyu Tae Park, Ge Gao, Wonil Han, Moon-Bum Kim, Hyungseok Lee, Jae Ho Kim, Dong-Woo Cho 3D cell-printing technique has been under spotlight as an appealing biofabrication platform due to its ability to precisely pattern living cells in pre-defined spatial locations. In skin tissue engineering, a major remaining challenge is to seek for a suitable source of bioink capable of supporting and stimulating printed cells for tissue development. However, current bioinks for skin printing rely on homogeneous biomaterials, which has several shortcomings such as insufficient mechanical properties and recapitulation of microenvironment. In this study, we investigated the capability of skin-derived extracellular matrix (S-dECM) bioink for 3D cell printing-based skin tissue engineering. S-dECM was for the first time formulated as a printable material and retained the major ECM compositions of skin as well as favorable growth factors and cytokines. This bioink was used to print a full thickness 3D human skin model. The matured 3D cell-printed skin tissue using S-dECM bioink was stabilized with minimal shrinkage, whereas the collagen-based skin tissue was significantly contracted during inávitro tissue culture. This physical stabilization and the tissue-specific microenvironment from our bioink improved epidermal organization, dermal ECM secretion, and barrier function. We further used this bioink to print 3D pre-vascularized skin patch able to promote inávivo wound healing. Inávivo results revealed that endothelial progenitor cells (EPCs)-laden 3D-printed skin patch together with adipose-derived stem cells (ASCs) accelerates wound closure, re-epithelization, and neovascularization as well as blood flow. We envision that the results of this paper can provide an insightful step towards the next generation source for bioink manufacturing.
June 2018
A tumor-activatable particle with antimetastatic potential in breast cancer via inhibiting the autophagy-dependent disassembly of focal adhesion
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Yang Wang, Sheng Yin, Li Zhang, Kairong Shi, Jiajing Tang, Zhirong Zhang, Qin He In attempts to explore the role of autophagy in breast cancer metastasis, we here report a tumor-activatable particle (named as ôD/PSP@CQ/CaPö) with the ability of efficient autophagy inhibition. D/PSP@CQ/CaP was prepared by coprecipitating chloroquine phosphate (CQ) with calcium chloride, in the form of chloroquine-calcium phosphate coprecipitate (CQ/CaP), onto the surface of a deep-tumor-penetrating doxorubicine (DOX)-loading core particle (named as ôD/PSPö). CQ/CaP could partly disintegrate and release CQ within tumor microenvironment and totally be dissolved within lysosomes. Paxillin is a key component of focal adhesion which functions to anchor tumors cells within the primary tumor for limiting cancer cells' detachment from the primary tumor. We tested that autophagy inhibition caused by CQ released from CQ/CaP could reduce the degradation of paxillin by 2.9 folds inávitro and 2.5 folds inávivo (vs. Control), respectively. Thus metastasis could be influenced by exploiting autophagy-dependent paxillin degradation. Data analysis together proved that D/PSP@CQ/CaP decreased the cancer metastatic extent by 7.5 folds (vs. Control) on mice model via inhibiting the autophagy-dependent disassembly of focal adhesion. At the same time, the growth rate of tumors treated by D/PSP@CQ/CaP was inhibited by 9.1 folds (vs. Control), which could be attributed to its effective tumor drug delivery.

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June 2018
Hyaluronic acid coated albumin nanoparticles for targeted peptide delivery in the treatment of retinal ischaemia
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Di Huang, Ying-Shan Chen, Colin R. Green, Ilva D. Rupenthal Recent studies have shown that Connexin43 mimetic peptide (Cx43
June 2018
Dynamics of dual-fluorescent polymersomes with durable integrity in living cancer cells and zebrafish embryos
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Sven H.C. Askes, Nelli Bossert, Jeroen Bussmann, Victorio Saez Talens, Michael S. Meijer, Roxanne E. Kieltyka, Alexander Kros, Sylvestre Bonnet, Doris Heinrich The long-term fate of biomedical nanoparticles after endocytosis is often only sparsely addressed inávitro and inávivo, while this is a crucial parameter to conclude on their utility. In this study, dual-fluorescent polyisobutylene-polyethylene glycol (PiB-PEG) polymersomes were studied for several days inávitro and inávivo. In order to optically track the vesicles' integrity, one fluorescent probe was located in the membrane and the other in the aqueous interior compartment. These non-toxic nanovesicles were quickly endocytosed in living A549 lung carcinoma cells but unusually slowly transported to perinuclear lysosomal compartments, where they remained intact and luminescent for at least 90
June 2018
Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy
Publication date: June 2018
Source:Biomaterials, Volume 168 Author(s): Chuan Hu, Xingli Cun, Shaobo Ruan, Rui Liu, Wei Xiao, Xiaotong Yang, Yuanyuan Yang, Chuanyao Yang, Huile Gao Chemotherapy remains restricted by poor drug delivery efficacy due to the heterogenous nature of tumor. Herein, we presented a novel nanoparticle that could not only response to the tumor microenvironment but also modulate it for deep tumor penetration and combination therapy. The intelligent nanoparticle (IDDHN) was engineered by hyaluronidase (HAase)-triggered size shrinkable hyaluronic acid shells, which were modified with NIR laser sensitive nitric oxide donor (HN), small-sized dendrimeric prodrug (IDD) of doxorubicin (DOX) as chemotherapy agent and indocyanine green (ICG) as photothermal agent into a single nanoparticle. IDDHN displayed synergistic deep penetration both inávitro and inávivo, owing to the enzymatically degradable HN shell mediated by HAase and laser-enhanced NO release triggered deep penetration upon strong hyperthermia effect of ICG under the NIR laser irradiation. The therapeutic effect of IDDHN was verified in 4T1 xenograft tumor model, and IDDHN showed a much better antitumor efficiency with few side effects upon NIR laser irradiation. Therefore, the valid of this study might provide a novel tactic for engineering nanoparticles both response to and modulate the tumor microenvironment for improving penetration and heterogeneity distribution of therapeutic agents in tumor.

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June 2018
Editorial Board
Publication date: June 2018
Source:Biomaterials, Volume 167

June 2018
Infections associated with mesh repairs of abdominal wall hernias: Are antimicrobial biomaterials the longed-for solution?
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): O. Guillaume, R. P
June 2018
Osteogenesis potential of different titania nanotubes in oxidative stress microenvironment
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Yonglin Yu, Xinkun Shen, Zhong Luo, Yan Hu, Menghuan Li, Pingping Ma, Qichun Ran, Liangliang Dai, Ye He, Kaiyong Cai Oxidative stress is commonly existed in bone degenerative disease (osteoarthritis, osteoporosis etc.) and some antioxidants had great potential to enhance osteogenesis. In this study, we aim to investigate the anti-oxidative properties of various TiO2 nanotubes (TNTs) so to screen the desirable size for improved osteogenesis and reveal the underlying molecular mechanism inávitro. Comparing cellular behaviors under normal and oxidative stress conditions, an interesting conclusion was obtained. In normal microenvironment, small TNTs were beneficial for adhesion and proliferation of osteoblasts, but large TNTs greatly increased osteogenic differentiation. However, after H2O2 (300
June 2018
Novel angiogenesis therapeutics by redox injectable hydrogel - Regulation of local nitric oxide generation for effective cardiovascular therapy
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Long Binh Vong, Thang Quoc Bui, Tsutomu Tomita, Hiroaki Sakamoto, Yuji Hiramatsu, Yukio Nagasaki Nitric oxide (NO) possesses various functions in cardiovascular diseases; however, due to an extremely short half-life and low bioavailability, its therapeutic application is limited. In inflamed tissues, overproduced reactive oxygen species (ROS) rapidly react with the endogenous NO, reducing its bioavailability. Here, we developed a controllable NO-releasing redox injectable hydrogel (NO-RIG) formed by the electrostatic crosslinking between the polyion complex flower-type micelles composing of functional polymers to scavenge overproduced ROS and regulate the local NO expression level simultaneously. After the intracardiac injection to mice, NO-RIG converted to gel via physiological temperature-responsive character, distributed homogeneously, and retained in the myocardial tissue for more than 10
June 2018
Non-eluting, surface-bound enzymes disrupt surface attachment of bacteria by continuous biofilm polysaccharide degradation
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Dalal Asker, Tarek S. Awad, Perrin Baker, P. Lynne Howell, Benjamin D. Hatton Bacterial colonization and biofilm formation on surfaces are typically mediated by the deposition of exopolysaccharides and conditioning protein layers. Pseudomonas aeruginosa is a nosocomial opportunistic pathogen that utilizes strain-specific exopolysaccharides such as Psl, Pel or alginate for both initial surface attachment and biofilm formation. To generate surfaces that resist P.áaeruginosa colonization, we covalently bound a Psl-specific glycoside hydrolase (PslGh) to several, chemically-distinct surfaces using amine functionalization (APTMS) and glutaraldehyde (GDA) linking. In situ quartz crystal microbalance (QCM) experiments and fluorescence microscopy demonstrated a complete lack of Psl adsorption on the PslGh-bound surfaces. Covalently-bound PslGh was also found to significantly reduce P.áaeruginosa surface attachment and biofilm formation over extended growth periods (8 days). The PslGh surfaces showed a
June 2018
Substrate stiffness modulates the multipotency of human neural crest derived ectomesenchymal stem cells via CD44 mediated PDGFR signaling
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Akshaya Srinivasan, Shu-Yung Chang, Shipin Zhang, Wei Seong Toh, Yi-Chin Toh Mesenchymal stem cells (MSCs) have been isolated from various mesodermal and ectodermal tissues. While the phenotypic and functional heterogeneity of MSCs stemming from their developmental origins has been acknowledged, the genetic and environmental factors underpinning these differences are not well-understood. Here, we investigated whether substrate stiffness mediated mechanical cues can directly modulate the development of ectodermal MSCs (eMSCs) from a precursor human neural crest stem cell (NCSC) population. We showed that NCSC-derived eMSCs were transcriptionally and functionally distinct from mesodermal bone marrow MSCs. eMSCs derived on lower substrate stiffness specifically increased their expression of the MSC marker, CD44 in a Rho-ROCK signaling dependent manner, which resulted in a concomitant increase in the eMSCs' adipogenic and chondrogenic differentiation potential. This mechanically-induced effect can only be maintained for short-term upon switching back to a stiff substrate but can be sustained for longer-term when the eMSCs were exclusively maintained on soft substrates. We also discovered that CD44 expression modulated eMSC self-renewal and multipotency via the downregulation of downstream platelet-derived growth factor receptor beta (PDGFR
June 2018
Polyphenol uses in biomaterials engineering
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Amin Shavandi, Alaa El-Din Ahmed Bekhit, Pouya Saeedi, Zohreh Izadifar, Adnan A. Bekhit, Ali Khademhosseini Polyphenols are micronutrients obtained from diet that have been suggested to play an important role in health. The health benefits of polyphenols and their protective effects in food systems as antioxidant compounds are well known and have been extensively investigated. However, their functional roles as a ôprocessing cofactorö in tissue engineering applications are less widely known. This review focuses on the functionality of polyphenols and their application in biomaterials. Polyphenols have been used to stabilize collagen and to improve its resistance to degradation in biological systems. Therefore, they have been proposed to improve the performance of biomedical devices used in cardiovascular systems by improving the mechanical properties of grafted heart valves, enhancing microcirculation through the relaxation of the arterial walls and improving the capillary blood flow and pressure resistance. Polyphenols have been found to stimulate bone formation, mineralization, as well as the proliferation, differentiation, and the survival of osteoblasts. These effects are brought about by the stimulatory effect of polyphenols on osteoblast cells and their protective effect against oxidative stress and inflammatory cytokines. In addition, polyphenols inhibit the differentiation of the osteoclast cells. Collectively, these actions lead to promote bone formation and to reduce bone resorption, respectively. Moreover, polyphenols can increase the cross-linking of dentine and hence its mechanical stability. Overall, polyphenols provide interesting properties that will stimulate further research in the bioengineering field.
June 2018
Understanding interactions between biomaterials and biological systems using proteomics
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Ziryan Othman, Berta Cillero Pastor, Sabine van Rijt, Pamela Habibovic The role that biomaterials play in the clinical treatment of damaged organs and tissues is changing. While biomaterials used in permanent medical devices were required to passively take over the function of a damaged tissue in the long term, current biomaterials are expected to trigger and harness the self-regenerative potential of the body in situ and then to degrade, the foundation of regenerative medicine. To meet these different requirements, it is imperative to fully understand the interactions biomaterials have with biological systems, in space and in time. This knowledge will lead to a better understanding of the regenerative capabilities of biomaterials aiding their design with improved functionalities (e.g. biocompatibility, bioactivity). Proteins play a pivotal role in the interaction between biomaterials and cells or tissues. Protein adsorption on the material surface is the very first event of this interaction, which is determinant for the subsequent processes of cell growth, differentiation, and extracellular matrix formation. Against this background, the aim of the current review is to provide insight in the current knowledge of the role of proteins in cellľbiomaterial and tissueľbiomaterial interactions. In particular, the focus is on proteomics studies, mainly using mass spectrometry, and the knowledge they have generated on protein adsorption of biomaterials, protein production by cells cultured on materials, safety and efficacy of new materials based on nanoparticles and the analysis of extracellular matrices and extracellular matrixľderived products. In the outlook, the potential and limitations of this approach are discussed and mass spectrometry imaging is presented as a powerful technique that complements existing mass spectrometry techniques by providing spatial molecular information about the material-biological system interactions.
June 2018
Regeneration of diaphragm with bio-3D cellular patch
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Xiu-Ying Zhang, Yusuke Yanagi, Zijing Sheng, Kouji Nagata, Koichi Nakayama, Tomoaki Taguchi Neonates with congenital diaphragmatic hernia often require surgical defect closure with a patch. Alternatives to native diaphragmatic tissue are critically needed for this paediatric surgery. The clinical efficacy of mesh patches is limited by complications associated with residual foreign material and by hernia recurrence. In this study, we used a novel bio-3D printer method to generate large scaffold-free tissue patches composed of human cells. The resulting large tissue constructs had high elasticity and strength. Cellular patches were transplanted into rats with surgically created diaphragmatic defects. Rats survived for over 710 days after implantation of tissue constructs. CT confirmed complete tissue integration of the grafts during rat growth. Histology revealed regeneration of muscle structure, neovascularization, and neuronal networks within the reconstructed diaphragms. Our results demonstrate that created cellular patches are a highly safe and effective therapeutic strategy for repairing diaphragmatic defects, and thus pave the way for a clinical trial.
June 2018
Inducing hair follicle neogenesis with secreted proteins enriched in embryonic skin
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Sabrina Mai-Yi Fan, Chia-Feng Tsai, Chien-Mei Yen, Miao-Hsia Lin, Wei-Hung Wang, Chih-Chieh Chan, Chih-Lung Chen, Kyle K.L. Phua, Szu-Hua Pan, Maksim V. Plikus, Sung-Liang Yu, Yu-Ju Chen, Sung-Jan Lin Organ development is a sophisticated process of self-organization. However, despite growing understanding of the developmental mechanisms, little is known about how to reactivate them postnatally for regeneration. We found that treatment of adult non-hair fibroblasts with cell-free extract from embryonic skin conferred upon them the competency to regenerate hair follicles. Proteomics analysis identified three secreted proteins enriched in the embryonic skin, apolipoprotein-A1, galectin-1 and lumican that together were essential and sufficient to induce new hair follicles. These 3 proteins show a stage-specific co-enrichment in the perifolliculogenetic embryonic dermis. Mechanistically, exposure to embryonic skin extract or to the combination of the 3 proteins altered the gene expression to an inductive hair follicle dermal papilla fibroblast-like profile and activated Igf and Wnt signaling, which are crucial for the regeneration process. Therefore, a cocktail of organ-specific extracellular proteins from the embryonic environment can render adult cells competent to re-engage in developmental interactions for organ neogenesis. Identification of factors that recreate the extracellular context of respective developing tissues can become an important strategy to promote regeneration in adult organs.
June 2018
The influence of hypoxia and IFN-
June 2018
The transgenic chicken derived anti-CD20 monoclonal antibodies exhibits greater anti-cancer therapeutic potential with enhanced Fc effector functions
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Young Min Kim, Jin Se Park, Sang Kyung Kim, Kyung Min Jung, Young Sun Hwang, Mookyoung Han, Hong Jo Lee, Hee Won Seo, Jeong-Yong Suh, Beom Ku Han, Jae Yong Han Modern genetic techniques, enable the use of animal bioreactor systems for the production and functional enhancement of anti-cancer antibodies. Chicken is the most efficient animal bioreactor for the production of anti-cancer antibodies because of its relatively short generation time, plentiful reproductive capacity, and daily deposition in the egg white. Although several studies have focused on the production of anti-cancer antibodies in egg white, in-depth studies of the biological activity and physiological characteristics of transgenic chicken-derived anti-cancer antibodies have not been fully carried out. Here, we report the production of an anti-cancer monoclonal antibody against the CD20 protein from egg whites of transgenic hens, and validated the bio-functional activity of the protein in B-lymphoma and B-lymphoblast cells. Quantitative analysis showed that deposition of the chickenised CD20 monoclonal antibody (cCD20 mAb) from transgenic chickens increased in successive generations and with increasing transgene copy number. Ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (LC/MS/MS) analysis showed that the cCD20 mAb exhibited 14
June 2018
Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Rong Deng, Na Shen, Yang Yang, Hongliang Yu, Shuping Xu, Ying-Wei Yang, Shujun Liu, Kamel Meguellati, Fei Yan Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NF
June 2018
Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Fan Niu, Jin Yan, Bohan Ma, Shichao Li, Yongping Shao, Pengcheng He, Wanggang Zhang, Wangxiao He, Peter X. Ma, Wuyuan Lu Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy. Two pharmacological barriers, however, remain a major obstacle to the development of peptide therapeutics: susceptibility to proteolytic degradation inávivo and inability to traverse the cell membrane. Here we report the design of a fluorescent lanthanide oxyfluoride nanoparticle (LONp)-based multifunctional peptide drug delivery system for potential treatment of acute myeloid leukemia (AML) that commonly harbors wild type p53, high levels of MDM2 and/or MDMX, and an overexpressed cell surface receptor, CD33. We conjugated to LONp via metal-thiolate bonds a dodecameric peptide antagonist of both MDM2 and MDMX, termed PMI, and a CD33-targeted, humanized monoclonal antibody to allow for AML-specific intracellular delivery of a stabilized PMI. The resultant nanoparticle antiCD33-LONp-PMI, while nontoxic to normal cells, induced apoptosis of AML cell lines and primary leukemic cells isolated from AML patients by antagonizing MDM2 and/or MDMX to activate the p53 pathway. Fluorescent antiCD33-LONp-PMI also enabled real-time visualization of a series of apoptotic events in AML cells, proving a useful tool for possible disease tracking and treatment response monitoring. Our studies shed light on the development of antiCD33-LONp-PMI as a novel class of antitumor agents, which, if further validated, may help targeted molecular therapy of AML.
June 2018
Near infrared-emitting persistent luminescent nanoparticles for Hepatocellular Carcinoma imaging and luminescence-guided surgery
Publication date: June 2018
Source:Biomaterials, Volume 167 Author(s): Ting Ai, Wenting Shang, Hao Yan, Chaoting Zeng, Kun Wang, Yuan Gao, Tianpei Guan, Chihua Fang, Jie Tian Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, is increasing nowadays and poses a serious threat to human health. However, if treated effectively and timely, it is clinically manageable or curable. Therefore, accurate detection and complete surgical resection remain priorities for HCC with a high potential of improving both survival and quality of life. Lacking of real-time guide technology, traditional surgery are usually relied on the subjective experience of surgeon, which have the limitation of high sensitivity detection tumor. Here, we developed a contrast agent, ZnGa2O4Cr0.00 4 (ZGC), used for guided surgery during operation to accurate delineation of HCC. ZGC showed excellent long-lasting afterglow properties that lasted for hours, which can aid in real-time guided surgery. Meanwhile, ZGC display high spatial resolution and deep penetration during pre-operation for diagnostic computed tomography (CT). Interestingly, we observed reverse imaging in the tumor region, known as a ôdark holeö, which further improves the contrast for surgery. This new multi-modality nanoparticle has great potential for accurate liver cancer imaging and resection guidance.

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The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine
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