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A bioengineered anti-VEGF protein with high affinity and high concentration for intravitreal treatment of wet age-related macular degeneration 一种高亲和力、高浓度的生物工程抗血管内皮生长因子蛋白,用于玻璃体内治疗湿性老年性黄斑变性
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-19 DOI: 10.1002/btm2.10632
Chengnan Huang, Yuelin Wang, Jinliang Huang, Huiqin Liu, Zhidong Chen, Yang Jiang, Youxin Chen, Feng Qian

Intravitreal (IVT) injection of anti-vascular endothelial growth factor (anti-VEGF) has greatly improved the treatment of many retinal disorders, including wet age-related macular degeneration (wAMD), which is the third leading cause of blindness. However, frequent injections can be difficult for patients and may lead to various risks such as elevated intraocular pressure, infection, and retinal detachment. To address this issue, researchers have found that IVT injection of anti-VEGF proteins at their maximally viable concentration and dose can be an effective strategy. However, the intrinsic protein structure can limit the maximum concentration due to stability and solution viscosity. To overcome this challenge, we developed a novel anti-VEGF protein called nanoFc by fusing anti-VEGF nanobodies with a crystallizable fragment (Fc). NanoFc has demonstrated high binding affinity to VEGF165 through multivalency and potent bioactivity in various bioassays. Furthermore, nanoFc maintains satisfactory chemical and physical stability at 4°C over 1 month and is easily injectable at concentrations up to 200 mg/mL due to its unique architecture that yields a smaller shape factor. The design of nanoFc offers a bioengineering strategy to ensure both strong anti-VEGF binding affinity and high protein concentration, with the goal of reducing the frequency of IV injections.

抗血管内皮生长因子(anti-VEGF)的玻璃体内注射(IVT)大大改善了许多视网膜疾病的治疗,包括湿性年龄相关性黄斑变性(wAMD),它是导致失明的第三大原因。然而,频繁注射会给患者带来困难,并可能导致眼压升高、感染和视网膜脱离等各种风险。为解决这一问题,研究人员发现,以最大可行浓度和剂量静脉注射抗血管内皮生长因子蛋白是一种有效的策略。然而,由于稳定性和溶液粘度的原因,蛋白质的固有结构会限制最大浓度。为了克服这一难题,我们通过将抗血管内皮生长因子纳米抗体与可结晶片段(Fc)融合,开发出了一种名为 nanoFc 的新型抗血管内皮生长因子蛋白。NanoFc 在各种生物测定中通过多价性和强效生物活性证明了与 VEGF165 的高结合亲和力。此外,nanoFc 还能在 4°C 温度下保持令人满意的化学和物理稳定性达 1 个月之久,而且由于其独特的结构产生了较小的形状系数,因此注射浓度高达 200 mg/mL,注射十分方便。nanoFc 的设计提供了一种生物工程策略,既能确保较强的抗 VEGF 结合亲和力,又能确保较高的蛋白质浓度,从而达到减少静脉注射次数的目的。
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引用次数: 0
Efficacy of catheter-based drug delivery in a hybrid in vitro model of cardiac microvascular obstruction with porcine microthrombi 在猪微血栓心脏微血管阻塞混合体外模型中导管给药的功效
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-08 DOI: 10.1002/btm2.10631
Yannick Rösch, Thorald Stolte, Miriam Weisskopf, Sabrina Frey, Rob Schwartz, Nikola Cesarovic, Dominik Obrist

Microvascular obstruction (MVO) often occurs in ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). Diagnosis and treatment of MVO lack appropriate and established procedures. This study focused on two major points by using an in vitro multiscale flow model, which comprised an aortic root model with physiological blood flow and a microfluidic model of the microcirculation with vessel diameters down to 50 μm. First, the influence of porcine microthrombi (MT), injected into the fluidic microchip, on perfusion was investigated. We found that only 43% of all injected MT were fully occlusive. Second, it could also be shown that the maximal concentration of a dye (representing therapeutic agent) during intracoronary infusion could be increased on average by 58%, when proximally occluding the coronary artery by a balloon during drug infusion. The obtained results and insights enhance the understanding of perfusion in MVO-affected microcirculation and could lead to improved treatment methods for MVO patients.

经皮冠状动脉介入治疗(PCI)后,ST 段抬高型心肌梗死(STEMI)患者常会出现微血管阻塞(MVO)。MVO 的诊断和治疗缺乏适当的既定程序。本研究采用体外多尺度血流模型,包括具有生理血流的主动脉根部模型和血管直径小至 50 μm 的微循环微流控模型,重点研究了两个要点。首先,研究了注入流体微芯片的猪微血栓(MT)对灌注的影响。我们发现,在所有注入的 MT 中,只有 43%$$ 43%$$ 是完全闭塞的。其次,还可以证明,在冠状动脉内输注药物时,如果用球囊近端堵塞冠状动脉,染料(代表治疗药物)的最大浓度平均可提高 58%。所获得的结果和见解加深了人们对受 MVO 影响的微循环灌注的理解,并可改进 MVO 患者的治疗方法。
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引用次数: 0
Immunogenicity of an adjuvanted broadly active influenza vaccine in immunocompromised and diverse populations 广谱活性流感佐剂疫苗在免疫力低下和不同人群中的免疫原性
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-08 DOI: 10.1002/btm2.10634
Dylan A. Hendy, Erik S. Pena, Luis Ontiveros-Padilla, Timothy A. Dixon, Denzel D. Middleton, Grace L. Williamson, Nicole Rose Lukesh, Sean R. Simpson, Rebeca T. Stiepel, Md Jahirul Islam, Michael A. Carlock, Ted M. Ross, Eric M. Bachelder, Kristy M. Ainslie

Influenza virus outbreaks are a major burden worldwide each year. Current vaccination strategies are inadequate due to antigenic drift/shift of the virus and the elicitation of low immune responses. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) immunogens subvert the constantly mutating viruses; however, they are poorly immunogenic on their own. To increase the immunogenicity of subunit vaccines such as this, adjuvants can be delivered with the vaccine. For example, agonists of the stimulator of interferon genes (STING) have proven efficacy as vaccine adjuvants. However, their use in high-risk populations most vulnerable to influenza virus infection has not been closely examined. Here, we utilize a vaccine platform consisting of acetalated dextran microparticles loaded with COBRA HA and the STING agonist cyclic GMP-AMP. We examine the immunogenicity of this platform in mouse models of obesity, aging, and chemotherapy-induced immunosuppression. Further, we examine vaccine efficacy in collaborative cross mice, a genetically diverse population that mimics human genetic heterogeneity. Overall, this vaccine platform had variable efficacy in these populations supporting work to better tailor adjuvants to specific populations.

流感病毒爆发是全球每年的一大负担。由于病毒的抗原漂移/转移以及引起的免疫反应低下,目前的疫苗接种策略并不完善。使用经过计算优化的广谱抗原(COBRA)血凝素(HA)免疫原可以颠覆不断变异的病毒,但它们本身的免疫原性很差。为了提高亚单位疫苗的免疫原性,可以在疫苗中加入佐剂。例如,干扰素基因刺激物(STING)的激动剂已被证明可作为疫苗佐剂。然而,这些佐剂在最易感染流感病毒的高危人群中的应用尚未得到仔细研究。在这里,我们利用了一个疫苗平台,该平台由载入 COBRA HA 和 STING 激动剂环 GMP-AMP 的乙缩醛葡聚糖微颗粒组成。我们在肥胖、衰老和化疗引起的免疫抑制小鼠模型中检验了该平台的免疫原性。此外,我们还研究了合作杂交小鼠的疫苗疗效,这是一个模拟人类基因异质性的基因多样性群体。总体而言,该疫苗平台在这些人群中的效力各不相同,这为更好地为特定人群定制佐剂提供了支持。
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引用次数: 0
Development of a multifunctional bioreactor to evaluate the promotion effects of cyclic stretching and electrical stimulation on muscle differentiation 多功能生物反应器的开发,以评估循环拉伸和电刺激对肌肉分化的促进作用
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-07 DOI: 10.1002/btm2.10633
Wei-Wen Hu, Yen-Chi Chen, Chia-Wen Tsao, Shen-Liang Chen, Chung-Yuh Tzeng

A multifunctional bioreactor was fabricated in this study to investigate the facilitation efficiency of electrical and mechanical stimulations on myogenic differentiation. This bioreactor consisted of a highly stretchable conductive membrane prepared by depositing polypyrrole (PPy) on a flexible polydimethylsiloxane (PDMS) film. The tensile deformation of the PPy/PDMS membrane can be tuned by adjusting the channel depth. In addition, PPy/PDMS maintained its electrical conductivity under continuous cyclic stretching in the strain range of 6.5%–13% for 24 h. This device can be used to individually or simultaneously perform cyclic stretching and electrical stimulation. The results of single stimulation showed that either cyclic stretching or electrical stimulation upregulated myogenic gene expression and promoted myotube formation, where electrical stimulation improved better than cyclic stretching. However, only cyclic stretching can align C2C12 cells perpendicular to the stretching direction, and electrical stimulation did not affect cell morphology. Myosin heavy chain (MHC) immunostaining demonstrated that oriented cells under cyclic stretching resulted in parallel myotubes. The combination of these two stimuli exhibited synergetic effects on both myogenic gene regulation and myotube formation, and the incorporated electrical field did not affect the orientation effect of the cyclic stretching. These results suggested that these two treatments likely influenced cells through different pathways. Overall, the simultaneous application of cyclic stretching and electrical stimulation preserved both stimuli's advantages, so myo-differentiation can be highly improved to obtain abundant parallel myotubes, suggesting that our developed multifunctional bioreactor should benefit muscle tissue engineering applications.

本研究制作多功能生物反应器,探讨电刺激和机械刺激对肌原性分化的促进效果。该生物反应器由在柔性聚二甲基硅氧烷(PDMS)薄膜上沉积聚吡咯(PPy)制备的高度可拉伸导电膜组成。通过调节通道深度,可以调节PPy/PDMS膜的拉伸变形。此外,在6.5 ~ 13%的应变范围内连续循环拉伸24 h, PPy/PDMS的电导率保持不变。该装置可单独或同时进行循环拉伸和电刺激。单次刺激结果显示,循环拉伸或电刺激均可上调肌源性基因表达,促进肌管形成,其中电刺激的改善效果优于循环拉伸。然而,只有循环拉伸才能使C2C12细胞垂直于拉伸方向排列,电刺激不影响细胞形态。肌球蛋白重链(MHC)免疫染色表明,定向细胞在循环拉伸下产生平行肌管。两种刺激组合对肌源性基因调控和肌管形成均有协同作用,且联合电场不影响循环拉伸的定向效应。这些结果表明,这两种处理可能通过不同的途径影响细胞。总的来说,同时应用循环拉伸和电刺激保留了两种刺激的优点,因此可以高度改善肌肉分化以获得丰富的平行肌管,这表明我们开发的多功能生物反应器应该有利于肌肉组织工程的应用。
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引用次数: 0
Establishment of bladder cancer spheroids and cultured in microfluidic platform for predicting drug response 建立膀胱癌球体并在微流控平台中培养,以预测药物反应
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-04 DOI: 10.1002/btm2.10624
Qiao Xiong, Ting Liu, Yidie Ying, Xiaowen Yu, Ziwei Wang, Hongliang Gao, Tianhai Lin, Weihua Fan, Zhensheng Zhang, Qiang Wei, Yuqing Ge, Shuxiong Zeng, Chuanliang Xu

Cisplatin-containing combination chemotherapy has been used as the standard treatment for bladder cancer patients at advanced stage. However, nearly 50% of patients are nonresponders. To guide the selection of more effective chemotherapeutic agents, a bladder cancer spheroids microfluidic drug sensitivity analysis system was established in this study. Bladder cancer spheroids were established and successfully cultured in a customized microfluidic device to assess their response to different chemotherapeutic agents. The in vitro drug sensitivity results were also compared to patient-derived xenograft (PDX) models and clinical responses of patients. As a result, bladder cancer spheroids faithfully recapitulate the histopathological and genetic features of their corresponding parental tumors. Furthermore, the in vitro drug sensitivity outcomes of spheroids (n = 8) demonstrated a high level of correlation with the PDX (n = 2) and clinical response in patients (n = 2). Our study highlights the potential of combining bladder cancer spheroids and microfluidic devices as an efficient and accurate platform for personalized selection of chemotherapeutic agents.

含顺铂联合化疗已成为晚期膀胱癌患者的标准治疗方案。然而,近50%的患者无反应。为了指导更有效的化疗药物的选择,本研究建立了膀胱癌球体微流控药物敏感性分析系统。在定制的微流体装置中建立并成功培养膀胱癌球体,以评估其对不同化疗药物的反应。体外药敏结果也与患者来源的异种移植(PDX)模型和患者的临床反应进行了比较。因此,膀胱癌球状体忠实地概括了其相应亲代肿瘤的组织病理和遗传特征。此外,球体的体外药敏结果(n = 8)与患者的PDX (n = 2)和临床反应(n = 2)高度相关。我们的研究强调了将膀胱癌球体和微流控装置结合起来作为个性化选择化疗药物的有效和准确平台的潜力。
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引用次数: 0
Advances in high throughput cell culture technologies for therapeutic screening and biological discovery applications 用于治疗筛选和生物发现应用的高通量细胞培养技术的进步
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-04 DOI: 10.1002/btm2.10627
Hyeon Ryoo, Hannah Kimmel, Evi Rondo, Gregory H. Underhill

Cellular phenotypes and functional responses are modulated by the signals present in their microenvironment, including extracellular matrix (ECM) proteins, tissue mechanical properties, soluble signals and nutrients, and cell–cell interactions. To better recapitulate and analyze these complex signals within the framework of more physiologically relevant culture models, high throughput culture platforms can be transformative. High throughput methodologies enable scientists to extract increasingly robust and broad datasets from individual experiments, screen large numbers of conditions for potential hits, better qualify and predict responses for preclinical applications, and reduce reliance on animal studies. High throughput cell culture systems require uniformity, assay miniaturization, specific target identification, and process simplification. In this review, we detail the various techniques that researchers have used to face these challenges and explore cellular responses in a high throughput manner. We highlight several common approaches including two-dimensional multiwell microplates, microarrays, and microfluidic cell culture systems as well as unencapsulated and encapsulated three-dimensional high throughput cell culture systems, featuring multiwell microplates, micromolds, microwells, microarrays, granular hydrogels, and cell-encapsulated microgels. We also discuss current applications of these high throughput technologies, namely stem cell sourcing, drug discovery and predictive toxicology, and personalized medicine, along with emerging opportunities and future impact areas.

细胞表型和功能反应受其微环境中存在的信号调节,包括细胞外基质(ECM)蛋白、组织机械特性、可溶性信号和营养物质以及细胞间相互作用。为了在生理相关的培养模型框架内更好地概括和分析这些复杂的信号,高通量培养平台可以是变革性的。高通量方法使科学家能够从单个实验中提取越来越强大和广泛的数据集,筛选大量潜在命中条件,更好地确定和预测临床前应用的反应,并减少对动物研究的依赖。高通量细胞培养系统需要均匀性,实验小型化,特定目标识别和过程简化。在这篇综述中,我们详细介绍了研究人员用来面对这些挑战的各种技术,并以高通量的方式探索细胞反应。我们重点介绍了几种常见的方法,包括二维多孔微孔板、微阵列和微流体细胞培养系统,以及未封装和封装的三维高通量细胞培养系统,包括多孔微孔板、微模具、微孔、微阵列、颗粒水凝胶和细胞封装微凝胶。我们还讨论了这些高通量技术的当前应用,即干细胞来源,药物发现和预测毒理学,个性化医疗,以及新兴机会和未来的影响领域。
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引用次数: 0
Therapeutic potential of mesenchymal stem cells from human iPSC-derived teratomas for osteochondral defect regeneration 人间充质干细胞衍生畸胎瘤对骨软骨缺损再生的治疗潜力
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-29 DOI: 10.1002/btm2.10629
Jiseong Kim, Jin-Su Kim, Dohyun Kim, Alvin Bacero Bello, Byoung Ju Kim, Byung-Hyun Cha, Soo-Hong Lee

Human induced pluripotent stem cells (iPSCs) hold great promise for personalized medicine, as they can be differentiated into specific cell types, especially mesenchymal stem cells (MSCs). Therefore, our study sought to assess the feasibility of deriving MSCs from teratomas generated from human iPSCs. Teratomas serve as a model to mimic multilineage human development, thus enriching specific somatic progenitors and stem cells. Here, we discovered a small, condensed mass of MSCs within iPSC-generated teratomas. Afterward, we successfully isolated MSCs from this condensed mass, which was a byproduct of teratoma development. To evaluate the characteristics and cell behaviors of iPSC-derived MSCs (iPSC-MSCs), we conducted comprehensive assessments using qPCR, immunophenotype analysis, and cell proliferation-related assays. Remarkably, iPSC-MSCs exhibited an immunophenotype resembling that of conventional MSCs, and they displayed robust proliferative capabilities, similar to those of higher pluripotent stem cell-derived MSCs. Furthermore, iPSC-MSCs demonstrated the ability to differentiate into multiple lineages in vitro. Finally, we evaluated the therapeutic potential of iPSC-MSCs using an osteochondral defect model. Our findings demonstrated that teratomas are a promising source for the isolation of condensed MSCs. More importantly, our results suggest that iPSC-MSCs derived from teratomas possess the capacity for tissue regeneration, highlighting their promise for future therapeutic applications.

人类诱导多能干细胞(iPSCs)可以分化为特定的细胞类型,特别是间充质干细胞(MSCs),因此在个性化医疗方面具有很大的前景。因此,我们的研究试图评估从人多能干细胞产生的畸胎瘤中提取间充质干细胞的可行性。畸胎瘤作为模拟人类多谱系发育的模型,从而丰富了特定的体细胞祖细胞和干细胞。在这里,我们在ipsc产生的畸胎瘤中发现了一个小的,凝聚的MSCs团块。之后,我们成功地从这个凝结的肿块中分离出间充质干细胞,这是畸胎瘤发展的副产品。为了评估ipsc衍生的MSCs (iPSC-MSCs)的特性和细胞行为,我们使用qPCR、免疫表型分析和细胞增殖相关分析进行了全面的评估。值得注意的是,iPSC-MSCs表现出与传统MSCs相似的免疫表型,并且它们表现出强大的增殖能力,类似于那些高级多能干细胞衍生的MSCs。此外,iPSC-MSCs在体外表现出分化成多个谱系的能力。最后,我们利用骨软骨缺损模型评估了iPSC-MSCs的治疗潜力。我们的研究结果表明,畸胎瘤是浓缩间充质干细胞分离的一个有希望的来源。更重要的是,我们的研究结果表明,来自畸胎瘤的iPSC-MSCs具有组织再生的能力,这突出了它们在未来治疗应用中的前景。
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引用次数: 0
First magnetic particle imaging to assess pulmonary vascular leakage in vivo in the acutely injured and fibrotic lung 首次磁颗粒成像评估急性损伤和纤维化肺的肺血管渗漏
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-29 DOI: 10.1002/btm2.10626
Xin Feng, Pengli Gao, Yabin Li, Hui Hui, Jingying Jiang, Fei Xie, Jie Tian

Increased pulmonary vascular permeability is a characteristic feature of lung injury. However, there are no established methods that allow the three-dimensional visualization and quantification of pulmonary vascular permeability in vivo. Evans blue extravasation test and total protein test of bronchoalveolar lavage fluid (BALF) are permeability assays commonly used in research settings. However, they lack the ability to identify the spatial and temporal heterogeneity of endothelial barrier disruption, which is typical in lung injuries. Magnetic resonance (MR) and near-infrared (NIR) imaging have been proposed to image pulmonary permeability, but suffer from limited sensitivity and penetration depth, respectively. In this study, we report the first use of magnetic particle imaging (MPI) to assess pulmonary vascular leakage noninvasively in vivo in mice. A dextran-coated superparamagnetic iron oxide (SPIO), synomag®, was employed as the imaging tracer, and pulmonary SPIO extravasation was imaged and quantified to evaluate the vascular leakage. Animal models of acute lung injury and pulmonary fibrosis (PF) were used to validate the proposed method. MPI sensitively detected the SPIO extravasation in both acutely injured and fibrotic lungs in vivo, which was confirmed by ex vivo imaging and Prussian blue staining. Moreover, 3D MPI illustrated the spatial heterogeneity of vascular leakage, which correlated well with CT findings. Based on the in vivo 3D MPI images, we defined the SPIO extravasation index (SEI) to quantify the vascular leakage. A significant increase in SEI was observed in the injured lungs, in consistent with the results obtained via ex vivo permeability assays. Overall, our results demonstrate that 3D quantitative MPI serves as a useful tool to examine pulmonary vascular integrity in vivo, which shows promise for future clinical translation.

肺血管通透性增加是肺损伤的特征性特征。然而,目前还没有确定的方法可以在体内对肺血管通透性进行三维可视化和量化。Evans蓝色外渗试验和支气管肺泡灌洗液(BALF)总蛋白试验是研究中常用的渗透性测定方法。然而,他们缺乏识别内皮屏障破坏的时空异质性的能力,这在肺损伤中是典型的。磁共振(MR)和近红外(NIR)成像已被提出用于肺通透性成像,但分别存在灵敏度和穿透深度有限的问题。在这项研究中,我们报告了首次使用磁颗粒成像(MPI)来评估小鼠体内肺血管渗漏的无创性。采用葡聚糖包被的超顺磁性氧化铁(SPIO) synomag®作为显像示踪剂,对肺SPIO外渗进行成像和量化以评估血管渗漏。用急性肺损伤和肺纤维化(PF)动物模型验证了该方法。体外显像和普鲁士蓝染色证实了MPI在体内对急性损伤肺和纤维化肺SPIO外渗的敏感性。此外,3D MPI显示血管渗漏的空间异质性,与CT表现吻合良好。基于体内三维MPI图像,我们定义了SPIO外渗指数(SEI)来量化血管渗漏。在受伤的肺中观察到SEI显著增加,这与通过体外渗透性测定获得的结果一致。总之,我们的研究结果表明,3D定量MPI可以作为一种有用的工具来检查体内肺血管的完整性,这显示了未来临床应用的前景。
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引用次数: 0
Deconvolution of synthetic mRNA expression: Nucleoside chemistry alters translatability 合成mRNA表达的反褶积:核苷化学改变可译性
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-11-28 DOI: 10.1002/btm2.10622
Hanieh Moradian, Marko Schwestka, Toralf Roch, Manfred Gossen

Recent technological advances in the production of in vitro transcribed messenger RNA (IVT-mRNA) facilitate its clinical use as well as its application in basic research. In this regard, numerous chemical modifications, which are not naturally observed in endogenous mRNA, have been implemented primarily to address the issue of immunogenicity and improve its biological performance. However, recent findings suggested pronounced differences between expression levels of IVT-mRNAs with different nucleoside modifications in transfected cells. Given the multistep process of IVT-mRNA delivery and subsequent intracellular expression, it is unclear which step is influenced by IVT-mRNA chemistry. Here, we deconvolute this process and show that the nucleoside modification does not interfere with complexation of carriers, their physicochemical properties, and extracellular stability, as exemplified by selected modifications. The immediate effect of mRNA chemistry on the efficiency of ribosomal protein synthesis as a contributor to differences in expression was quantified by in vitro cell-free translation. Our results demonstrate that for the nucleoside modifications tested, translatability was the decisive step in determining overall protein production. Also of special importance for future work on rational selection of tailored synthetic mRNA chemistries, our findings set a workflow to identify potentially limiting, modification-dependent steps in the complex delivery process.

体外转录信使RNA (IVT-mRNA)生产的最新技术进步促进了其临床应用以及在基础研究中的应用。在这方面,许多在内源性mRNA中不自然观察到的化学修饰已被实施,主要是为了解决免疫原性问题并提高其生物学性能。然而,最近的研究结果表明,转染细胞中不同核苷修饰的ivt - mrna的表达水平存在显著差异。考虑到IVT-mRNA的传递和随后的细胞内表达的多步骤过程,尚不清楚哪一步受到IVT-mRNA化学的影响。在这里,我们对这一过程进行反卷积,并表明核苷修饰不会干扰载体的络合、它们的物理化学性质和细胞外稳定性,如选择修饰的例子所示。mRNA化学对核糖体蛋白合成效率的直接影响是表达差异的一个因素,通过体外无细胞翻译进行了量化。我们的研究结果表明,对于核苷修饰测试,可译性是决定整体蛋白质生产的决定性步骤。对于未来合理选择定制合成mRNA化学物质的工作也特别重要,我们的研究结果设置了一个工作流程,以确定复杂递送过程中潜在的限制,修饰依赖步骤。
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引用次数: 0
Microfluidic chip as a promising evaluation method in assisted reproduction: A systematic review 微流控芯片作为一种有前景的辅助生殖评价方法:系统综述
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-24 DOI: 10.1002/btm2.10625
Tong Wu, Yangyang Wu, Jinfeng Yan, Jinjin Zhang, Shixuan Wang

The aim of assisted reproductive technology (ART) is to select the high-quality sperm, oocytes, and embryos, and finally achieve a successful pregnancy. However, functional evaluation is hindered by intra- and inter-operator variability. Microfluidic chips emerge as the one of the most powerful tools to analyze biological samples for reduced size, precise control, and flexible extension. Herein, a systematic search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and IEEE Xplore databases until March 2023. We displayed and prospected all detection strategies based on microfluidics in the ART field. After full-text screening, 71 studies were identified as eligible for inclusion. The percentages of human and mouse studies equaled with 31.5%. The prominent country in terms of publication number was the USA (n = 13). Polydimethylsiloxane (n = 49) and soft lithography (n = 28) were the most commonly used material and fabrication method, respectively. All articles were classified into three types: sperm (n = 38), oocytes (n = 20), and embryos (n = 13). The assessment contents included motility, counting, mechanics, permeability, impedance, secretion, oxygen consumption, and metabolism. Collectively, the microfluidic chip technology facilitates more efficient, accurate, and objective evaluation in ART. It can even be combined with artificial intelligence to assist the daily activities of embryologists. More well-designed clinical studies and affordable integrated microfluidic chips are needed to validate the safety, efficacy, and reproducibility.

Trial registration: The protocol was registered in the Open Science Frame REGISTRIES (identification: osf.io/6rv4a).

辅助生殖技术(ART)的目的是选择高质量的精子、卵母细胞和胚胎,最终实现成功妊娠。然而,功能评估受到操作员内部和操作员之间可变性的阻碍。微流控芯片因其体积小、控制精确、扩展灵活等优点,成为分析生物样品最有力的工具之一。本文系统检索了PubMed、Scopus、Web of Science、ScienceDirect和IEEE explore数据库,检索截止至2023年3月。我们展示并展望了基于微流控技术在ART领域的所有检测策略。经过全文筛选,有71项研究符合纳入条件。人类和小鼠的研究比例为31.5%。发表数量最多的国家是美国(n = 13)。聚二甲基硅氧烷(n = 49)和软光刻(n = 28)分别是最常用的材料和制作方法。所有文章被分为三种类型:精子(n = 38)、卵母细胞(n = 20)和胚胎(n = 13)。评估内容包括运动性、计数、力学、渗透性、阻抗、分泌、耗氧量和代谢。总的来说,微流控芯片技术有助于在ART中进行更高效、准确和客观的评估。它甚至可以与人工智能相结合,以协助胚胎学家的日常活动。需要更多精心设计的临床研究和负担得起的集成微流控芯片来验证安全性,有效性和可重复性。
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Bioengineering & Translational Medicine
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