Recent Trends and Innovations in Bead-Based Biosensors for Cancer Detection.

Demand is strong for sensitive, reliable, and cost-effective diagnostic tools for cancer detection. Accordingly, bead-based biosensors have emerged in recent years as promising diagnostic platforms based on wide-ranging cancer biomarkers owing to the versatility, high sensitivity, and flexibility to perform the multiplexing of beads. This comprehensive review highlights recent trends and innovations in the development of bead-based biosensors for cancer-biomarker detection. We introduce various types of bead-based biosensors such as optical, electrochemical, and magnetic biosensors, along with their respective advantages and limitations. Moreover, the review summarizes the latest advancements, including fabrication techniques, signal-amplification strategies, and integration with microfluidics and nanotechnology. Additionally, the challenges and future perspectives in the field of bead-based biosensors for cancer-biomarker detection are discussed. Understanding these innovations in bead-based biosensors can greatly contribute to improvements in cancer diagnostics, thereby facilitating early detection and personalized treatments.

On the Application of Microfluidic-Based Technologies in Forensics: A Review.

Microfluidic technology is a powerful tool to enable the rapid, accurate, and on-site analysis of forensically relevant evidence on a crime scene. This review paper provides a summary on the application of this technology in various forensic investigation fields spanning from forensic serology and human identification to discriminating and analyzing diverse classes of drugs and explosives. Each aspect is further explained by providing a short summary on general forensic workflow and investigations for body fluid identification as well as through the analysis of drugs and explosives. Microfluidic technology, including fabrication methodologies, materials, and working modules, are touched upon. Finally, the current shortcomings on the implementation of the microfluidic technology in the forensic field are discussed along with the future perspectives.

Emerging microfluidics-enabled platforms for osteoarthritis management: from benchtop to bedside.

Osteoarthritis (OA) is a prevalent debilitating age-related joint degenerative disease. It is a leading cause of pain and functional disability in older adults. Unfortunately, there is no cure for OA once the damage is established. Therefore, it promotes an urgent need for early detection and intervention of OA. Theranostics, combining therapy and diagnosis, emerges as a promising approach for OA management. However, OA theranostics is still in its infancy. Three fundamental needs have to be firstly fulfilled: i) a reliable OA model for disease pathogenesis investigation and drug screening, ii) an effective and precise diagnostic platform, and iii) an advanced fabrication approach for drug delivery and therapy. Meanwhile, microfluidics emerges as a versatile technology to address each of the needs and eventually boost the development of OA theranostics. Therefore, this review focuses on the applications of microfluidics, from benchtop to bedside, for OA modelling and drug screening, early diagnosis, and clinical therapy. We first introduce the basic pathophysiology of OA and point out the major unfilled research gaps in current OA management including lack of disease modelling and drug screening platforms, early diagnostic modalities and disease-modifying drugs and delivery approaches. Accordingly, we then summarize the state-of-the-art microfluidics technology for OA management from in vitro modelling and diagnosis to therapy. Given the existing promising results, we further discuss the future development of microfluidic platforms towards clinical translation at the crossroad of engineering and biomedicine.

Progress of Microfluidic Continuous Separation Techniques for Micro-/Nanoscale Bioparticles.

Separation of micro- and nano-sized biological particles, such as cells, proteins, and nucleotides, is at the heart of most biochemical sensing/analysis, including in vitro biosensing, diagnostics, drug development, proteomics, and genomics. However, most of the conventional particle separation techniques are based on membrane filtration techniques, whose efficiency is limited by membrane characteristics, such as pore size, porosity, surface charge density, or biocompatibility, which results in a reduction in the separation efficiency of bioparticles of various sizes and types. In addition, since other conventional separation methods, such as centrifugation, chromatography, and precipitation, are difficult to perform in a continuous manner, requiring multiple preparation steps with a relatively large minimum sample volume is necessary for stable bioprocessing. Recently, microfluidic engineering enables more efficient separation in a continuous flow with rapid processing of small volumes of rare biological samples, such as DNA, proteins, viruses, exosomes, and even cells. In this paper, we present a comprehensive review of the recent advances in microfluidic separation of micro-/nano-sized bioparticles by summarizing the physical principles behind the separation system and practical examples of biomedical applications.

Application of lateral flow and microfluidic bio-assay and biosensing towards identification of DNA-methylation and cancer detection: Recent progress and challenges in biomedicine.

DNA methylation is an important epigenetic alteration that results from the covalent transfer of a methyl group to the fifth carbon of a cytosine residue in CpG dinucleotides by DNA methyltransferase. This modification mostly happens in the promoter region and the first exon of most genes and suppresses gene expression. Therefore, aberrant DNA methylation cause tumor progression, metastasis, and resistance to current anti-cancer therapies. So, the detection of DNA methylation is an important issue in diagnosis and therapy of most diseases. Conventional methods for the assay of DNA methylation and activity of DNA methyltransferases are time consuming. So, we need to multiplex operations and expensive instrumentation. To overcome the limitations of conventional methods, new methods such as microfluidic platforms and lateral flow tests have been developed to evaluate DNA methylation. The microfluidic tests are based on optical and electrical biosensing. These tests able us to can analyze DNA methylation with high efficiency and sensitivity without the need for expensive equipment and skilled people. Lateral flow strip tests are another type of rapid, simple, and sensitive test with advanced technology used to assess DNA methylation. Lateral flow strip tests are based on optical biosensors. This review attempts to evaluate new methods for assessing DNA extraction, DNA methylation and DNA methyltransferase activity as well as recent developments in microfluidic technology application for bisulfite treatment and restriction enzyme (bisulfite free), and lateral flow relying on their application in the field of recognition of DNA methylation in blood and body fluids. Also, the advantages and disadvantages of each test are reviewed. Finally, future prospects for the development of the microfluidics biodevices for the detection of DNA methylation is briefly discussed.

Advances in microfluidic in vitro systems for neurological disease modeling.

Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.

Microfluidic Point-of-Care Devices: New Trends and Future Prospects for eHealth Diagnostics.

Point-of-care (PoC) diagnostics is promising for early detection of a number of diseases, including cancer, diabetes, and cardiovascular diseases, in addition to serving for monitoring health conditions. To be efficient and cost-effective, portable PoC devices are made with microfluidic technologies, with which laboratory analysis can be made with small-volume samples. Recent years have witnessed considerable progress in this area with "epidermal electronics", including miniaturized wearable diagnosis devices. These wearable devices allow for continuous real-time transmission of biological data to the Internet for further processing and transformation into clinical knowledge. Other approaches include bluetooth and WiFi technology for data transmission from portable (non-wearable) diagnosis devices to cellphones or computers, and then to the Internet for communication with centralized healthcare structures. There are, however, considerable challenges to be faced before PoC devices become routine in the clinical practice. For instance, the implementation of this technology requires integration of detection components with other fluid regulatory elements at the microscale, where fluid-flow properties become increasingly controlled by viscous forces rather than inertial forces. Another challenge is to develop new materials for environmentally friendly, cheap, and portable microfluidic devices. In this review paper, we first revisit the progress made in the last few years and discuss trends and strategies for the fabrication of microfluidic devices. Then, we discuss the challenges in lab-on-a-chip biosensing devices, including colorimetric sensors coupled to smartphones, plasmonic sensors, and electronic tongues. The latter ones use statistical and big data analysis for proper classification. The increasing use of big data and artificial intelligence methods is then commented upon in the context of wearable and handled biosensing platforms for the Internet of things and futuristic healthcare systems.

Liquid Metal-Based Soft Microfluidics.

Motivated by the increasing demand of wearable and soft electronics, liquid metal (LM)-based microfluidics has been subjected to tremendous development in the past decade, especially in electronics, robotics, and related fields, due to the unique advantages of LMs that combines the conductivity and deformability all-in-one. LMs can be integrated as the core component into microfluidic systems in the form of either droplets/marbles or composites embedded by polymer materials with isotropic and anisotropic distribution. The LM microfluidic systems are found to have broad applications in deformable antennas, soft diodes, biomedical sensing chips, transient circuits, mechanically adaptive materials, etc. Herein, the recent progress in the development of LM-based microfluidics and their potential applications are summarized. The current challenges toward industrial applications and future research orientation of this field are also summarized and discussed.

Colloidal Crystals from Microfluidics.

Colloidal crystals are of great interest to researchers because of their excellent optical properties and broad applications in barcodes, sensors, displays, drug delivery, and other fields. Therefore, the preparation of high quality colloidal crystals in large quantities with high speed is worth investigating. After decades of development, microfluidics have been developed that provide new choices for many fields, especially for the generation of functional materials in microscale. Through the design of microfluidic chips, colloidal crystals can be prepared controllably with the advantages of fast speed and low cost. In this Review, research progress on colloidal crystals from microfluidics is discussed. After summarizing the classifications, the generation of colloidal crystals from microfluidics is discussed, including basic colloidal particles preparation, and their assembly inside or outside of microfluidic devices. Then, applications of the achieved colloidal crystals from microfluidics are illustrated. Finally, the future development and prospects of microfluidic-based colloidal crystals are summarized.

Pulsatile Flow in Microfluidic Systems.

This review describes the current knowledge and applications of pulsatile flow in microfluidic systems. Elements of fluid dynamics at low Reynolds number are first described in the context of pulsatile flow. Then the practical applications in microfluidic processes are presented: the methods to generate a pulsatile flow, the generation of emulsion droplets through harmonic flow rate perturbation, the applications in mixing and particle separation, and the benefits of pulsatile flow for clog mitigation. The second part of the review is devoted to pulsatile flow in biological applications. Pulsatile flows can be used for mimicking physiological systems, to alter or enhance cell cultures, and for bioassay automation. Pulsatile flows offer unique advantages over a steady flow, especially in microfluidic systems, but also require some new physical insights and more rigorous investigation to fully benefit future applications.

Microfluidic Single-Cell Omics Analysis.

The commonly existing cellular heterogeneity plays a critical role in biological processes such as embryonic development, cell differentiation, and disease progress. Single-cell omics-based heterogeneous studies have great significance for identifying different cell populations, discovering new cell types, revealing informative cell features, and uncovering significant interrelationships between cells. Recently, microfluidics has evolved to be a powerful technology for single-cell omics analysis due to its merits of throughput, sensitivity, and accuracy. Herein, the recent advances of microfluidic single-cell omics analysis, including different microfluidic platform designs, lysis strategies, and omics analysis techniques, are reviewed. Representative applications of microfluidic single-cell omics analysis in complex biological studies are then summarized. Finally, a few perspectives on the future challenges and development trends of microfluidic-assisted single-cell omics analysis are discussed.

Microfluidic Platforms toward Rational Material Fabrication for Biomedical Applications.

The emergence of micro/nanomaterials in recent decades has brought promising alternative approaches in various biomedicine-related fields such as pharmaceutics, diagnostics, and therapeutics. These micro/nanomaterials for specific biomedical applications shall possess tailored properties and functionalities that are closely correlated to their geometries, structures, and compositions, therefore placing extremely high demands for manufacturing techniques. Owing to the superior capabilities in manipulating fluids and droplets at microscale, microfluidics has offered robust and versatile platform technologies enabling rational design and fabrication of micro/nanomaterials with precisely controlled geometries, structures and compositions in high throughput manners, making them excellent candidates for a variety of biomedical applications. This review briefly summarizes the progress of microfluidics in the fabrication of various micro/nanomaterials ranging from 0D (particles), 1D (fibers) to 2D/3D (film and bulk materials) materials with controllable geometries, structures, and compositions. The applications of these microfluidic-based materials in the fields of diagnostics, drug delivery, organs-on-chips, tissue engineering, and stimuli-responsive biodevices are introduced. Finally, an outlook is discussed on the future direction of microfluidic platforms for generating materials with superior properties and on-demand functionalities. The integration of new materials and techniques with microfluidics will pave new avenues for preparing advanced micro/nanomaterials with enhanced performance for biomedical applications.

Microfluidic Generation of Nanomaterials for Biomedical Applications.

As nanomaterials (NMs) possess attractive physicochemical properties that are strongly related to their specific sizes and morphologies, they are becoming one of the most desirable components in the fields of drug delivery, biosensing, bioimaging, and tissue engineering. By choosing an appropriate methodology that allows for accurate control over the reaction conditions, not only can NMs with high quality and rapid production rate be generated, but also designing composite and efficient products for therapy and diagnosis in nanomedicine can be realized. Recent evidence implies that microfluidic technology offers a promising platform for the synthesis of NMs by easy manipulation of fluids in microscale channels. In this Review, a comprehensive set of developments in the field of microfluidics for generating two main classes of NMs, including nanoparticles and nanofibers, and their various potentials in biomedical applications are summarized. Furthermore, the major challenges in this area and opinions on its future developments are proposed.

Inner Surface Design of Functional Microchannels for Microscale Flow Control.

Fluidic flow behaviors in microfluidics are dominated by the interfaces created between the fluids and the inner surface walls of microchannels. Microchannel inner surface designs, including the surface chemical modification, and the construction of micro-/nanostructures, are good examples of manipulating those interfaces between liquids and surfaces through tuning the chemical and physical properties of the inner walls of the microchannel. Therefore, the microchannel inner surface design plays critical roles in regulating microflows to enhance the capabilities of microfluidic systems for various applications. Most recently, the rapid progresses in micro-/nanofabrication technologies and fundamental materials have also made it possible to integrate increasingly complex chemical and physical surface modification strategies with the preparation of microchannels in microfluidics. Besides, a wave of researches focusing on the ideas of using liquids as dynamic surface materials is identified, and the unique characteristics endowed with liquid-liquid interfaces have revealed that the interesting phenomena can extend the scope of interfacial interactions determining microflow behaviors. This review extensively discusses the microchannel inner surface designs for microflow control, especially evaluates them from the perspectives of the interfaces resulting from the inner surface designs. In addition, prospective opportunities for the development of surface designs of microchannels, and their applications are provided with the potential to attract scientific interest in areas related to the rapid development and applications of various microchannel systems.

Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor-On-A-Chip.

Cancer remains the leading cause of death worldwide despite the enormous efforts that are made in the development of cancer biology and anticancer therapeutic treatment. Furthermore, recent studies in oncology have focused on the complex cancer metastatic process as metastatic disease contributes to more than 90% of tumor-related death. In the metastatic process, isolation and analysis of circulating tumor cells (CTCs) play a vital role in diagnosis and prognosis of cancer patients at an early stage. To obtain relevant information on cancer metastasis and progression from CTCs, reliable approaches are required for CTC detection and isolation. Additionally, experimental platforms mimicking the tumor microenvironment in vitro give a better understanding of the metastatic microenvironment and antimetastatic drugs' screening. With the advancement of microfabrication and rapid prototyping, microfluidic techniques are now increasingly being exploited to study cancer metastasis as they allow precise control of fluids in small volume and rapid sample processing at relatively low cost and with high sensitivity. Recent advancements in microfluidic platforms utilized in various methods for CTCs' isolation and tumor models recapitulating the metastatic microenvironment (tumor-on-a-chip) are comprehensively reviewed. Future perspectives on microfluidics for cancer metastasis are proposed.

Microfluidics for Production of Particles: Mechanism, Methodology, and Applications.

In the past two decades, microfluidics-based particle production is widely applied for multiple biological usages. Compared to conventional bulk methods, microfluidic-assisted particle production shows significant advantages, such as narrower particle size distribution, higher reproducibility, improved encapsulation efficiency, and enhanced scaling-up potency. Herein, an overview of the recent progress of the microfluidics technology for nano-, microparticles or droplet fabrication, and their biological applications is provided. For both nano-, microparticles/droplets, the previously established mechanisms behind particle production via microfluidics and some typical examples during the past five years are discussed. The emerging interdisciplinary technologies based on microfluidics that have produced microparticles or droplets for cellular analysis and artificial cells fabrication are summarized. The potential drawbacks and future perspectives are also briefly discussed.

Bioinspired Engineering of Organ-on-Chip Devices.

The human body can be viewed as an organism consisting of a variety of cellular and non-cellular materials interacting in a highly ordered manner. Its complex and hierarchical nature inspires the multi-level recapitulation of the human body in order to gain insights into the inner workings of life. While traditional cell culture models have led to new insights into the cellular microenvironment and biological control in vivo, deeper understanding of biological systems and human pathophysiology requires the development of novel model systems that allow for analysis of complex internal and external interactions within the cellular microenvironment in a more relevant organ context. Engineering organ-on-chip systems offers an unprecedented opportunity to unravel the complex and hierarchical nature of human organs. In this chapter, we first highlight the advances in microfluidic platforms that enable engineering of the cellular microenvironment and the transition from cells-on-chips to organs-on-chips. Then, we introduce the key features of the emerging organs-on-chips and their proof-of-concept applications in biomedical research. We also discuss the challenges and future outlooks of this state-of-the-art technology.

[Development of microfluidic technology in reproductive researches].

Reproduction is one of the most basic characteristics of organisms, and the guarantee of the continuation and evolution of a species. As the country with world's largest population, China has been gradually increasing its investment in research on the reproductive system in recent years, particularly in the field of basic research. The rapid development and wide application of the microfluidic technology since its birth are sufficient to explain its application prospect. Currently, infertility and birth defects are major problems in the field of reproduction. Micro-reproductive technologies, including microfluidic and organs-on-chips, are formed through the combination of a wide range of basic science and bioengineering technologies. In reproductive research, microfluidic technology display several advantages:flexible design of the microchannel shape and size to better simulate the physiological environment, the low consumption of microfluidic chip, and highly integrated microfluidic technology. Microfluidic technology has been applied to various processes including sperm vitality evaluation and screening, sperm chemotaxis, cumulus oophorus cell removal, zona pellucida removal, ootid localization and screening, fertilization, early embryo culture and reproductive organ simulation. This paper introduces the recent progress in reproductive research based on microfluidic technology and its application prospects.

[Advances in microfluidic chip-based extracellular vesicle separation].

Extracellular vesicles (EVs) are hemispherical vesicles that have a lipid bilayer. Studies have shown that EVs have important biological functions. The amount, types, and compositional changes of proteins, lipids and ribonucleic acids are closely related to diseases. The separation and capture of EVs from the complicated body fluid samples is a prerequisite for medical research and liquid biopsy based on EVs. However, presently the majority of EVs separation and capture still use the traditional separation methods with low purity and low efficiency. Therefore, efficient and highly selective EVs separation method is in urgent need. To meet this challenge, advanced microfluidic chip technology, which has the advantages of miniaturization, integration, and automation, can be utilized. The development of EV separation technology combined with microfluidic chips has become the focus of research. This paper summarizes the latest research progress in this area.

Random-Reaction-Seed Method for Automated Identification of Neurite Elongation and Branching.

Conventional deterministic algorithms (i.e., skeletonization and edge-detection) lack robustness and sensitivity to reliably detect the neurite elongation and branching of low signal-to-noise-ratio microscopy images. Neurite outgrowth experiments produce an enormous number of images that require automated measurement; however, the tracking of neurites is easily lost in the automated process due to the intrinsic variability of neurites (either axon or dendrite) under stimuli. We have developed a stochastic random-reaction-seed (RRS) method to identify neurite elongation and branching accurately and automatically. The random-seeding algorithm of RRS is based on the hidden-Markov-model (HMM) to offer a robust enough way for tracing arbitrary neurite structures, while the reaction-seeding algorithm of RRS secures the efficiency of random seeding. It is noteworthy that RRS is capable of tracing a whole neurite branch by only one initial seed, so that RRS is proficient at quantifying extensive amounts of neurite outgrowth images with noisy background in microfluidic devices of biomedical engineering fields. The method also showed notable performance for reconstructing of net-like structures, and thus is expected to be proficient for biomedical feature extractions in a wide range of applications, such as retinal vessel segmentation and cell membrane profiling in spurious-edge-tissues.