One-pot synthesis of dual-stimuli responsive hybrid PNIPAAm-chitosan microgels

The incorporation of magnetic nanoparticles into poly(N-isopropylacrylamide) (PNIPAAm) and chitosan microgels gives rise to hybrid systems that combine the microgels swelling capacity with the interesting features presented in magnetic nanoparticles. The presence of chitosan that act as surfactant for magnetic nanoparticles provides a simplistic approach which allows the encapsulation of magnetic nanoparticles without any previous surface modification. Spherical and highly monodisperse microgels with diameters in the range of 200 to 500 nm were obtained. The encapsulation of magnetic nanoparticles in the polymer matrix was confirmed by high resolution Scanning Electron Microscopy in transmission mode. Volume phase transition of the microgels was accessed by Dynamic Light Scattering measurements. It was observed that the thermosensitivity of the PNIPAM microgels still persists in the hybrid microgels; however, the swelling ability is compromised in the microgels with highest chitosan content. The heating performance of the hybrid magnetic microgels, when submitted to an alternating magnetic field, was also evaluated demonstrating the potential of these systems for hyperthermia treatments.     

Microfluidic Templated Multicompartment Microgels for 3D Encapsulation and Pairing of Single Cells

Controlled encapsulation and pairing of single cells within a confined 3D matrix can enable the replication of the highly ordered cellular structure of human tissues. Microgels with independently controlled compartments that can encapsulate cells within separately confined hydrogel matrices would provide precise control over the route of pairing single cells. Here, a one‐step microfluidic method is presented to generate monodisperse multicompartment microgels that can be used as a 3D matrix to pair single cells in a highly biocompatible manner. A method is presented to induce microgels formation on chip, followed by direct extraction of the microgels from oil phase, thereby avoiding prolonged exposure of the microgels to the oil. It is further demonstrated that by entrapping stem cells with niche cells within separate but adjacent compartments of the microgels, it can create complex stem cell niche microenvironments in a controlled manner, which can serve as a useful tool for the study of cell–cell interactions. This microfluidic technique represents a significant step toward high‐throughput single cells encapsulation and pairing for the study of intercellular communications at single cell level, which is of significant importance for cell biology, stem cell therapy, and tissue engineering.     

Cell Encapsulation in Soft,Anisometric Poly(ethylene) Glycol Microgels Using a Novel Radical‐Free Microfluidic System

Complex 3D artificial tissue constructs are extensively investigated for tissue regeneration. Frequently, materials and cells are delivered separately without benefitting from the synergistic effect of combined administration. Cell delivery inside a material construct provides the cells with a supportive environment by presenting biochemical, mechanical, and structural signals to direct cell behavior. Conversely, the cell/material interaction is poorly understood at the micron scale and new systems are required to investigate the effect of micron‐scale features on cell functionality. Consequently, cells are encapsulated in microgels to avoid diffusion limitations of nutrients and waste and facilitate analysis techniques of single or collective cells. However, up to now, the production of soft cell‐loaded microgels by microfluidics is limited to spherical microgels. Here, a novel method is presented to produce monodisperse, anisometric poly(ethylene) glycol microgels to study cells inside an anisometric architecture. These microgels can potentially direct cell growth and can be injected as rod‐shaped mini‐tissues that further assemble into organized macroscopic and macroporous structures post‐injection. Their aspect ratios are adjusted with flow parameters, while mechanical and biochemical properties are altered by modifying the precursors. Encapsulated primary fibroblasts are viable and spread and migrate across the 3D microgel structure.     

Ultrastrong Anchoring Yet Barrier‐Free Adsorption of Composite Microgels at Liquid Interfaces

Microgel particles display an interesting duality with properties attributed typically both to polymeric and colloidal systems. When adsorbed at a liquid‐liquid interface, this duality becomes particularly apparent as the various phenomena at play are governed by different aspects of these soft and responsive particles. The introduction of a solid, fluorescently labeled, polystyrene core into the microgels allows direct and accurate visualization without the necessity of potential perturbing sample preparation techniques. By combining in‐situ imaging and tensiometry, we determine that composite microgels at a wide variety of oil‐water interfaces anchor strongly, with adsorption energies of approximately 10⁶ k_BT, typical for particle adsorption, yet accumulate at the interface spontaneously without any energy barrier, which is more typical for polymers. The high adsorption energies allow the particle to spontaneously form very dense crystalline packings at the liquid interface in which the microgels are significantly compressed with respect to their swollen state in bulk solutions. Finally, we demonstrate the unique nature of these particles by producing highly stable and monodisperse microgel‐stabilized droplets using microfluidics.     

Uniform Microgels Containing Agglomerates of Silver Nanocubes for Molecular Size‐Selectivity and High SERS Activity

Surface‐enhanced Raman scattering (SERS) is a promising technique for molecular analysis as the molecular fingerprints (Raman spectra) are amplified to detectable levels compared with common spectroscopy. Metal nanostructures localize electromagnetic field on their surfaces, which can lead to dramatic increase of Raman intensity of molecules adsorbed. However, the metal surfaces are prone to contamination, thereby requiring pretreatment of samples to remove adhesive molecules. To avoid the pretreatment and potentially achieve point‐of‐care (POC) analysis, we have developed SERS‐active microgels using the droplet‐microfluidic system. As the microgels are composed of water‐swollen network with consistent mesh size, they selectively allow diffusion of molecules smaller than the mesh, thereby excluding large adhesives. To render the microgels highly SERS‐active, we destabilize silver nanocubes to form agglomerates, which are embedded in the matrix of microgels. The nanogaps in the agglomerates provide high sensitivity in Raman measurement and size‐selective permeability of the microgel matrix obviates the pretreatment of samples. To validate the functions, we demonstrate the direct detection of Aspirin dissolved in whole blood without any pretreatment.     

Compartmentalized Jet Polymerization as a High‐Resolution Process to Continuously Produce Anisometric Microgel Rods with Adjustable Size and Stiffness

In the past decade, anisometric rod‐shaped microgels have attracted growing interest in the materials‐design and tissue‐engineering communities. Rod‐shaped microgels exhibit outstanding potential as versatile building blocks for 3D hydrogels, where they introduce macroscopic anisometry, porosity, or functionality for structural guidance in biomaterials. Various fabrication methods have been established to produce such shape‐controlled elements. However, continuous high‐throughput production of rod‐shaped microgels with simultaneous control over stiffness, size, and aspect ratio still presents a major challenge. A novel microfluidic setup is presented for the continuous production of rod‐shaped microgels from microfluidic plug flow and jets. This system overcomes the current limitations of established production methods for rod‐shaped microgels. Here, an on‐chip gelation setup enables fabrication of soft microgel rods with high aspect ratios, tunable stiffness, and diameters significantly smaller than the channel diameter. This is realized by exposing jets of a microgel precursor to a high intensity light source, operated at specific pulse sequences and frequencies to induce ultra‐fast photopolymerization, while a change in flow rates or pulse duration enables variation of the aspect ratio. The microgels can assemble into 3D structures and function as support for cell culture and tissue engineering.     

Gelothermal Synthesis of Monodisperse MIL-88A Nanoparticles with Tunable Sizes and Metal Centers for Potential Bioapplications

Developing novel synthetic strategies to downsize metal-organic frameworks (MOFs) from polydisperse crystals to monodisperse nanoparticles is of great importance for their potential bioapplications. In this work, a novel synthetic strategy termed gelothermal synthesis is proposed, in which coordination polymer gel is first prepared and followed by a thermal reaction to give the monodisperse MOF nanoparticles. This novel synthetic strategy successfully leads to the isolation of Materials of Institute Lavoisier (MIL-88), Cu(II)-fumarate MOFs (CufumDMF), and Zeolitic Imidazolate Frameworks (ZIF-8) nanoparticles. Focused on MIL-88A, the studies reveal that the size can be well-tuned from nanoscale to microscale without significant changes in polydispersity index (PDI) even in the case of in situ metal substitution. A possible mechanism is consequently proposed based on extensive studies on the gelothermal condition including sol-gel chemistry, thermal condition, kinds of solvents, and so on. The unique advantages of monodisperse MIL-88A nanoparticles over polydisperse ones are further demonstrated in terms of in vitro magnetic resonance imaging (MRI), cellular uptake, and drug-carrying properties.     

《二氧化硅孔材料的模板合成》化学综合实验的建设

化学综合实验"二氧化硅孔材料的模板合成"是为大学化学专业本科生开设的一个实验教学课程。其实验的主要内容是,首先合成制备单分散的聚苯乙烯乳胶粒子,然后以此单分散的聚苯乙烯乳胶粒子为初始材料,利用胶体晶模板法制备二氧化硅三维有序孔材料。利用透射电子显微镜和扫描电子显微镜对所制备的各级样品进行表征。教学实践发现,当作为初始材料的聚苯乙烯乳胶粒子尺寸较大时,三维有序孔材料的制备成功率高。文中介绍了此实验的建立以及对其进行改进的过程。     

Dual‐Functional Alginic Acid Hybrid Nanospheres for Cell Imaging and Drug Delivery

An effective and facile approach to prepare gold‐nanoparticle‐encapsulated alginic acid‐poly[2‐(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG–PDEA–Au) is developed by using monodisperse ALG–PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle‐interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG–PDEA–Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG–PDEA–Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical‐contrast reagents in tumor‐cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti‐cancer drug doxorubicin. In vitro cell viability tests reveal that drug‐loaded ALG–PDEA–Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical‐related areas.     

Creation of Faceted Polyhedral Microgels from Compressed Emulsions

Compressed monodisperse emulsions in confined space exhibit highly ordered structures. The influence of the volume fraction and the confinement geometry on the organized structures is investigated and the mechanism by which structural transition occurs is studied. Based on the understanding of ordering behavior of compressed emulsions, a simple and high‐throughput method to fabricate monodisperse polyhedral microgels using the emulsions as the template is developed. By controlling the geometry of the confined spaces, a variety of shapes such as hexagonal prism, Fejes Toth honeycomb prism, truncated octahedron, pyritohedron, and truncated hexagonal trapezohedron are implemented. Moreover, the edge sharpness of each shape is controllable by adjusting the drop volume fraction. This design principle can be readily extended to other shapes and materials, and therefore provides a useful means to create polyhedral microparticles for both fundamental study and practical applications.     

Template synthesis of highly crystalline and monodisperse iron oxide pigments of nanosize

Synthesis of highly crystalline and monodisperse iron oxide nanoparticles is reported. The separation of Fe centers through site-specific binding to a polysaccharide–alginate matrix enables the generation of particles with a monodisperse or narrow size distribution character, resulting in transparent pigments. Site-specific interactions coupled with gel like character of alginate is proposed as the mechanism behind generation of lower particle sizes. Alginate-Fe complexes developed were subjected to heat treatment to provide for crystalline character and development of hematite (α-Fe₂O₃). Conditions most ideal for achieving monodispersity and lower sizes have been optimized and confirmed through microscopic and photon correlation spectroscopic measurements.     

Self‐Healing Zwitterionic Microgels as a Versatile Platform for Malleable Cell Constructs and Injectable Therapies

Injectable and malleable hydrogels that combine excellent biocompatibility, physiological stability, and ease of use are highly desirable for biomedical applications. Here, a simple and scalable strategy is reported to make injectable and malleable zwitterionic polycarboxybetaine hydrogels, which are superhydrophilic, nonimmunogenic, and completely devoid of nonspecific interactions. When zwitterionic microgels are reconstructed, the combination of covalent crosslinking inside each microgel and supramolecular interactions between them gives the resulting zwitterionic injectable pellet (ZIP) constructs supportive moduli and tunable viscoelasticity. ZIP constructs can be lyophilized to a sterile powder that fully recovers its strength and elasticity upon rehydration, simplifying storage and formulation. The lyophilized powder can be reconstituted with any aqueous suspension of cells or therapeutics, and rapidly and spontaneously self‐heals into a homogeneous composite construct. This versatile and highly biocompatible platform material shows great promise for many applications, including as an injectable cell culture scaffold that promotes multipotent stem cell expansion and provides oxidative stress protection.     

Properties and drug release profile of poly(N-isopropylacrylamide) microgels functionalized with maleic anhydride and alginate

This study highlights the advantages of functionalized poly(N-isopropylacrylamide) (PNIPAAm) microgels over pure PNIPAAm microgels in terms of polymer network properties and drug release profiles. PNIPAAm network was modified by addition of maleic anhydride (MA) as a comonomer and by formation of interpenetrating polymer network in the presence of alginate. The functionalized thermosensitive microgels in the size range from 20 to 80 μm and with better performance in comparison with pure PNIPAAm microgels were prepared by inverse suspension polymerization. The impact of MA and alginate on the PNIPAAm microgel structure was evaluated through analysis of microgel size, size distribution, volume phase transition temperature (VPTT), equilibrium swelling ratio as well as morphology of the system. It was shown that the controlled modification of PNIPAAm network could result in microgels of considerably improved swelling capacity with unchanged thermosensitivity and maintained open pore morphology. In addition, drug release behavior of microgels could be markedly altered. Release of procaine hydrochloride from the selected microgels was studied using Franz diffusion cell at temperatures below and above VPTT of the microgels. Temperature-controlled drug release pattern was dependent on the type of functionalization of PNIPAAm network. According to drug loading properties and drug release mechanism, PNIPAAm/MA copolymer microgels demonstrated the optimal performances.     

Use of a trapping agent for simultaneous capturing and high-throughput screening of both "soft" and "hard" reactive metabolites

Glutathione (GSH) has been widely used for in vitro trapping and subsequently detecting reactive metabolites using liquid chromatography-mass spectrometry. A major drawback of GSH is its low trapping efficiency for "hard" reactive metabolites such as reactive aldehydes. In the present study, a bifunctional trapping agent (gamma GSK, gamma-glutamylcysteinlysine) is investigated as an alternative of GSH for simultaneous trapping both "hard" and "soft" reactive metabolites. In microsomal incubations, soft and hard reactive metabolites are captured by conjugation to the free thiol and the amine group of gamma GSK, respectively, resulting in formation of stable peptide adducts. Similar to GSH conjugates, all gamma GSK adducts derived from both soft and hard reactive metabolites contain a gamma-glutamyl moiety and, thus, undergo a neutral loss of 129 Da under collision-induced dissociation. As a result, an NL MS/MS scan can be utilized as a generic method for rapid detecting of both hard or soft reactive metabolites. As demonstrated by a number of model compounds, this approach, in combination with the isotope trapping technique, is reliable, sensitive, and efficient and can be potentially utilized as a high-throughput method for screening and rapid identification of both soft and hard reactive metabolites. In comparison with other methods, this approach is highly efficient and suitable in drug discovery for screening a wide variety of compounds for different reactive metabolites.     

Size-controlled model Co nanoparticle catalysts for CO₂ hydrogenation: synthesis, characterization, and catalytic reactions

Model cobalt catalysts for CO(2) hydrogenation were prepared using colloidal chemistry. The turnover frequency at 6 bar and at 200-300 °C increased with cobalt nanoparticle size from 3 to 10 nm. It was demonstrated that near monodisperse nanoparticles in the size range of 3-10 nm could be generated without using trioctylphosphine oxide, a capping ligand that we demonstrate results in phosphorus being present on the metal surface and poisoning catalyst activity in our application.     

Preparation and characterization of thermo-, pH-, and magnetic-field-responsive organic/inorganic hybrid microgels based on poly(ethylene glycol)

Nanocomposite microgels are a new class of intelligent materials because of their fast response time, large surface area, and so on. In this study, we demonstrate a new kind of multiple stimulus-responsive organic/inorganic hybrid microgels by combining dual stimuli-responsive poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol)methacrylate-co-acrylic acid) (PMOA) microgels with magnetic attapulgite/Fe₃O₄ (AT–Fe₃O₄) nanoparticles. AT–Fe₃O₄ nanoparticles were introduced into the dual-responsive (temperature and pH) PMOA microgels network by in situ polymerization. The responsive behaviors, microstructures, and the interaction between AT–Fe₃O₄ and PMOA microgels matrix of the prepared microgels were systematically characterized using field emission scanning electron microscopy, particle size and Zeta potential analyzer, vibrating sample magnetometer, and Fourier transform infrared spectroscopy. The results showed that the AT–Fe₃O₄ nanoparticles dispersed well in the microgel matrix, and the nanoparticles could be stably present in PMOA without phase separation because of the hydrogen bond (H-bond) interactions between AT–Fe₃O₄ nanoparticles and PMOA matrix. In addition, the multifunctional AT–Fe₃O₄/PMOA nanocomposite microgels had both temperature/pH sensitivity and magnetic functionality.     

Au@pNIPAM SERRS Tags for Multiplex Immunophenotyping Cellular Receptors and Imaging Tumor Cells

Detection technologies employing optically encoded particles have gained much interest toward clinical diagnostics and drug discovery, but the portfolio of available systems is still limited. The fabrication and characterization of highly stable surface‐enhanced resonance Raman scattering (SERRS)‐encoded colloids for the identification and imaging of proteins expressed in cells are reported. These plasmonic nanostructures are made of gold octahedra coated with poly(N‐isopropylacrylamide) microgels and can be readily encoded with Raman active dyes while retaining high colloidal stability in biofluids. A layer‐by‐layer polyelectrolyte coating is used to seal the outer surface of the encoded particles and to provide a reactive surface for covalent conjugation with antibodies. The targeted multiplexing capabilities of the SERRS tags are demonstrated by the simultaneous detection and imaging of three tumor‐associated surface biomarkers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), and homing cell adhesion molecule (CD44) by SERRS spectroscopy. The plasmonic microgels are able to discriminate tumor A431 (EGFR+/EpCAM+/CD44+) and nontumor 3T3 2.2 (EGFR?/EpCAM?/CD44+) cells while cocultured in vitro.     

Monodisperse, Submicrometer Droplets via Condensation of Microfluidic-Generated Gas Bubbles

Microfluidics (MFs) can produce monodisperse droplets with precise size control. However, the synthesis of monodisperse droplets much smaller than the minimum feature size of the microfluidic device (MFD) remains challenging, thus limiting the production of submicrometer droplets. To overcome the minimum micrometer-scale droplet sizes that can be generated using typical MFDs, the droplet material is heated above its boiling point (bp), and then MFs is used to produce monodisperse micrometer-scale bubbles (MBs) that are easily formed in the size regime where standard MFDs have excellent size control. After MBs are formed, they are cooled, condensing into dramatically smaller droplets that are beyond the size limit achievable using the original MFD, with a size decrease corresponding to the density difference between the gas and liquid phases of the droplet material. Herein, it is shown experimentally that monodisperse, submicrometer droplets of predictable sizes can be condensed from a monodisperse population of MBs as generated by MFs. Using perfluoropentane (PFP) as a representative solvent due to its low bp (29.2 °C), it is demonstrated that monodisperse PFP MBs can be produced at MFD temperatures >3.6 °C above the bp of PFP over a wide range of sizes (i.e., diameters from 2 to 200 μm). Independent of initial size, the generated MBs shrink rapidly in size from about 3 to 0 °C above the bp of PFP, corresponding to a phase change from gas to liquid, after which they shrink more slowly to form fully condensed droplets with diameters 5.0 ± 0.1 times smaller than the initial size of the MBs, even in the submicrometer size regime. This new method is versatile and flexible, and may be applied to any type of low-bp solvent for the manufacture of different submicrometer droplets for which precisely controlled dimensions are required.     

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.     

Graphene Quantum Dots‐Capped Magnetic Mesoporous Silica Nanoparticles as a Multifunctional Platform for Controlled Drug Delivery,Magnetic Hyperthermia,and Photothermal Therapy

A multifunctional platform is reported for synergistic therapy with controlled drug release, magnetic hyperthermia, and photothermal therapy, which is composed of graphene quantum dots (GQDs) as caps and local photothermal generators and magnetic mesoporous silica nanoparticles (MMSN) as drug carriers and magnetic thermoseeds. The structure, drug release behavior, magnetic hyperthermia capacity, photothermal effect, and synergistic therapeutic efficiency of the MMSN/GQDs nanoparticles are investigated. The results show that monodisperse MMSN/GQDs nanoparticles with the particle size of 100 nm can load doxorubicin (DOX) and trigger DOX release by low pH environment. Furthermore, the MMSN/GQDs nanoparticles can efficiently generate heat to the hyperthermia temperature under an alternating magnetic field or by near infrared irradiation. More importantly, breast cancer 4T1 cells as a model cellular system, the results indicate that compared with chemotherapy, magnetic hyperthermia or photothermal therapy alone, the combined chemo‐magnetic hyperthermia therapy or chemo‐photothermal therapy with the DOX‐loaded MMSN/GQDs nanosystem exhibits a significant synergistic effect, resulting in a higher efficacy to kill cancer cells. Therefore, the MMSN/GQDs multifunctional platform has great potential in cancer therapy for enhancing the therapeutic efficiency.