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Hepatic spheroid-on-a-chip: Fabrication and characterization of a spheroid-based in vitro model of the human liver for drug screening applications 肝脏球形芯片:为药物筛选应用制作和表征基于球形的人体肝脏体外模型
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-28 DOI: 10.1063/5.0210955
Sultan K. AlShmmari, Roa S. Fardous, Zakia Shinwari, Dana Cialla-May, Jürgen Popp, Qasem Ramadan, Mohammed Zourob
The integration of microfabrication and microfluidics techniques into cell culture technology has significantly transformed cell culture conditions, scaffold architecture, and tissue biofabrication. These tools offer precise control over cell positioning and enable high-resolution analysis and testing. Culturing cells in 3D systems, such as spheroids and organoids, enables recapitulating the interaction between cells and the extracellular matrix, thereby allowing the creation of human-based biomimetic tissue models that are well-suited for pre-clinical drug screening. Here, we demonstrate an innovative microfluidic device for the formation, culture, and testing of hepatocyte spheroids, which comprises a large array of patterned microwells for hosting hepatic spheroid culture in a reproducible and organized format in a dynamic fluidic environment. The device allows maintaining and characterizing different spheroid sizes as well as exposing to various drugs in parallel enabling high-throughput experimentation. These liver spheroids exhibit physiologically relevant hepatic functionality, as evidenced by their ability to produce albumin and urea at levels comparable to in vivo conditions and the capability to distinguish the toxic effects of selected drugs. This highlights the effectiveness of the microenvironment provided by the chip in maintaining the functionality of hepatocyte spheroids. These data support the notion that the liver-spheroid chip provides a favorable microenvironment for the maintenance of hepatocyte spheroid functionality.
微加工和微流体技术与细胞培养技术的整合极大地改变了细胞培养条件、支架结构和组织生物制造。这些工具可精确控制细胞定位,实现高分辨率分析和测试。在球形和有机体等三维系统中培养细胞,可以重现细胞与细胞外基质之间的相互作用,从而创建出非常适合临床前药物筛选的人体生物仿真组织模型。在这里,我们展示了一种用于肝细胞球体的形成、培养和测试的创新型微流体设备,它包括一个大型图案微孔阵列,用于在动态流体环境中以可重现和有组织的形式进行肝球体培养。该装置可维持和表征不同大小的球体,并可同时接触各种药物,从而实现高通量实验。这些肝脏球体表现出了与生理相关的肝脏功能,其产生白蛋白和尿素的能力可与体内条件相媲美,并能区分特定药物的毒性作用。这凸显了芯片提供的微环境在维持肝细胞球体功能方面的有效性。这些数据支持肝球芯片为维持肝细胞球功能提供有利微环境的观点。
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引用次数: 0
Manipulation of magnetic beads for actively capturing Vibrio parahaemolyticus and nucleic acid based on microfluidic system. 基于微流体系统的磁珠主动捕获副溶血性弧菌和核酸的操作。
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-10 eCollection Date: 2024-05-01 DOI: 10.1063/5.0193442
Zhaoxuan Zhang, Xue Deng, Wenqiang Zhang, Kehan Chen, Yuan Su, Chao Gao, De Gong, Longjiao Zhu, Jun Cai

Rapid biological detection of pathogen micro-organisms has attracted much attention for practical biomedical applications. Despite the development in this field, it is still challenging to achieve simple and rapid biological detection using the microfluidic method. Herein, we propose a novel strategy of biological detection that combines precise detection control of the capillary microfluidic chip and versatile manipulation of magnetic beads. The microfluidic chip was fabricated via laser cutting, which utilized capillary pressure to realize rapid passive injection of liquid samples. Under an external magnetic field, the aptamer-modified magnetic beads were actuated to mix with Vibrio parahaemolyticus (V. parahaemolyticus) and its nucleic acid in the capillary microfluidic chip for rapid selective capture and detection, which could be achieved within 40 min. The experimental results demonstrated that V. parahaemolyticus could be captured using on-chip immunomagnetic beads with a high efficiency and significantly enhanced detection value. Due to these superior performances, the capillary microfluidic system, based on the manipulation of magnetic beads, demonstrated great potential for automatic biological detection.

病原微生物的快速生物检测在实际生物医学应用中备受关注。尽管这一领域在不断发展,但利用微流体方法实现简单快速的生物检测仍具有挑战性。在此,我们提出了一种新型生物检测策略,将毛细管微流控芯片的精确检测控制与磁珠的多功能操作相结合。微流控芯片通过激光切割制作而成,利用毛细管压力实现液体样品的快速被动注入。在外加磁场的作用下,合子修饰的磁珠被驱动与毛细管微流控芯片中的副溶血弧菌及其核酸混合,实现快速选择性捕获和检测,整个过程可在 40 分钟内完成。实验结果表明,使用芯片上的免疫磁珠可高效捕获副溶血性弧菌,并显著提高检测值。由于这些优异的性能,基于磁珠操作的毛细管微流控系统在生物自动检测方面展现出巨大的潜力。
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引用次数: 0
Organ-specific vasculature-on-a-chip systems. 器官特异性血管芯片系统。
IF 2.6 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-06 eCollection Date: 2024-05-01 DOI: 10.1063/5.0214265
Hasan Erbil Abaci, Mandy B Esch
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引用次数: 0
The mechanism of biofilm detachment in porous medium under flow field 流场作用下多孔介质中生物膜脱落的机理
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-06 DOI: 10.1063/5.0203061
Yangyang Tang, Zheng Zhang, Cong Tao, Xiaoling Wang
Biofilms are communities formed by bacteria adhering to surfaces, widely present in porous medium, and their growth can lead to clogging. Our experiment finds that under certain flow conditions, biofilms detach in pores and form a dynamically changing flow path. We define detachment that occurs far from the boundary of the flow path (with a distance greater than 200 μm) as internal detachment and detachment that occurs at the boundary of the flow path as external detachment. To understand the mechanism of biofilm detachment, we study the detachment behaviors of the Bacillus subtilis biofilm in a porous medium in a microfluidic device, where Bacillus subtilis strain is triple fluorescent labeled, which can represent three main phenotypes during the biofilm formation: motile cells, matrix-producing cells, and spores. We find that slow small-scale internal detachment occurs in regions with very few motile cells and matrix-producing cells, and bacterial movement in these areas is disordered. The increase in the number of matrix-producing cells induces clogging, and after clogging, the rapid detachment of the bulk internal biofilm occurs due to the increased pressure difference at the inlet and outlet. When both internal and external detachments occur simultaneously, the number of matrix-producing cells in the internal detachment area is 2.5 times that in the external detachment area. The results indicate that biofilm detachment occurs in areas with fewer matrix-producing cells, as matrix-producing cells can help resist detachment by secreting extracellular polymeric substances (EPSs).
生物膜是由附着在表面的细菌形成的群落,广泛存在于多孔介质中,它们的生长会导致堵塞。我们的实验发现,在特定的流动条件下,生物膜会在孔隙中脱离,并形成动态变化的流动路径。我们将发生在远离流道边界(距离大于 200 μm)的脱落定义为内部脱落,而发生在流道边界的脱落定义为外部脱落。为了了解生物膜脱离的机理,我们研究了微流体装置中多孔介质中枯草芽孢杆菌生物膜的脱离行为,枯草芽孢杆菌菌株被三重荧光标记,可代表生物膜形成过程中的三种主要表型:运动细胞、基质生成细胞和芽孢。我们发现,在运动细胞和基质产生细胞极少的区域会发生缓慢的小规模内部分离,细菌在这些区域的运动是无序的。基质产生细胞数量的增加会导致堵塞,堵塞后,由于入口和出口处的压力差增大,内部大面积生物膜会迅速脱离。当内部和外部脱落同时发生时,内部脱落区域的基质生成细胞数量是外部脱落区域的 2.5 倍。结果表明,生物膜脱落发生在基质产生细胞较少的区域,因为基质产生细胞可以通过分泌胞外聚合物物质(EPSs)来帮助抵抗脱落。
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引用次数: 0
Mimicking blood and lymphatic vasculatures using microfluidic systems. 利用微流体系统模拟血液和淋巴管。
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-06 eCollection Date: 2024-05-01 DOI: 10.1063/5.0175154
Eva Hall, Kailee Mendiola, N Keilany Lightsey, Donny Hanjaya-Putra

The role of the circulatory system, containing the blood and lymphatic vasculatures, within the body, has become increasingly focused on by researchers as dysfunction of either of the systems has been linked to serious complications and disease. Currently, in vivo models are unable to provide the sufficient monitoring and level of manipulation needed to characterize the fluidic dynamics of the microcirculation in blood and lymphatic vessels; thus in vitro models have been pursued as an alternative model. Microfluidic devices have the required properties to provide a physiologically relevant circulatory system model for research as well as the experimental tools to conduct more advanced research analyses of microcirculation flow. In this review paper, the physiological behavior of fluid flow and electrical communication within the endothelial cells of the systems are detailed and discussed to highlight their complexities. Cell co-culturing methods and other relevant organ-on-a-chip devices will be evaluated to demonstrate the feasibility and relevance of the in vitro microfluidic model. Microfluidic systems will be determined as a noteworthy model that can display physiologically relevant flow of the cardiovascular and lymphatic systems, which will enable researchers to investigate the systems' prevalence in diseases and identify potential therapeutics.

循环系统(包括血液和淋巴管)在人体内的作用日益受到研究人员的关注,因为其中任何一个系统的功能障碍都与严重的并发症和疾病有关。目前,体内模型无法提供足够的监测和所需的操作水平来描述血液和淋巴管中微循环的流体动力学特征;因此,体外模型已被用作替代模型。微流控装置具有所需的特性,可为研究提供与生理相关的循环系统模型,以及对微循环流动进行更高级研究分析的实验工具。在这篇综述论文中,详细讨论了系统内皮细胞内流体流动和电子通讯的生理行为,以突出其复杂性。将对细胞共培养方法和其他相关的芯片上器官装置进行评估,以证明体外微流体模型的可行性和相关性。微流控系统将被确定为一种值得注意的模型,它可以显示心血管和淋巴系统的生理相关流动,这将使研究人员能够研究这些系统在疾病中的普遍性,并确定潜在的治疗方法。
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引用次数: 0
Microfluidic paper analytic device (μPAD) technology for food safety applications. 用于食品安全应用的微流控纸质分析装置(μPAD)技术。
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-02 eCollection Date: 2024-05-01 DOI: 10.1063/5.0192295
Soja Saghar Soman, Shafeek Abdul Samad, Priyamvada Venugopalan, Nityanand Kumawat, Sunil Kumar

Foodborne pathogens, food adulterants, allergens, and toxic chemicals in food can cause major health hazards to humans and animals. Stringent quality control measures at all stages of food processing are required to ensure food safety. There is, therefore, a global need for affordable, reliable, and rapid tests that can be conducted at different process steps and processing sites, spanning the range from the sourcing of food to the end-product acquired by the consumer. Current laboratory-based food quality control tests are well established, but many are not suitable for rapid on-site investigations and are costly. Microfluidic paper analytical devices (μPADs) are a fast-growing field in medical diagnostics that can fill these gaps. In this review, we describe the latest developments in the applications of microfluidic paper analytic device (μPAD) technology in the food safety sector. State-of-the-art μPAD designs and fabrication methods, microfluidic assay principles, and various types of μPAD devices with food-specific applications are discussed. We have identified the prominent research and development trends and future directions for maximizing the value of microfluidic technology in the food sector and have highlighted key areas for improvement. We conclude that the μPAD technology is promising in food safety applications by using novel materials and improved methods to enhance the sensitivity and specificity of the assays, with low cost.

食品中的食源性病原体、食品掺假物、过敏原和有毒化学物质可对人类和动物的健康造成重大危害。为确保食品安全,必须在食品加工的各个阶段采取严格的质量控制措施。因此,全球都需要可在不同加工步骤和加工场所进行的经济、可靠和快速的检测,检测范围从食品来源到消费者获得的最终产品。目前以实验室为基础的食品质量控制检测方法已经非常成熟,但很多都不适合现场快速调查,而且成本高昂。微流控纸质分析装置(μPAD)是医疗诊断领域快速发展的一个领域,可以填补这些空白。在本综述中,我们将介绍微流控纸质分析装置(μPAD)技术在食品安全领域应用的最新进展。文中讨论了最先进的微流体纸分析装置设计和制造方法、微流体分析原理以及具有食品特定应用的各类微流体纸分析装置。我们确定了突出的研发趋势和未来方向,以最大限度地发挥微流控技术在食品领域的价值,并强调了需要改进的关键领域。我们的结论是,通过使用新型材料和改进方法来提高检测的灵敏度和特异性,μPAD 技术在食品安全领域的应用前景广阔,而且成本低廉。
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引用次数: 0
A bionic mimosa soft robot based on a multi-responsive PNIPAM-PEGDA hydrogel composition. 基于多反应 PNIPAM-PEGDA 水凝胶成分的仿生含羞草软机器人。
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-01 DOI: 10.1063/5.0203482
Wenguang Yang, Xiaowen Wang, Xiangyu Teng, Zezheng Qiao, Haibo Yu, Zheng Yuan

Deformation plays a vital role in the survival of natural organisms. One example is that plants deform themselves to face the sun for sufficient sunlight exposure, which allows them to produce nutrients through photosynthesis. Drawing inspiration from nature, researchers have been exploring the development of 3D deformable materials. However, the traditional approach to manufacturing deformable hydrogels relies on complex technology, which limits their potential applications. In this study, we simulate the stress variations observed in the plant tissue to create a 3D structure from a 2D material. Using UV curing technology, we create a single-layer poly(N-isopropylacrylamide) hydrogel sheet with microchannels that exhibit distinct swelling rates when subjected to stimulation. After a two-step curing process, we produce a poly(N-isopropylacrylamide)-polyethylene glycol diacrylatedouble-layer structure that can be manipulated to change its shape by controlling the light and solvent content. Based on the double-layer structure, we fabricate a dual-response driven bionic mimosa robot that can perform a variety of functions. This soft robot can not only reversibly change its shape but also maintain a specific shape without continuous stimulation. Its capacity for reversible deformation, resulting from internal stress, presents promising application prospects in the biomedical and soft robotics domain. This study delivers an insightful framework for the development of programmable soft materials.

变形在自然生物的生存中起着至关重要的作用。其中一个例子是,植物通过变形来面向太阳,以获得充足的阳光照射,从而通过光合作用产生养分。从大自然中汲取灵感,研究人员一直在探索开发三维可变形材料。然而,制造可变形水凝胶的传统方法依赖于复杂的技术,这限制了它们的潜在应用。在这项研究中,我们模拟在植物组织中观察到的应力变化,从二维材料中创造出三维结构。利用紫外线固化技术,我们创建了一种带有微通道的单层聚(N-异丙基丙烯酰胺)水凝胶片材,这种水凝胶在受到刺激时会表现出不同的膨胀率。经过两步固化过程后,我们制备出了一种聚(N-异丙基丙烯酰胺)-聚乙二醇二丙烯酰胺双层结构,可以通过控制光和溶剂含量来改变其形状。在双层结构的基础上,我们制造出了一种能实现多种功能的双响应驱动仿生含羞草机器人。这种软机器人不仅能可逆地改变形状,还能在没有持续刺激的情况下保持特定形状。它因内应力而产生的可逆变形能力为生物医学和软机器人领域带来了广阔的应用前景。这项研究为开发可编程软材料提供了一个富有洞察力的框架。
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引用次数: 0
Numerical simulation of cellular blood flow in curved micro-vessels with saccular aneurysms: Effect of curvature degree and hematocrit level 带有囊状动脉瘤的弯曲微血管中细胞血流的数值模拟:弯曲度和血细胞比容水平的影响
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-04-29 DOI: 10.1063/5.0203220
Ahmed Elhanafy, Samir Elsagheer, Shinichi Ookawara, Sameh Nada
The dynamics of cellular blood flow in curved vessels considerably differ from those in straight vessels. It is reported that clotting development is significantly affected by vessel shape irregularities. Thus, the current study aims to investigate the effect of curvature degree and hematocrit level on cellular blood flow in a curved micro-vessel with a saccular aneurysm. Accordingly, a three-dimensional numerical simulation is performed using a validated code developed for cellular blood flow problems. The obtained results show that the cell-free layer thickness is highly dependent on the curvature degree and hematocrit level, which may have a remarkable impact on the apparent viscosity of blood as well as the dynamics of other particles such as drug particulates. The near-wall region exhibits the highest degree of cell deformation, whereas the red blood cells within the aneurysm zone remain nearly undeformed. Meanwhile, the velocity of the red blood cells decreases with the increase in curvature degree, which can affect the quality of the oxygenation process. Because of the saccular aneurysm, a considerable decrease in plasma velocity is predicted. Moreover, no secondary flows are detected in the curved vessel except in the aneurysm zone. An increase in the curvature degree is expected to reduce the blood flow rate by about 10%. Furthermore, low wall shear stress values are predicted in the straight case compared to the values at the apex of the curved vessel, which may affect the structure and function of the endothelial cells of the vessel wall and, hence, increase the aneurysm rupture possibility.
弯曲血管中的细胞血流动力学与直血管中的细胞血流动力学有很大不同。据报道,血管形状不规则会严重影响凝血过程。因此,本研究旨在探讨弯曲度和血细胞比容水平对带有囊状动脉瘤的弯曲微血管中细胞血流的影响。因此,使用针对细胞血流问题开发的有效代码进行了三维数值模拟。结果表明,无细胞层厚度与弯曲度和血细胞比容高度相关,这可能会对血液的表观粘度以及药物颗粒等其他颗粒的动态产生显著影响。近壁区域的细胞变形程度最高,而动脉瘤区域内的红细胞几乎没有变形。同时,红细胞的速度会随着弯曲度的增加而降低,从而影响氧合过程的质量。由于存在囊状动脉瘤,预计血浆速度会大幅下降。此外,在弯曲的血管中,除了动脉瘤区域外,没有检测到二次流动。弯曲度的增加预计会使血流速度降低约 10%。此外,与弯曲血管顶点的值相比,直血管的壁剪应力值较低,这可能会影响血管壁内皮细胞的结构和功能,从而增加动脉瘤破裂的可能性。
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引用次数: 0
A brief overview of passive microvalves in microfluidics: Mechanism, manufacturing, and applications 微流体中的无源微阀概述:机理、制造和应用
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-04-22 DOI: 10.1063/5.0188807
Bin Li, Ludan Zhang, Siwei Bai, Jing Jin, Huaying Chen
Microvalves play a crucial role in manipulating fluid states within a microfluidic system and are finding widespread applications in fields such as biology, medicine, and environmental preservation. Leveraging the characteristics and features of microvalves enables the realization of various complicated microfluidic functions. Continuous advancement in the manufacturing process contributes to more flexible control modes for passive microvalves. As a consequence, these valves are progressively shrinking in size while simultaneously improving in precision and stability. Although active microvalves have the benefits of low leakage, rapid response time, and wide adaptability range, the energy supply system limits the size and even their applicability in integration and miniaturization. In comparison, passive microvalves have the advantage of relying solely on the fluid flow or fluid driving pressure to control the open/close of fluid flow over active microvalves, in spite of having slightly reduced control accuracy. Their self-sustaining feature is highly consistent with the need for assembly and miniaturization in the point-of-care testing technology. Hence, these valves have attracted significant interest for research and application purposes. This review focuses on the recent literature on passive microvalves and details existing passive microvalves from three different aspects: operating principle, processing method, and applications. This work aims to increase the visibility of passive microvalves among researchers and enhance their comprehension by classifying them according to the aforementioned three aspects, facilitating the practical applications and further developments of passive microvalves. Additionally, this paper is expected to serve as a comprehensive and systematic reference for interdisciplinary researchers that intend to design related microfluidic systems.
微阀在操纵微流体系统内的流体状态方面发挥着至关重要的作用,并在生物、医学和环境保护等领域得到广泛应用。利用微阀的特性和功能可以实现各种复杂的微流体功能。制造工艺的不断进步为无源微阀提供了更灵活的控制模式。因此,这些阀门在逐渐缩小尺寸的同时,精度和稳定性也在不断提高。虽然有源微阀具有泄漏率低、响应速度快、适应范围广等优点,但能源供应系统限制了它们的尺寸,甚至限制了它们在集成和微型化方面的应用。相比之下,无源微阀的优势在于完全依靠流体流量或流体驱动压力来控制流体流量的开/关,尽管控制精度略有降低。它们的自持特性与床旁检测技术对装配和微型化的需求高度一致。因此,这些阀门在研究和应用方面引起了极大的兴趣。本综述重点关注近期有关无源微阀的文献,并从工作原理、加工方法和应用三个不同方面详细介绍了现有的无源微阀。这项工作旨在提高无源微阀在研究人员中的知名度,并通过按照上述三个方面对无源微阀进行分类来加深对无源微阀的理解,从而促进无源微阀的实际应用和进一步发展。此外,本文有望为有意设计相关微流控系统的跨学科研究人员提供全面系统的参考。
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引用次数: 0
Acoustohydrodynamic micromixers: Basic mixing principles, programmable mixing prospectives, and biomedical applications 声流体动力微搅拌器:基本混合原理、可编程混合前景和生物医学应用
IF 3.2 4区 工程技术 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-04-18 DOI: 10.1063/5.0179750
Chenhao Bai, Xiaoqing Tang, Yuyang Li, Tatsuo Arai, Qiang Huang, Xiaoming Liu
Acoustohydrodynamic micromixers offer excellent mixing efficiency, cost-effectiveness, and flexible controllability compared with conventional micromixers. There are two mechanisms in acoustic micromixers: indirect influence by induced streamlines, exemplified by sharp-edge micromixers, and direct influence by acoustic waves, represented by surface acoustic wave micromixers. The former utilizes sharp-edge structures, while the latter employs acoustic wave action to affect both the fluid and its particles. However, traditional micromixers with acoustic bubbles achieve significant mixing performance and numerous programmable mixing platforms provide excellent solutions with wide applicability. This review offers a comprehensive overview of various micromixers, elucidates their underlying principles, and explores their biomedical applications. In addition, advanced programmable micromixing with impressive versatility, convenience, and ability of cross-scale operations is introduced in detail. We believe this review will benefit the researchers in the biomedical field to know the micromixers and find a suitable micromixing method for their various applications.
与传统微搅拌器相比,声流体动力微搅拌器具有出色的搅拌效率、成本效益和灵活的可控性。声学微搅拌器有两种机制:以锐边微搅拌器为例,通过诱导流线产生间接影响;以表面声波微搅拌器为例,通过声波产生直接影响。前者利用锐边结构,而后者则利用声波作用来影响流体及其颗粒。不过,传统的带声波气泡的微搅拌器可实现显著的搅拌性能,而众多可编程搅拌平台则提供了具有广泛适用性的优秀解决方案。本综述全面概述了各种微搅拌器,阐明了它们的基本原理,并探讨了它们在生物医学方面的应用。此外,还详细介绍了具有令人印象深刻的多功能性、便利性和跨尺度操作能力的先进可编程微搅拌技术。我们相信,这篇综述将有助于生物医学领域的研究人员了解微搅拌器,并为其各种应用找到合适的微搅拌方法。
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引用次数: 0
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