Biopolymer Microparticles Prepared by Microfluidics for Biomedical Applications

Biopolymers are macromolecules that are derived from natural sources and have attractive properties for a plethora of biomedical applications due to their biocompatibility, biodegradability, low antigenicity, and high bioactivity. Microfluidics has emerged as a powerful approach for fabricating polymeric microparticles (MPs) with designed structures and compositions through precise manipulation of multiphasic flows at the microscale. The synergistic combination of materials chemistry afforded by biopolymers and precision provided by microfluidic capabilities make it possible to design engineered biopolymer‐based MPs with well‐defined physicochemical properties that are capable of enabling an efficient delivery of therapeutics, 3D culture of cells, and sensing of biomolecules. Here, an overview of microfluidic approaches is provided for the design and fabrication of functional MPs from three classes of biopolymers including polysaccharides, proteins, and microbial polymers, and their advances for biomedical applications are highlighted. An outlook into the future research on microfluidically‐produced biopolymer MPs for biomedical applications is also provided.     

Lipid Nanovesicles by Microfluidics: Manipulation,Synthesis, and Drug Delivery

Lipid nanovesicles, including endogenous exosomes and synthetic lipid nanoparticles, have shown great potential in disease diagnostics, drug delivery, and cancer biology. Naturally secreted nanovesicles are promising biomarkers for early detection of cancers in vitro. Synthetic nanovesicles serve as robust drug delivery systems with enhanced tumor targeting in vivo. Microfluidic platforms with features of excellent flow control and rapid mixing are exploited as versatile tools for studying lipid nanovesicles of small sizes and delicate structures. Here, an overview of microfluidics for precise manipulation and synthesis of lipid nanovesicles is provided. The mechanisms of isolation and detection of exosomes in microfluidics, as well as the clinical utility of exosomes for cancer diagnosis, are discussed. Several microfluidic designs for controlled assembly of a variety of lipid nanovesicles are highlighted. Opportunities and outstanding challenges of microfluidics‐based investigation of lipid nanovesicles are discussed.     

Lithographic Microneedle-Motors from Multimodal Microfluidics for Cargo Delivery

Micromotors have led to an unprecedented revolution in the field of cargo delivery. Attempts in this area trend toward enriching their structures and improving their functions to promote their further applications. Herein, novel microneedle-motors (MNMs) for active drug delivery through a flexible multimodal microfluidic lithographic approach are presented. The multimodal microfluidics is composed of a co-flow geometry-derived droplet fluid and an active cargo mixed laminar flow in a triangular microchannel. The MNMs with sharp tips and spherical fuel-loading cavities are obtained continuously from microfluidics with the assistance of flow lithography. The structural parameters of the MNMs could be precisely tailored by simply choosing the flow speed or the shape of the photomask. As the actives are mixed into the phase solution during the generation, the resultant MNMs are loaded with cargoes for direct applications without any extra complex operation. Based on these features, it is demonstrated that with sharp tips and autonomous movement, the MNMs can efficiently penetrate the tissue-like substrates, indicating the potential in overcoming physiological barriers for cargo release. These results indicate that the proposed multimodal microfluidic lithographic MNMs are valuable for practical active cargo delivery in biomedical and other relative areas.     

Group IV Nanoparticles: Synthesis,Properties, and Biological Applications

In this review, the emerging roles of group IV nanoparticles including silicon, diamond, silicon carbide, and germanium are summarized and discussed from the perspective of biologists, engineers, and medical practitioners. The synthesis, properties, and biological applications of these new nanomaterials have attracted great interest in the past few years. They have gradually evolved into promising biomaterials due to their innate biocompatibility; toxic ions are not released when they are used in vitro or in vivo, and their wide fluorescence spectral regions span the near‐infrared, visible, and near‐ultraviolet ranges. Additionally, they generally have good resistance against photobleaching and have lifetimes on the order of nanoseconds to microseconds, which are suitable for bioimaging. Some of the materials possess unique mechanical, chemical, or physical properties, such as ultrachemical and thermal stability, high hardness, high photostability, and no blinking. Recent data have revealed the superiority of these nanoparticles in biological imaging and drug delivery.     

Flow Focusing: a versatile technology to produce size-controlled and specific-morphology microparticles

The Flow Focusing platform is especially advantageous for micro- and nanoparticle production. This versatile technique is amenable to designing the size, surface treatment and internal topology of the particles; mechanical stresses are minimal-an optimal feature for the manipulation of delicate substances. Multiplexing and high-rate production are readily implemented. Adaptive operational design can lead, in one single step, to finely tuned microcapsules encasing different products within a targeted morphology. This achievement is of great significance for most microcapsule applications in the biosciences (for example, drug delivery, cell encapsulation, and the production of bead arrays).     

Preparation of Monodisperse Biodegradable Polymer Microparticles Using a Microfluidic Flow‐Focusing Device for Controlled Drug Delivery

Degradable microparticles have broad utility as vehicles for drug delivery and form the basis of several therapies approved by the US Food and Drug Administration. Conventional emulsion‐based methods of manufacturing produce particles with a wide range of diameters (and thus kinetics of release) in each batch. This paper describes the fabrication of monodisperse, drug‐loaded microparticles from biodegradable polymers using the microfluidic flow‐focusing (FF) devices and the drug‐delivery properties of those particles. Particles are engineered with defined sizes, ranging from 10 µm to 50 µm. These particles are nearly monodisperse (polydispersity index = 3.9%). A model amphiphilic drug (bupivacaine) is incorporated within the biodegradable matrix of the particles. Kinetic analysis shows that the release of the drug from these monodisperse particles is slower than that from conventional methods of the same average size but a broader distribution of sizes and, most importantly, exhibit a significantly lower initial burst than that observed with conventional particles. The difference in the initial kinetics of drug release is attributed to the uniform distribution of the drug inside the particles generated using the microfluidic methods. These results demonstrate the utility of microfluidic FF for the generation of homogenous systems of particles for the delivery of drugs.     

Microfluidics for Cancer Nanomedicine: From Fabrication to Evaluation

Self‐assembled drug delivery systems (sDDSs), made from nanocarriers and drugs, are one of the major types of nanomedicines, many of which are in clinical use, under preclinical investigation, or in clinical trials. One of the hurdles of this type of nanomedicine in real applications is the inherent complexity of their fabrication processes, which generally lack precise control over the sDDS structures and the batch‐to‐batch reproducibility. Furthermore, the classic 2D in vitro cell model, monolayer cell culture, has been used to evaluate sDDSs. However, 2D cell culture cannot adequately replicate in vivo tissue‐level structures and their highly complex dynamic 3D environments, nor can it simulate their functions. Thus, evaluations using 2D cell culture often cannot correctly correlate with sDDS behaviors and effects in humans. Microfluidic technology offers novel solutions to overcome these problems and facilitates studying the structure–performance relationships for sDDS developments. In this Review, recent advances in microfluidics for 1) fabrication of sDDSs with well‐defined physicochemical properties, such as size, shape, rigidity, and drug‐loading efficiency, and 2) fabrication of 3D‐cell cultures as “tissue/organ‐on‐a‐chip” platforms for evaluations of sDDS biological performance are in focus.     

Injectable Granular Hydrogels with Multifunctional Properties for Biomedical Applications

Injectable hydrogels are useful for numerous biomedical applications, such as to introduce therapeutics into tissues or for 3D printing. To expand the complexity of available injectable hydrogels, shear‐thinning and self‐healing granular hydrogels are developed from microgels that interact via guest–host chemistry. The microgel properties (e.g., degradation, molecule release) are tailored through their crosslinking chemistry, including degradation in response to proteases. When microgels of varied formulations are mixed, complex release and degradation behaviors are observed, including after injection to permit cellular invasion.     

液体弹珠的微流体操作及工程应用

微流体技术是一种精确操控和检测微量流体的新兴技术,广泛应用于生物、化学、材料等领域的实验及工程中.液体弹珠作为一种新兴的数字微流体平台在近几年快速发展.它是一种将疏水的微纳米级颗粒包裹在液滴表面形成的软物质,体积通常在几微升到几百微升之间.区别于构建特殊表面微结构或化学改性制备的超疏水表面,液体弹珠是通过颗粒层阻隔内部液体与载体的微观接触,构建类似于莱顿弗罗斯特液滴的结构来实现微量液体在固体或液体表面不润湿且稳定存在的目的.目前的研究已经证明液体弹珠拥有独特优越的物理性能,如液体弹珠表面的颗粒层将固-液接触转化为固-固和固-气接触,因此具有不粘的特性,与载体表面的摩擦很小,在很小的外力作用下就可以实现灵活移动且不污染弹珠内的液体和载体.当表面颗粒呈多层且致密分布时也并非完全阻隔外界环境,在很大程度上能够减缓内部液体的蒸发且具有良好的气体渗透性,而且液体弹珠具有较好的稳固性,往往能够承受30％的可逆线性弹性形变,这些性能使液体弹珠可以作为理想的数字微流体平台.液体弹珠的原材料十分丰富,从而决定了其性状具有灵活的可调控性,所用颗粒的疏水性和形状会直接影响液体弹珠的力学性能,例如棒状颗粒包裹的液体弹珠具有更大的刚度,链状颗粒包裹的液体弹珠具有优越的弹性性能.颗粒的化学性质可以按需赋予液体弹珠不同的响应特性,从而衍生出多种操控手段,主要方式包括静电力、磁力、自推进、光辐射、温度、超声等,完成液体弹珠的精确移动、定位、颗粒层开启和关闭以及释放内部液体的操作.以上特性使液体弹珠能够应用于各种工程中,在细胞组织和微生物的培养以及微型化学反应器方面具有很好的应用前景,同时还被广泛应用于传感器、制药和精密仪器等领域,例如光电传感、污水检测、微型胶囊制备、构建纳米复合透镜以及精准电化学沉积等.同时液体弹珠制备方法较简单,无需复杂仪器设备,具有很高的经济效益.本文结合近年来液体弹珠相关研究的发展现状介绍了液体弹珠的制备方法、结构特点、材料和不同于纯液滴的性质主要包括有效表面张力、力学稳定性和蒸发速率,归纳了几种主流操作控制液体弹珠移动和释放的手段并分析优势与不足,总结了目前液体弹珠在工程上的主要应用并对其未来的发展趋势和应用前景进行展望.     

Cellular Association and Assembly of a Multistage Delivery System

The realization that blood‐borne delivery systems must overcome a multiplicity of biological barriers has led to the fabrication of a multistage delivery system (MDS) designed to temporally release successive stages of particles or agents to conquer sequential barriers, with the goal of enhancing delivery of therapeutic and diagnostic agents to the target site. In its simplest form, the MDS comprises stage‐one porous silicon microparticles that function as carriers of second‐stage nanoparticles. Cellular uptake of nontargeted discoidal silicon microparticles by macrophages is confirmed by electron and atomic force microscopy (AFM). Using superparamagnetic iron oxide nanoparticles (SPIONs) as a model of secondary nanoparticles, successful loading of the porous matrix of silicon microparticles is achieved, and retention of the nanoparticles is enhanced by aminosilylation of the loaded microparticles with 3‐aminopropyltriethoxysilane. The impact of silane concentration and reaction time on the nature of the silane polymer on porous silicon is investigated by AFM and X‐ray photoelectron microscopy. Tissue samples from mice intravenously administered the MDS support co‐localization of silicon microparticles and SPIONs across various tissues with enhanced SPION release in spleen, compared to liver and lungs, and enhanced retention of SPIONs following silane capping of the MDS. Phantom models of the SPION‐loaded MDS display negative contrast in magnetic resonance images. In addition to forming a cap over the silicon pores, the silane polymer provides free amines for antibody conjugation to the microparticles, with both VEGFR‐2‐ and PECAM‐specific antibodies leading to enhanced endothelial association. This study demonstrates the assembly and cellular association of a multiparticle delivery system that is biomolecularly targeted and has potential for applications in biological imaging.     

Applications of Nanoparticles in Biology

The wide variety of core materials available, coupled with tunable surface properties, make nanoparticles an excellent platform for a broad range of biological and biomedical applications. This Review provides an introduction to nanoparticle–biomolecular interactions as well as recent applications of nanoparticles in biological sensing, delivery, and imaging of live cells and tissues.

     

Multiphase Microfluidics: Fundamentals,Fabrication, and Functions

Multiphase microfluidics enables an alternative approach with many possibilities in studying, analyzing, and manufacturing functional materials due to its numerous benefits over macroscale methods, such as its ultimate controllability, stability, heat and mass transfer capacity, etc. In addition to its immense potential in biomedical applications, multiphase microfluidics also offers new opportunities in various industrial practices including extraction, catalysis loading, and fabrication of ultralight materials. Herein, aiming to give preliminary guidance for researchers from different backgrounds, a comprehensive overview of the formation mechanism, fabrication methods, and emerging applications of multiphase microfluidics using different systems is provided. Finally, major challenges facing the field are illustrated while discussing potential prospects for future work.     

Microfluidic Assisted Synthesis of Multipurpose Polymer Nanoassembly Particles for Fluorescence,LSPR, and SERS Activities

Potential biomedical applications such as controlled delivery with sustained drug release profile demand for multifunctional polymeric particles of precise chemical composition and with welldefined physicochemical properties. The real challenge is to obtain the reproducible and homogeneous nanoparticles in a minimum number of preparation steps. Here, single‐step nanoarchitectures of soft surface layered copolymer nanoparticles with a regular tuning in the size via micro flow‐through assisted synthesis are reported. Interfacial copolymerization induces the controlled compartmentalization where a hydrophobic core adopts spherical shape in order to minimize the surface energy and simultaneously shelter in the hydrophilic shelllike surface layer. Surface layer can swell in the aqueous medium and allow controlled entrapping of functional hydrophobic nanoparticles in the hydrophilic interior via electrostatic interaction which can be particularly interesting for combined fluorescence activity. Furthermore, the nanoarchitecture of size and concentration controlled polymer–metal nanoassembly particles can be implemented as an ideal surface‐enhanced Raman scattering substrate for detection of the trace amounts of various analytes.