首页期刊导航|Acta biomaterialia
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Acta biomaterialia
Elsevier
Acta biomaterialia

Elsevier

1742-7061

Acta biomaterialia/Journal Acta biomaterialiaEIISTPSCI
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    In vivo stiffness of multiple sclerosis lesions is similar to that of normal-appearing white matter

    Herthum, HelgeHetzer, StefanScheel, MichaelShahryari, Mehrgan...
    12页
    查看更多>>摘要：In 1868, French neurologist Jean-Martin Charcot coined the term multiple sclerosis (MS) after his observation that numerous white matter (WM) glial scars felt like sclerotic tissue. Nowadays, magnetic resonance elastography (MRE) can generate images with contrast of stiffness (CS) in soft in vivo tissues and may therefore be sensitive to MS lesions, provided that sclerosis is indeed a mechanical signature of this disease. We analyzed CS in a total of 147 lesions in patients with relapsing-remitting MS, compared with control regions in contralateral brain regions, and phantom data as well as performed numerical simulations to determine the delineation limits of multifrequency MRE (20 -40 Hz) in MS. MRE analysis of simulated waves revealed a delineation limit of approximately 10% CS for detecting 9-mm lesions (mean size in our patient population). Due to inversion bias, this limit is reached when true CS is-11% for soft and 35% for stiff lesions. In vivo MRE identified 35 stiffer lesions and 17 softer lesions compared with surrounding WM (mean stiffness: 934 +/- 82 Pa). However, a similar pattern was found in the contralateral brain, suggesting that the range of stiffness changes in WM lesions due to MS is within the normal range of WM variability and normal heterogeneity-related CS. Consequently, Charcot's original intuition that MS is a focal sclerotic disease can neither be dismissed nor confirmed by in vivo MRE. However, the observation that MS lesions do not markedly differ in stiffness from surrounding brain tissue suggests that marked tissue sclerosis is not a mechanical signature of MS. Statement of significance Multiple sclerosis (MS) was named by J.M. Charcot after the sclerotic changes in brain tissue he found in post-mortem autopsies. Since then, nothing has been revealed about the actual stiffening of MS lesions in vivo . Studying the viscoelastic properties of plaques in their natural environment is a major challenge that can only be overcome by MR elastography (MRE). Therefore, we used multifrequency MRE to answer the question whether MS lesions in patients with a relapsing-remitting disease course are mechanically different than surrounding tissue. Our findings suggest that the range of stiffness changes in white matter lesions due to MS is within the normal range of white matter variability and in vivo tissue sclerosis might not be a mechanical signature of MS. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    The flying insect thoracic cuticle is heterogenous in structure and in thickness-dependent modulus gradation

    Casey, CailinYager, ClaireJankauski, MarkHeveran, Chelsea M....
    8页
    查看更多>>摘要：The thorax is a specialized structure central to insect flight. In the thorax, flight muscles are surrounded by a thin layer of cuticle. The structure, composition, and material properties of this chitinous structure may influence the efficiency of the thorax in flight. However, these properties, as well as their variation throughout the thorax and between insect taxa, are not known. We provide a multi-faceted assessment of thorax cuticle for fliers with asynchronous (honey bee; Apis mellifera) and synchronous (hawkmoth; Manduca sexta) muscles. These muscle types are defined by the relationship between their activation frequency and the insect's wingbeat frequency. We investigated cuticle structure using histology, resilin distribution through confocal laser scanning microscopy, and modulus gradation with nanoindentation. Our results suggest that thorax cuticle properties are highly dependent on anatomical region and species. Modulus gradation, but not mean modulus, differed between the two types of fliers. In some regions, A. mellifera had a positive linear modulus gradient from cuticle interior to exterior of about 2 GPa. In M. sexta, modulus values through cuticle thickness were not well represented by linear fits. We utilized finite element modeling to assess how measured modulus gradients influenced maximum stress in cuticle. Stress was reduced when cuticle with a linear gradient was compressed from the high modulus side. These results support the protective role of the A. mellifera thorax cuticle. Our multi-faceted assessment advances our understanding of thorax cuticle structural and material heterogeneity and the potential benefits of material gradation to flying insects. Statement of significance The insect thorax is essential for efficient flight but questions remain about the contribution of the exoskeletal cuticle. We investigated the microscale properties of the thorax cuticle, a crucial step to determine its role in flight. Techniques including histology, nanoindentation, and confocal laser scanning microscopy revealed that cuticle properties vary through cuticle thickness, by thorax region, and between species with asynchronous (honey bee; Apis mellifera) and synchronous (hawkmoth; Manduca sexta) muscles. This variation highlights the importance of high resolution cuticle assessment for flying insect lineages and points to factors that may (modulus gradation) and may not (mean modulus) contribute to different flight forms. Understanding material variation in the thorax may inform design of technologies inspired by insects, such as mobile micro robots. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Seed protection strategies of the brainy Elaeocarpus ganitrus endocarp: Gradient motif yields fracture tolerance

    Ghimire, AshishChen, Po-Yu
    13页
    查看更多>>摘要：Be it animals or plants, most of the organism's offspring come into existence after their embryos de-velop inside a protective shell. In plants, these hard protective shells are called endocarps. They serve the function of nourishing and protecting the seeds from external mechanical damage. Through evolu-tion, endocarps of plants have developed various structural strategies to protect the enclosed seeds from external threats, and these strategies can vary according to the habitat or lifestyle of a particular plant. One such intriguing hard plant shell is the endocarp of the Elaeocarpus ganitrus fruit. It mostly grows in South Asia's mountainous forests, and its endocarps are known in the local communities as unbreakable and everlasting prayer beads. We report an in-depth investigation on microstructure, tomography, and mechanical properties to cast light on its performance and the underlying structure-property relation. The 3D structural quantifications by micro-CT demonstrate that the endocarp has gradient microarchitec-ture. In addition, the endocarp also exhibits gradient hardness and stiffness. The toughening mechanisms arising from the layered cellular structure enable the endocarps to withstand higher loads up to 50 0 0 N before they fracture. Our findings provide experimental evidence of outstanding fracture tolerance and seed protection strategies developed by Elaeocarpus ganitrus endocarp that encourage the design of syn-thetic fracture tolerant structures. Statement of significance Endocarps are low-density plant shells that exhibit remarkable fracture resistance and energy absorp-tion when they encounter impact by falling from high trees and prolonged compression and abrasion by the predators. Such outstanding mechanical performance originates through structural design strate-gies developed to protect their seeds. Here we demonstrate previously undiscovered structural features and mechanical properties of Elaeocarpus ganitrus endocarp. We scrutinize the microstructure using high -resolution x-ray tomography scans and the 3D structural quantifications reveal a gradient microstructure which is in agreement with the gradient hardness and stiffness. The multiscale hierarchical structures combined with the gradient motif yield impressive fracture tolerance in Elaeocarpus ganitrus endocarp. These findings advance the knowledge of the structure-property relation in hard plant shells, and the procured structural design strategies can be utilized to design fracture-resistant structures. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Folate-mediated targeted PLK1 inhibition therapy for ovarian cancer: A comparative study of molecular inhibitors and siRNA therapeutics

    Yuan, JiandongZhong, ZhiyuanWang, ZheZhao, Songsong...
    10页
    查看更多>>摘要：PLK1 is a promising target for clinical treatment of diverse malignancies including ovarian cancer (OC), in which PLK1 over-expression is often correlated with poor prognosis and short survival. PLK1 can be blocked with small molecular inhibitors like volasertib (Vol) or silenced with PLK1-specific siRNA (siPLK1), hence effectively suppressing tumor growth. Surprisingly, despite intensive work on molecular inhibitor and siRNA therapeutics, there is no direct comparison between them reported for targeted tumor therapy. Herein, we employing folate as a ligand and polymersomes as a nanovehicle performed a comparative study on Vol and siPLK1 in inhibiting OC in vitro and in vivo . Folate-targeted polymersomal Vol and siPLK1 (termed as FA-Ps-Vol and FA-Ps-siPLK1, respectively) were both nano-sized and stable, and displayed an optimal FA density of 20% for SKOV-3 cells. Notably, FA-Ps-Vol and FA-Ps-siPLK1 exhibited an IC50 of 193 and 770 nM, respectively, to SKOV-3 cells, indicating a greater potency of Vol than siPLK1. The markedly increased uptake for FA-Ps-Vol and FA-Ps-siPLK1 compared with respective non-targeted controls by SKOV-3 tumor xenografts in mice confirmed that FA mediates strong OC-targeting in vivo . Intriguingly, FA-Ps-Vol while greatly lessening toxic effects of Vol potently repressed tumor growth with a remarkable tumor inhibition rate (TIR) of 97% at 20 mg (i.e. 32.4 mu mol) Vol equiv./kg. FA-Ps-siPLK1 achieved effective tumor inhibition (TIR = ca. 87% or 90%) at 2 or 4 mg (i.e. 0.15 or 0.3 mu mol) siPLK1 equiv./kg without causing adverse effects. This com parative study highlights that molecular inhibitor has the advantage of easy dose escalation and potent protein inhibition at the expense of certain adverse effects while siRNA therapeutics has low toxicity with moderate protein inhibition in vivo . Statement of significance PLK1 is a promising target for the development of innovative and specific treatments against diverse malignancies. Interestingly, despite intensive work on molecular inhibitors and siRNA against PLK1, little work has been directed to compare their efficacy in targeted tumor therapy. Here, we employed folate as a ligand and polymersomes as a nanovehicle and have performed a comparative study on volasertib and siPLK1 in inhibiting ovarian cancer in vitro and in vivo . Our data show that the dose of volasertib can be easily escalated to induce prominent antitumor efficacy at the expense of certain adverse effects, while siPLK1 brings about moderate protein inhibition and antitumor therapy without causing toxicity at two-orders-of-magnitude lower dose. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Synergistic interventional photothermal therapy and immunotherapy using an iron oxide nanoplatform for the treatment of pancreatic cancer

    Wang, MengLi, YongWang, MiaoLiu, Kaili...
    10页
    查看更多>>摘要：Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8(+) in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. Statement of significance Pancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Biodegradable oxygen-producing manganese-chelated metal organic frameworks for tumor-targeted synergistic chemo/photothermal/photodynamic therapy

    Feng, LeiChen, MengyaoLi, RuihaoZhou, Lulu...
    15页
    查看更多>>摘要：Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that can convert oxygen to highly cytotoxic singlet oxygen (O-1(2)) through the co-localization of excitation light and photosen-sitizers. However, compromised by the hypoxic tumor microenvironment, the therapeutic efficacy of PDT is reduced seriously. Herein, to overcome tumor-associated hypoxia, and further achieve tumor-targeted synergistic chemotherapy/PDT/photothermal therapy (PTT), we have constructed a biodegrad-able oxygen-producing nanoplatform (named Ini@PM-HP), which was composed of the porous metal-organic framework (PCN-224(Mn)), the poly (ADP-ribose) polymerase (PARP) inhibitor (Iniparib), and the polydopamine-modified hyaluronic acid (HA-PDA). Since HA can specifically bind to the overexpressed HA receptors (cluster determinant 44, CD44) on tumor cell, Ini@PM-HP prefers to accumulate at the tumor site once injected intravenously. Then iniparib can be released in tumor environment (TME), thereby dysfunctioning DNA damage repair and promoting cell apoptosis. At the same time, the chelating of Mn and tetrakis(4-carboxyphenyl) porphyrin (Mn-TCPP) can generate O-2 in situ by reacting with endogenous H2O2, relieving the hypoxic TME and achieving enhanced PDT. Moreover, owing to the high photother-mal conversion efficiency of PDA, PTT can be driven by the 808 nm laser irradiation. As systematically demonstrated in vitro and in vivo, this nanotherapeutic approach enables the combined therapy with great inhibition on tumor. Overall, the as-prepared nanoplatform provide a promising strategy to over-come tumor-associated hypoxia, and shows great potential for combination tumor therapy. Statement of significance A delicately designed biodegradable oxygen-producing nanoplatform Ini@PM-HP is constructed to achieve combination therapy of solid tumors. Taking advantage of the active-targeting, PTT, enhanced PDT and PARPi, this nanotherapeutic approach successfully enables the combined chemo/photothermal/photodynamic therapy with great inhibition of solid tumors. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Core-shell lipoplexes inducing active macropinocytosis promote intranasal delivery of c-Myc siRNA for treatment of glioblastoma

    Wang, HuanSong, JieZhou, JianfenFan, Xingyan...
    13页
    查看更多>>摘要：Glioblastoma is the most common and aggressive primary brain tumor, whose malignancy is closely correlated with elevated proto-oncogene c-myc. Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting siRNA (sic-Myc) by octaarginine and subsequent encapsulation by liposome modified with a selected peptide derived from penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc mRNA and protein expression of glioma cells. Furthermore, due to significantly enhanced permeability in tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more siRNA to orthotopic glioma after intranasal administration, and therefore prolonged the survival time of glioma-bearing mice by inducing apoptosis. Statement of significance In the present work, a lipoplex was designed to address the unmet demands on intranasal siRNA delivery to the brain for treatment of glioma. First, a powerful peptide was selected to enable the lipoplex to penetrate nasal mucosa. Second, we found the lipoplex could be selectively internalized along with cell debris by glioma cells via active macropinocytosis, and recorded the entire process. This cellular uptake pathway not only prevented the lipoplex being entrapped by lysosome, but also increased distribution of the lipoplex in orthotopic glioma. Third, this lipoplex provided additional protection for siRNA to avoid premature release during transport from nasal to brain. Overall, this lipoplex improved the gene delivery efficiency of intranasal administration and was promising in the perspective of selectively silencing disease-related genes in intracranial tumor. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    An efficient and safe MUC1-dendritic cell-derived exosome conjugate vaccine elicits potent cellular and humoral immunity and tumor inhibition in vivo

    Zhu, HaomiaoWang, KunWang, ZhaoyuWang, Danyang...
    14页
    查看更多>>摘要：Antitumor vaccines are a promising strategy for preventing or treating cancers by eliciting antitumor immune responses and inducing protective immunity against specific antigens expressed on tumor cells. Vaccine formulations that enhance the humoral and cellular immune responses of vaccine candidates would be highly beneficial but are still limited. Here we developed an antitumor vaccine candidate by conjugating a MUC1 glycopeptide antigen to dendritic cell-derived exosomes (Dex). In vivo , the MUC1-Dex construct induced high MUC1-specific IgG antibody titers with strong binding affinities for MUC1-positive tumor cells and promoted cytokine secretion. Moreover, CD8(+) T cells from immunized mice exhibited strong cytotoxicity against MUC1-positive tumor cells. Importantly, in both preventative and therapeutic tumor-bearing mouse models, the construct inhibited tumor growth and prolonged survival. Collectively, these results demonstrate that Dex is a promising vaccine carrier that can be used as adjuvant to enhance the immunological efficacy of tumor vaccines. Statement of significance We prepared an efficient and biosafe antitumor vaccine candidate by conjugating Dex with MUC1 glycopeptide using a two-step biorthogonal crosslinking strategy. MUC1-Dex enhanced the expression of costimulatory molecules CD80 and CD86 on DCs to promote their maturation whilst simultaneously upregulating MHC I and MHC II expression to increase antigen presentation by DCs. MUC1-Dex conjugates stimulated the production of MUC1-specific IgG antibodies in vivo , and the antibodies bound strongly to MUC1-expressing tumor cells. The constructed vaccines induced a strong antibody response and antigen specific CTLs to kill the tumor and delayed tumor development in a therapeutic and prophylactic tumor bearing mouse model. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    Binary regulation of the tumor microenvironment by a pH-responsive reversible shielding nanoplatform for improved tumor chemo-immunotherapy

    Zhao, XiuliSun, XiaoyanZhang, JiulongZhao, Xiufeng...
    13页
    查看更多>>摘要：The limited infiltration of specific T cells in an immunosuppressive microenvironment is a major challenge for cancer immunotherapy. Reversing tumor microenvironment and inducing an antitumor immune response are crucial for cancer therapy. Here, phenylboronic acid (PBA) derivative-stabilized ultrasmall platinum nanoparticles (PBA-Pt) and dextran-coated BLZ-945 nanoparticles (DNPs) were co-assembled through a pH-responsive borate ester bond to construct a versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) for the first time. Pt@DNPs dissociated into two individual components, namely PBA-Pt and DNPs, in the tumor acid microenvironment. Both in vitro and in vivo studies revealed that Pt@DNPs induced immunogenic cell death (ICD) (through multimechanisms involving PtII release and a multienzyme catalytic process by PBA-Pt) and relieved immunosuppressive microenvironment (depletion of tumor-associated macrophages by BLZ-945), which led to tumor-associated antigen release, maturation of dendritic cells, and infiltration of cytotoxic T cells for efficient antitumor immune response against both primary tumor and pulmonary metastatic tumor nodules. Therefore, Pt@DNPs is a promising option for cancer chemo-immunotherapy. Statement of significance A versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) was engineered for the first time for combinational cancer chemo-immunotherapy. Multimechanisms involving induction of immunogenic cell death by PBA-Pt and sufficient TAM depletion by DNPs could efficiently relieve tumor immunosuppressive microenvironment and activate the antitumor immune response. The synergistic effect not only increased the infiltration of specific T cells in primary tumor, but it also induced a strong immune response against pulmonary metastatic nodules. Collectively, this nanoplatform may represent a promising strategy for combinational chemo-immunotherapy for cancers. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier

    A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis

    Luo, ShiweiMa, DiWei, RuiliYao, Wang...
    10页
    查看更多>>摘要：As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we de-signed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to gen-erate abundant center dot OH levels. The generation of reactive oxygen species (ROS) further accelerates CA acti-vation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates center dot OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T-1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy Statement of significance Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective sup-plement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by exces-sive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
      原文链接:
    • NSTL
    • Elsevier