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Photothermal therapy using graphene quantum dots. 石墨烯量子点光热疗法。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0160324
Mohammad Suhaan Dar, Tanveer A Tabish, Nanasaheb D Thorat, G Swati, Niroj Kumar Sahu

The rapid development of powerful anti-oncology medicines have been possible because of advances in nanomedicine. Photothermal therapy (PTT) is a type of treatment wherein nanomaterials absorb the laser energy and convert it into localized heat, thereby causing apoptosis and tumor eradication. PTT is more precise, less hazardous, and easy-to-control in comparison to other interventions such as chemotherapy, photodynamic therapy, and radiation therapy. Over the past decade, various nanomaterials for PTT applications have been reviewed; however, a comprehensive study of graphene quantum dots (GQDs) has been scantly reported. GQDs have received huge attention in healthcare technologies owing to their various excellent properties, such as high water solubility, chemical stability, good biocompatibility, and low toxicity. Motivated by the fascinating scientific discoveries and promising contributions of GQDs to the field of biomedicine, we present a comprehensive overview of recent progress in GQDs for PTT. This review summarizes the properties and synthesis strategies of GQDs including top-down and bottom-up approaches followed by their applications in PTT (alone and in combination with other treatment modalities such as chemotherapy, photodynamic therapy, immunotherapy, and radiotherapy). Furthermore, we also focus on the systematic study of in vitro and in vivo toxicities of GQDs triggered by PTT. Moreover, an overview of PTT along with the synergetic application used with GQDs for tumor eradication are discussed in detail. Finally, directions, possibilities, and limitations are described to encourage more research, which will lead to new treatments and better health care and bring people closer to the peak of human well-being.

纳米医学的进步使强效抗肿瘤药物的快速发展成为可能。光热疗法(PTT)是一种纳米材料吸收激光能量并将其转化为局部热,从而引起细胞凋亡和肿瘤根除的治疗方法。与化疗、光动力治疗和放射治疗等其他干预措施相比,PTT更精确、危害更小、易于控制。在过去的十年中,各种纳米材料用于PTT的应用进行了综述;然而,对石墨烯量子点(GQDs)的全面研究鲜有报道。由于GQDs具有水溶性高、化学稳定性好、生物相容性好、毒性低等优良特性,在医疗保健领域受到了广泛关注。鉴于GQDs在生物医学领域的重大科学发现和巨大贡献,本文对GQDs在PTT领域的最新进展进行了综述。本文综述了GQDs的性质和合成策略,包括自顶向下和自底向上的方法,以及它们在PTT中的应用(单独或与化疗、光动力治疗、免疫治疗和放疗等其他治疗方式联合)。此外,我们还对PTT引发的GQDs的体内外毒性进行了系统的研究。此外,还详细讨论了PTT的概况以及与GQDs在肿瘤根除中的协同应用。最后,描述了方向、可能性和局限性,以鼓励更多的研究,这将导致新的治疗方法和更好的医疗保健,使人们更接近人类福祉的顶峰。
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引用次数: 1
Magnetic self-assembly of 3D multicellular microscaffolds: A biomimetic brain tumor-on-a-chip for drug delivery and selectivity testing. 三维多细胞微支架的磁性自组装:用于药物传递和选择性测试的仿生脑肿瘤芯片。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0155037
Attilio Marino, Matteo Battaglini, Alessio Carmignani, Francesca Pignatelli, Daniele De Pasquale, Omar Tricinci, Gianni Ciofani

In recent years, the need for highly predictive brain cancer models to test new anticancer compounds and experimental therapeutic approaches has significantly increased. Realistic in vitro brain tumor-on-a-chip platforms would allow a more accurate selection of valid candidate drugs and nanomedicines, therefore alleviating the economic and ethical issues of unsuccessful studies in vivo. Here, we present a multi-functional self-assembled brain tumor-on-a-chip model characterized by 3D glioma cultures interfaced both to nonmalignant brain cells of the peritumoral niche and to a 3D-real-scale blood-brain barrier (BBB) microfluidic system. This platform allowed us to screen multiple features, such as BBB crossing capabilities, apoptotic efficacy against GBM cells, and side effects on nonmalignant brain cells of a promising anticancer drug, nutlin-3a, which is fundamental for the treatment of brain cancer.

近年来,对高预测脑癌模型的需求显著增加,以测试新的抗癌化合物和实验性治疗方法。现实的体外脑肿瘤芯片平台将允许更准确地选择有效的候选药物和纳米药物,从而减轻体内研究不成功的经济和伦理问题。在这里,我们提出了一个多功能自组装的脑肿瘤芯片模型,其特征是3D胶质瘤培养物与肿瘤周围生态位的非恶性脑细胞和3D真实规模的血脑屏障(BBB)微流控系统相结合。这个平台使我们能够筛选多种特征,如血脑屏障穿越能力,对GBM细胞的凋亡功效,以及一种有前途的抗癌药物nutlin-3a对非恶性脑细胞的副作用,这是治疗脑癌的基础。
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引用次数: 4
Hemodynamics of thrombus formation in intracranial aneurysms: An in silico observational study. 颅内动脉瘤血栓形成的血流动力学:一项计算机观察研究。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0144848
Qiongyao Liu, Ali Sarrami-Foroushani, Yongxing Wang, Michael MacRaild, Christopher Kelly, Fengming Lin, Yan Xia, Shuang Song, Nishant Ravikumar, Tufail Patankar, Zeike A Taylor, Toni Lassila, Alejandro F Frangi

How prevalent is spontaneous thrombosis in a population containing all sizes of intracranial aneurysms? How can we calibrate computational models of thrombosis based on published data? How does spontaneous thrombosis differ in normo- and hypertensive subjects? We address the first question through a thorough analysis of published datasets that provide spontaneous thrombosis rates across different aneurysm characteristics. This analysis provides data for a subgroup of the general population of aneurysms, namely, those of large and giant size (>10 mm). Based on these observed spontaneous thrombosis rates, our computational modeling platform enables the first in silico observational study of spontaneous thrombosis prevalence across a broader set of aneurysm phenotypes. We generate 109 virtual patients and use a novel approach to calibrate two trigger thresholds: residence time and shear rate, thus addressing the second question. We then address the third question by utilizing this calibrated model to provide new insight into the effects of hypertension on spontaneous thrombosis. We demonstrate how a mechanistic thrombosis model calibrated on an intracranial aneurysm cohort can help estimate spontaneous thrombosis prevalence in a broader aneurysm population. This study is enabled through a fully automatic multi-scale modeling pipeline. We use the clinical spontaneous thrombosis data as an indirect population-level validation of a complex computational modeling framework. Furthermore, our framework allows exploration of the influence of hypertension in spontaneous thrombosis. This lays the foundation for in silico clinical trials of cerebrovascular devices in high-risk populations, e.g., assessing the performance of flow diverters in aneurysms for hypertensive patients.

在包含各种大小颅内动脉瘤的人群中,自发性血栓形成有多普遍?我们如何根据已发表的数据校准血栓形成的计算模型?自发性血栓形成在正常人和高血压患者中有何不同?我们通过对已发表的数据集进行全面分析来解决第一个问题,这些数据集提供了不同动脉瘤特征的自发性血栓形成率。该分析提供了一般动脉瘤亚群的数据,即那些大尺寸和巨型(>10 mm)的动脉瘤。基于这些观察到的自发血栓形成率,我们的计算建模平台能够首次在更广泛的动脉瘤表型中对自发血栓形成率进行计算机观察研究。我们生成了109名虚拟患者,并使用一种新颖的方法来校准两个触发阈值:停留时间和剪切速率,从而解决了第二个问题。然后,我们通过利用这个校准模型来解决第三个问题,为高血压对自发性血栓形成的影响提供新的见解。我们展示了在颅内动脉瘤队列上校准的机械血栓形成模型如何有助于估计更广泛的动脉瘤人群中自发性血栓形成的患病率。这项研究是通过一个全自动的多尺度建模管道实现的。我们使用临床自发性血栓形成数据作为复杂计算建模框架的间接人群水平验证。此外,我们的框架允许探索高血压对自发性血栓形成的影响。这为高危人群脑血管装置的计算机临床试验奠定了基础,例如评估高血压患者动脉瘤分流器的性能。
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引用次数: 1
Surface electromyography using dry polymeric electrodes. 干聚合物电极表面肌电图。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0148101
Nicolas Steenbergen, Ivan Busha, Alexis Morgan, Collin Mattathil, Arieh Levy Pinto, Fotios Spyridakos, Ivan Sokolovskiy, Bogachan Tahirbegi, Christopher Chapman, Estelle Cuttaz, Karina Litvinova, Josef Goding, Rylie Green

Conventional wet Ag/AgCl electrodes are widely used in electrocardiography, electromyography (EMG), and electroencephalography (EEG) and are considered the gold standard for biopotential measurements. However, these electrodes require substantial skin preparation, are single use, and cannot be used for continuous monitoring (>24 h). For these reasons, dry electrodes are preferable during surface electromyography (sEMG) due to their convenience, durability, and longevity. Dry conductive elastomers (CEs) combine conductivity, flexibility, and stretchability. In this study, CEs combining poly(3,4-ehtylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) in polyurethane are explored as dry, skin contacting EMG electrodes. This study compares these CE electrodes to commercial wet Ag/AgCl electrodes in five subjects, classifying four movements: open hand, fist, wrist extension, and wrist flexion. Classification accuracy is tested using a backpropagation artificial neural network. The control Ag/AgCl electrodes have a 98.7% classification accuracy, while the dry conductive elastomer electrodes have a classification accuracy of 99.5%. As a conclusion, PEDOT based dry CEs were shown to successfully function as on-skin electrodes for EMG recording, matching the performance of Ag/AgCl electrodes, while addressing the need for minimal skin prep, no gel, and wearable technology.

传统的湿式Ag/AgCl电极广泛应用于心电图、肌电图(EMG)和脑电图(EEG),被认为是生物电位测量的金标准。然而,这些电极需要大量的皮肤准备,是一次性使用的,不能用于连续监测(>24小时)。由于这些原因,干电极在表面肌电图(sEMG)中更可取,因为它们方便,耐用和长寿。干式导电弹性体(CEs)结合了导电性、柔韧性和拉伸性。本研究将聚(3,4-乙炔二氧噻吩):聚苯乙烯磺酸盐(PEDOT:PSS)结合在聚氨酯中的ce作为干燥的皮肤接触肌电电极进行了研究。本研究将这些CE电极与商用湿式Ag/AgCl电极在五个受试者身上进行了比较,并对四种动作进行了分类:张开手、握拳、手腕伸展和手腕弯曲。采用反向传播人工神经网络对分类精度进行了测试。对照Ag/AgCl电极的分类精度为98.7%,而干燥导电弹性体电极的分类精度为99.5%。综上所述,基于PEDOT的干燥ce被证明可以成功地作为肌电记录的皮肤电极,与Ag/AgCl电极的性能相匹配,同时解决了对皮肤准备最少、无凝胶和可穿戴技术的需求。
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引用次数: 0
Oscillatory shear stress-induced downregulation of TET1s injures vascular endothelial planar cell polarity by suppression of actin polymerization. 振荡剪切应力诱导的TET1s下调通过抑制肌动蛋白聚合损伤血管内皮平面细胞极性。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0141289
Kai Qu, Caihong Wang, Lu Huang, Xian Qin, Kun Zhang, Juhui Qiu, Guixue Wang

Vascular endothelial polarity induced by blood flow plays crucial roles in the development of atherosclerosis. Loss of endothelial polarity leads to an increase in permeability and leukocyte recruitment, which are crucial hallmarks of atherosclerotic initiation. Endothelial cells exhibit a morphological adaptation to hemodynamic shear stress and possesses planar cell polarity to the direction of blood flow. However, the mechanism of how hemodynamic shear stress regulates endothelial planar cell polarity has not been firmly established. Here, we found that TET1s, a short isoform of Tet methylcytosine dioxygenase 1, was a mediator in the regulation of the planar cell polarity in endothelial cells in response to hemodynamic shear stress. In the process, low expression of TET1s induced by oscillatory shear stress led to the endothelial planar polarity damage through inhibition of F-actin polymerization. TET1s can regulate demethylation level of the sFRP-1 promoter to alter the expression of sFRP-1, which affects the interaction of sFRP-1/Fzd4 and F-actin polymerization. Our study revealed the mechanism of how TET1s mediates endothelial planar cell polarity in response to hemodynamic shear stress and provides a new insight for the prevention of atherosclerosis.

血流诱导的血管内皮极性在动脉粥样硬化的发展中起着至关重要的作用。内皮极性的丧失导致通透性和白细胞募集的增加,这是动脉粥样硬化起始的关键标志。内皮细胞表现出对血流动力学剪切应力的形态学适应,并具有对血流方向的平面细胞极性。然而,血流动力学剪切应力如何调节内皮平面细胞极性的机制尚未明确。在这里,我们发现Tet甲基胞嘧啶双加氧酶1的短异构体TET1s是内皮细胞响应血流动力学剪切应力时平面细胞极性调节的介质。在此过程中,振荡剪切应力诱导TET1s低表达,通过抑制F-actin聚合导致内皮平面极性损伤。TET1s可以调节sFRP-1启动子的去甲基化水平,从而改变sFRP-1的表达,从而影响sFRP-1/Fzd4与F-actin聚合的相互作用。我们的研究揭示了TET1s如何介导内皮平面细胞极性以响应血流动力学剪切应力的机制,并为预防动脉粥样硬化提供了新的见解。
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引用次数: 0
Emerging trends in the development of flexible optrode arrays for electrophysiology. 用于电生理的柔性光电阵列发展的新趋势。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0153753
Reem M Almasri, François Ladouceur, Damia Mawad, Dorna Esrafilzadeh, Josiah Firth, Torsten Lehmann, Laura A Poole-Warren, Nigel H Lovell, Amr Al Abed

Optical-electrode (optrode) arrays use light to modulate excitable biological tissues and/or transduce bioelectrical signals into the optical domain. Light offers several advantages over electrical wiring, including the ability to encode multiple data channels within a single beam. This approach is at the forefront of innovation aimed at increasing spatial resolution and channel count in multichannel electrophysiology systems. This review presents an overview of devices and material systems that utilize light for electrophysiology recording and stimulation. The work focuses on the current and emerging methods and their applications, and provides a detailed discussion of the design and fabrication of flexible arrayed devices. Optrode arrays feature components non-existent in conventional multi-electrode arrays, such as waveguides, optical circuitry, light-emitting diodes, and optoelectronic and light-sensitive functional materials, packaged in planar, penetrating, or endoscopic forms. Often these are combined with dielectric and conductive structures and, less frequently, with multi-functional sensors. While creating flexible optrode arrays is feasible and necessary to minimize tissue-device mechanical mismatch, key factors must be considered for regulatory approval and clinical use. These include the biocompatibility of optical and photonic components. Additionally, material selection should match the operating wavelength of the specific electrophysiology application, minimizing light scattering and optical losses under physiologically induced stresses and strains. Flexible and soft variants of traditionally rigid photonic circuitry for passive optical multiplexing should be developed to advance the field. We evaluate fabrication techniques against these requirements. We foresee a future whereby established telecommunications techniques are engineered into flexible optrode arrays to enable unprecedented large-scale high-resolution electrophysiology systems.

光电极阵列利用光来调制可兴奋的生物组织和/或将生物电信号转导到光域中。与电线相比,光有几个优点,包括在一束光中编码多个数据通道的能力。这种方法处于创新的最前沿,旨在提高多通道电生理系统的空间分辨率和通道数。本文综述了利用光进行电生理记录和刺激的设备和材料系统。工作重点是当前和新兴的方法及其应用,并提供了柔性阵列器件的设计和制造的详细讨论。光电阵列具有传统多电极阵列中不存在的组件,如波导、光学电路、发光二极管、光电和光敏感功能材料,以平面、穿透或内窥镜形式封装。这些通常与介电和导电结构相结合,不太常见的是与多功能传感器相结合。虽然创建柔性光电二极管阵列是可行的,并且是必要的,以尽量减少组织与设备的机械不匹配,但必须考虑监管批准和临床使用的关键因素。这些包括光学和光子元件的生物相容性。此外,材料选择应与特定电生理应用的工作波长相匹配,最大限度地减少生理诱导应力和应变下的光散射和光损失。在传统刚性光子电路的基础上,开发柔性和软型的无源光复用电路,以促进该领域的发展。我们根据这些要求评估制造技术。我们预见到未来,现有的电信技术被设计成灵活的光电阵列,以实现前所未有的大规模高分辨率电生理系统。
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引用次数: 0
3D photopolymerized microstructured scaffolds influence nuclear deformation, nucleo/cytoskeletal protein organization, and gene regulation in mesenchymal stem cells. 3D光聚合微结构支架影响间充质干细胞的核变形、核/细胞骨架蛋白组织和基因调控。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0153215
Francesca Donnaloja, Manuela Teresa Raimondi, Letizia Messa, Bianca Barzaghini, Federica Carnevali, Emanuele Colombo, Davide Mazza, Chiara Martinelli, Lucia Boeri, Federica Rey, Cristina Cereda, Roberto Osellame, Giulio Cerullo, Stephana Carelli, Monica Soncini, Emanuela Jacchetti

Mechanical stimuli from the extracellular environment affect cell morphology and functionality. Recently, we reported that mesenchymal stem cells (MSCs) grown in a custom-made 3D microscaffold, the Nichoid, are able to express higher levels of stemness markers. In fact, the Nichoid is an interesting device for autologous MSC expansion in clinical translation and would appear to regulate gene activity by altering intracellular force transmission. To corroborate this hypothesis, we investigated mechanotransduction-related nuclear mechanisms, and we also treated spread cells with a drug that destroys the actin cytoskeleton. We observed a roundish nuclear shape in MSCs cultured in the Nichoid and correlated the nuclear curvature with the import of transcription factors. We observed a more homogeneous euchromatin distribution in cells cultured in the Nichoid with respect to the Flat sample, corresponding to a standard glass coverslip. These results suggest a different gene regulation, which we confirmed by an RNA-seq analysis that revealed the dysregulation of 1843 genes. We also observed a low structured lamina mesh, which, according to the implemented molecular dynamic simulations, indicates reduced damping activity, thus supporting the hypothesis of low intracellular force transmission. Also, our investigations regarding lamin expression and spatial organization support the hypothesis that the gene dysregulation induced by the Nichoid is mainly related to a reduction in force transmission. In conclusion, our findings revealing the Nichoid's effects on MSC behavior is a step forward in the control of stem cells via mechanical manipulation, thus paving the way to new strategies for MSC translation to clinical applications.

来自细胞外环境的机械刺激影响细胞形态和功能。最近,我们报道了在定制的3D微支架Nichoid中生长的间充质干细胞(MSCs)能够表达更高水平的干细胞标记物。事实上,Nichoid在临床翻译中是一种有趣的自体间充质干细胞扩增装置,似乎可以通过改变细胞内力传递来调节基因活性。为了证实这一假设,我们研究了机械转导相关的核机制,我们也用一种破坏肌动蛋白细胞骨架的药物治疗扩散细胞。我们在Nichoid培养的MSCs中观察到一个圆形的核形状,并将核曲率与转录因子的输入相关联。我们观察到在Nichoid中培养的细胞中有一个更均匀的常染色质分布,相对于扁平样品,对应于一个标准的玻璃盖。这些结果表明了一种不同的基因调控,我们通过RNA-seq分析证实了这一点,该分析显示了1843个基因的失调。我们还观察到低结构的层状网格,根据实施的分子动力学模拟,表明阻尼活性降低,从而支持细胞内力传递低的假设。此外,我们对层粘胶蛋白表达和空间组织的研究支持了Nichoid诱导的基因失调主要与力传递减少有关的假设。总之,我们的发现揭示了Nichoid对MSC行为的影响,这是通过机械操作控制干细胞的一步,从而为MSC转化为临床应用的新策略铺平了道路。
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引用次数: 0
Gelatin-modified 3D printed PGS elastic hierarchical porous scaffold for cartilage regeneration. 明胶改性3D打印PGS弹性分层多孔软骨再生支架。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0152151
Sinan Wang, Hongying Chen, Jinyi Huang, Sisi Shen, Zhengya Tang, Xiaoyan Tan, Dong Lei, Guangdong Zhou

Regenerative cartilage replacements are increasingly required in clinical settings for various defect repairs, including bronchial cartilage deficiency, articular cartilage injury, and microtia reconstruction. Poly (glycerol sebacate) (PGS) is a widely used bioelastomer that has been developed for various regenerative medicine applications because of its excellent elasticity, biodegradability, and biocompatibility. However, because of inadequate active groups, strong hydrophobicity, and limited ink extrusion accuracy, 3D printed PGS scaffolds may cause insufficient bioactivity, inefficient cell inoculation, and inconsistent cellular composition, which seriously hinders its further cartilage regenerative application. Here, we combined 3D printed PGS frameworks with an encapsulated gelatin hydrogel to fabricate a PGS@Gel composite scaffold. PGS@Gel scaffolds have a controllable porous microstructure, with suitable pore sizes and enhanced hydrophilia, which could significantly promote the cells' penetration and adhesion for efficient chondrocyte inoculation. Furthermore, the outstanding elasticity and fatigue durability of the PGS framework enabled the regenerated cartilage built by the PGS@Gel scaffolds to resist the dynamic in vivo environment and maintain its original morphology. Importantly, PGS@Gel scaffolds increased the rate of cartilage regeneration concurrent with scaffold degradation. The scaffold was gradually degraded and integrated to form uniform, dense, and mature regenerated cartilage tissue with little scaffold residue.

在临床环境中,越来越多地需要再生软骨替代物来修复各种缺陷,包括支气管软骨缺损、关节软骨损伤和小体重建。聚甘油癸二酸酯(PGS)是一种广泛使用的生物弹性体,由于其优异的弹性、生物可降解性和生物相容性,已被开发用于各种再生医学应用。然而,由于活性基团不足,疏水性强,油墨挤出精度有限,3D打印的PGS支架可能导致生物活性不足,细胞接种效率低,细胞组成不一致,严重阻碍了其进一步的软骨再生应用。在这里,我们将3D打印的PGS框架与胶囊明胶水凝胶相结合,制造了PGS@Gel复合支架。PGS@Gel支架具有可控的多孔微观结构,孔径适宜,亲水性增强,可显著促进细胞的渗透和粘附,有效接种软骨细胞。此外,PGS框架出色的弹性和疲劳耐久性使PGS@Gel支架构建的再生软骨能够抵抗体内动态环境并保持其原始形态。重要的是,PGS@Gel支架在支架降解的同时增加了软骨再生的速度。支架逐渐降解、整合,形成均匀、致密、成熟的再生软骨组织,支架残留少。
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引用次数: 1
User-friendly microfluidic system reveals native-like morphological and transcriptomic phenotypes induced by shear stress in proximal tubule epithelium. 用户友好的微流控系统揭示了近端小管上皮剪切应力诱导的原生形态和转录组表型。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0143614
Natalie N Khalil, Andrew P Petersen, Cheng J Song, Yibu Chen, Kaelyn Takamoto, Austin C Kellogg, Elaine Zhelan Chen, Andrew P McMahon, Megan L McCain

Drug-induced nephrotoxicity is a leading cause of drug attrition, partly due to the limited relevance of pre-clinical models of the proximal tubule. Culturing proximal tubule epithelial cells (PTECs) under fluid flow to mimic physiological shear stress has been shown to improve select phenotypes, but existing flow systems are expensive and difficult to implement by non-experts in microfluidics. Here, we designed and fabricated an accessible and modular flow system for culturing PTECs under physiological shear stress, which induced native-like cuboidal morphology, downregulated pathways associated with hypoxia, stress, and injury, and upregulated xenobiotic metabolism pathways. We also compared the expression profiles of shear-dependent genes in our in vitro PTEC tissues to that of ex vivo proximal tubules and observed stronger clustering between ex vivo proximal tubules and PTECs under physiological shear stress relative to PTECs under negligible shear stress. Together, these data illustrate the utility of our user-friendly flow system and highlight the role of shear stress in promoting native-like morphological and transcriptomic phenotypes in PTECs in vitro, which is critical for developing more relevant pre-clinical models of the proximal tubule for drug screening or disease modeling.

药物引起的肾毒性是药物损耗的主要原因,部分原因是近端肾小管临床前模型的相关性有限。在流体流动下培养近端小管上皮细胞(PTECs)以模拟生理剪切应力已被证明可以改善选择的表型,但现有的流动系统昂贵且难以由非微流体专家实施。在这里,我们设计并制造了一个可访问的模块化流动系统,用于在生理剪切应力下培养ptec,诱导原生样立方形态,与缺氧,应激和损伤相关的下调通路,以及上调外源代谢途径。我们还将体外PTEC组织中剪切依赖基因的表达谱与离体近端小管的表达谱进行了比较,发现在生理剪切应力下,离体近端小管与PTEC之间的聚类比在可忽略剪切应力下的PTEC更强。总之,这些数据说明了我们的用户友好型流动系统的实用性,并强调了剪切应力在体外促进ptec中原生样形态和转录组表型中的作用,这对于开发更相关的近端小管临床前模型用于药物筛选或疾病建模至关重要。
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引用次数: 0
A sense of proximity: Cell packing modulates oxygen consumption. 接近感:细胞包装调节氧气消耗。
IF 6 3区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-09-01 DOI: 10.1063/5.0160422
Ermes Botte, Piera Mancini, Chiara Magliaro, Arti Ahluwalia

Accurately modeling oxygen transport and consumption is crucial to predict metabolic dynamics in cell cultures and optimize the design of tissue and organ models. We present a methodology to characterize the Michaelis-Menten oxygen consumption parameters in vitro, integrating novel experimental techniques and computational tools. The parameters were derived for hepatic cell cultures with different dimensionality (i.e., 2D and 3D) and with different surface and volumetric densities. To quantify cell packing regardless of the dimensionality of cultures, we devised an image-based metric, referred to as the proximity index. The Michaelis-Menten parameters were related to the proximity index through an uptake coefficient, analogous to a diffusion constant, enabling the quantitative analysis of oxygen dynamics across dimensions. Our results show that Michaelis-Menten parameters are not constant for a given cell type but change with dimensionality and cell density. The maximum consumption rate per cell decreases significantly with cell surface and volumetric density, while the Michaelis-Menten constant tends to increase. In addition, the dependency of the uptake coefficient on the proximity index suggests that the oxygen consumption rate of hepatic cells is superadaptive, as they modulate their oxygen utilization according to its local availability and to the proximity of other cells. We describe, for the first time, how cells consume oxygen as a function of cell proximity, through a quantitative index, which combines cell density and dimensionality. This study enhances our understanding of how cell-cell interaction affects oxygen dynamics and enables better prediction of aerobic metabolism in tissue models, improving their translational value.

准确建模氧气运输和消耗是至关重要的预测代谢动力学在细胞培养和优化组织和器官模型的设计。我们提出了一种方法来表征体外Michaelis-Menten耗氧量参数,整合了新的实验技术和计算工具。这些参数是针对不同维度(即二维和三维)、不同表面和体积密度的肝细胞培养而得出的。无论培养物的维度如何,为了量化细胞包装,我们设计了一种基于图像的度量,称为接近指数。Michaelis-Menten参数通过吸收系数(类似于扩散常数)与接近指数相关联,从而可以跨维度定量分析氧动力学。我们的研究结果表明Michaelis-Menten参数对于给定的细胞类型不是恒定的,而是随着细胞密度和维数的变化而变化。每个细胞的最大消耗率随细胞表面积和体积密度的增加而显著降低,Michaelis-Menten常数呈增加趋势。此外,摄取系数对接近指数的依赖性表明,肝细胞的耗氧率是超适应性的,因为它们根据其局部可用性和与其他细胞的接近程度来调节其氧利用。我们首次通过结合细胞密度和维度的定量指数,描述了细胞如何消耗氧气作为细胞接近度的函数。这项研究增强了我们对细胞-细胞相互作用如何影响氧动力学的理解,使我们能够更好地预测组织模型中的有氧代谢,提高它们的翻译价值。
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APL Bioengineering
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