Hydrogel Shell Research Articles

Flexible fluorescent metal-organic frameworks towards highly stable optical fibers and biocompatible cell platforms

Fluorescent metal-organic frameworks (FMOFs) have emerged as promising materials for optoelectronic and biological applications. However, their widespread use in these areas is limited due to some major drawbacks. First, it is difficult to construct flexible free-standing platforms with FMOF crystals. Moreover, these materials exhibit a low optical stability against external stimuli, and frequently, the metal ions used for their synthesis are toxic. Herein, a coaxial microfluidic spinning approach is developed to continuously generate core-shell FMOF-based microfibers in a one-step and large-scale fashion. The free-standing FMOF-based microfibers obtained showcase a high tensile strength of 85.6 MPa, the highest tensile strength reported for polymer@MOF-based composites. Moreover, it is also demonstrated that the cross-linked hydrogel shell generated with our microfluidic approach can effectively improve the optical stability of the FMOF crystals located at the core of the microfibers against a solution containing chemical species that can damage the FMOF crystals (e.g., a metal ion), acid and/or alkali treatments as well as heat. Most importantly, the FMOF-based microfibers exhibit high cell viability (ca. 96.6%) and versatile extracellular fluorescence imaging capabilities owing to both the biocompatibility of the hydrogel shell and the intrinsic fluorescence of the micofibers core. Accordingly, the herein reported flexible FMOF-based microfibers provide an advanced platform to design new concepts and material assemblies for optical and biomedical applications.

Conductance-stable and integrated helical fiber electrodes toward stretchy energy storage and self-powered sensing utilization

Highly conductive and stretchable fibers are of great significance for wearable applications. Practical applications usually require high robustness and repeatability for these electronics under various mechanical deformations, which is a contradiction for most of existing strain-sensitive fibers conductors. In this work, core–shell hydrogel fiber with adjustable three-dimensional (3D) helical structure was fabricated, in which Ti3C2Tx (MXene)/poly(3,4-ethylenedioxythiophene) (PEDOT) were modified onto the surface of helical sodium alginate/polyacrylic acid (SA/PAA) hydrogel fibers via the combination of in situ polymerization and electrostatic assembly. The hybrid fiber possess a insensitive conductance (<5% resistance change) under various deformation, including stretching (0–800 %), bending (0-180°), pressuring and twisting, attributed to both the double tortuous conductive network and pre-strain release from helical structure. Moreover, conductance-stable helical fibers could be appropriately assembled into coaxial energy fibers and integrated into fabric, both acting as strain-insensitive energy storage device and self-powered wearable sensor.

Cell Dome as an Evaluation Platform for Organized HepG2 Cells.

Human-hepatoblastoma-derived cell line, HepG2, has been widely used in liver and liver cancer studies. HepG2 spheroids produced in a three-dimensional (3D) culture system provide a better biological model than cells cultured in a two-dimensional (2D) culture system. Since cells at the center of spheroids exhibit specific behaviors attributed to hypoxic conditions, a 3D cell culture system that allows the observation of such cells using conventional optical or fluorescence microscopes would be useful. In this study, HepG2 cells were cultured in "Cell Dome", a micro-dome in which cells are enclosed in a cavity consisting of a hemispherical hydrogel shell. HepG2 cells formed hemispherical cell aggregates which filled the cavity of Cell Domes on 18 days of culture and the cells could continue to be cultured for 29 days. The cells at the center of hemispherical cell aggregates were observed using a fluorescence microscope. The cells grew in Cell Domes for 18 days exhibited higher Pi-class Glutathione S-Transferase enzymatic activity, hypoxia inducible factor-1α gene expression, and higher tolerance to mitomycin C than those cultured in 2D on tissue culture dishes (* p &lt; 0.05). These results indicate that the center of the glass adhesive surface of hemispherical cell aggregates which is expected to have the similar environment as the center of the spheroids can be directly observed through glass plates. In conclusion, Cell Dome would be useful as an evaluation platform for organized HepG2 cells.

Microfluidic Construction of Responsive Photonic Microcapsules of Cholesteric Liquid Crystal for Colorimetric Temperature Microsensors

AbstractAs alternatives to electronic devices, optically active structures from responsive nanomaterials offer great opportunity for building up smart functional sensors. This work reports on the construction and application of photonic microcapsules (PMCs) for colorimetric temperature microsensors, enabling miniaturization for injectable local micro‐area sensing and integration for large‐area sensing. Monodispersed PMCs are produced by in situ photopolymerization of hydrogel shells of cholesteric liquid crystal (CLC)‐in‐water‐in‐oil double emulsion droplets prepared using microfluidic devices, with controllable physical structures and chemical compositions. Constructed PMCs exhibit thermal responsive structural color according to the selective Bragg reflection of CLC's periodical helical structures within the microdroplet's spherical confinement. CLC mixtures with phase transition temperature of 56.0 and 37.8 °C have been prepared and employed to construct PMCs exhibiting obviously visible and quantifiable optical response in 52–56 and 33–38 °C, respectively. The PMCs have been successfully applied for monitoring the living cell extracellular temperature via co‐incubation with cell suspension, and for sensing human forehead temperature via a flexible device from assembled PMCs. These PMCs can be flexibly applied in either micro‐environment or large‐area surface, enabling wide applications for a precision temperature monitoring of biological activities (e.g., cells or organs), optoelectronic devices working conditions (e.g., temperature indicators under extreme conditions), etc.

Perfusable cell-laden micropatterned hydrogels for delivery of spatiotemporal vascular-like cues to tissues.

The integration of vasculature at physiological scales within 3D cultures of cell-laden hydrogels for the delivery of spatiotemporal mass transport, chemical and mechanical cues, is a stepping-stone towards building in vitro tissue models that recapitulate in vivo cues. To address this challenge, we present a versatile method to micropattern adjoining hydrogel shells with a perfusable channel or lumen core, for enabling facile integration with fluidic control systems, on one hand, and to cell-laden biomaterial interfaces, on the other hand. This microfluidic imprint lithography methodology utilizes the high tolerance and reversible nature of the bond alignment process to lithographically position multiple layers of imprints within a microfluidic device for sequential filling and patterning of hydrogel lumen structures with single or multiple shells. Through fluidic interfacing of the structures, the ability to deliver physiologically relevant mechanical cues for recapitulating cyclical stretch on the hydrogel shell and shear stress on endothelial cells in the lumen are validated. We envision application of this platform for recapitulation of the bio-functionality and topology of micro-vasculatures, alongside the ability to deliver transport and mechanical cues, as needed for 3D culture to construct in vitro tissue models.

Marangoni-driven biomimetic salt secretion evaporator

Solar-driven steam generation is regarded as a sustainable strategy for high salinity wastewater treatment. However, the salt accumulation problems associated with vigorous water evaporation limit the practicality of solar evaporators. Herein, inspired by the salt secretion mechanism of natural mangrove leaves, a biomimetic salt secretion evaporator (BSSE) composed of a wood shell and photothermal hydrogel was designed to induce salt crystallization outside the steam generation interface during brine evaporation. Directional salt migration, secretion, and crystallization was driven through region-dependent inhomogeneous thermal and water evaporation management. This exceptional function endows BSSE with superior high-salinity brine evaporation (2.08 kg m−2 h−1, 20 wt% NaCl) and long-term salt rejecting (continuous operation 100 h without any post-cleaning treatment). Experiments characterization and numerical simulations provide a consistent result in which Marangoni convection induced by the thermocapillary and solute capillary effect formed in evaporation interface is the origin of dynamic salt secretion. Moreover, due to the salt secretion characteristics of biomimetic structure design, BSSE can effectively extract the salt from salinized soil and permanently reduce its internal salinity, which provides a logical solution for simultaneously solve global water and food problems.

Development of non-adherent cell-enclosing domes with enzymatically cross-linked hydrogel shell

Non-adherent cells, such as hematopoietic cells and lymphocytes, are important research subjects in medical and biological fields. Therefore, a system that enables the handling of non-adherent cells in solutions in the same manner as that of adhering cells during medium exchange, exposure to chemicals, washing, and staining in imaging applications would be useful. Here, we report a ‘Cell Dome’ platform in which non-adherent cells can be enclosed and grown in the cavities of about 1 mm diameter and 270 μm height. The domes consist of an alginate-based hydrogel shell of 90 μm thickness. Cell Domes were formed on glass plates by horseradish peroxidase-mediated cross-linking. Human leukaemia cell line K562 cells enclosed in Cell Domes were stable for 29 days with every 2–3 days of medium change. The enclosed cells grew in the cavities and were stained and differentiated with reagents supplied from the surrounding medium. Additionally, K562 cells that filled the cavities (a 3D microenvironment) were more hypoxic and highly resistant to mitomycin C than those cultured in 2D. These findings demonstrate that the ‘Cell Dome’ may be a promising tool for conveniently culturing and evaluating non-adherent cells.

Multiphysics-informed deep learning for swelling of pH/temperature sensitive cationic hydrogels and its inverse problem

This paper proposes a field theory of constrained swelling of pH/temperature sensitive cationic hydrogels in equilibrium with their chemical and mechanical environment. A general formulation is obtained based on a variational approach, yielding a set of governing equations coupling mechanical and chemical equilibrium conditions, which is employed to investigate some benchmark problems involving homogeneous and inhomogeneous swelling of the pH/temperature sensitive cationic hydrogels. The simulation results are compared with experimental data available in the literature to verify the present model. By encoding the underlying physical and chemical laws into the deep learning neural networks as prior information, we introduce the multiphysics-informed deep learning (MIDL) to investigate the effects of temperature and pH on the distributions of concentration of solvent and stresses in the hydrogel shell. In addition, the MIDL is extended to solve inverse identification problem of inhomogeneous swelling of core-shell hydrogels, which yields a reasonable identification accuracy even if the observed data is corrupted due to uncorrelated noise.

Structural Insights into Cellulose-Coated Oil in Water Emulsions.

Cellulose is a renewable biopolymer, abundant on Earth, with a multi-level supramolecular structure. There has been significant interest and advancement in utilizing natural cellulose to stabilize emulsions. In our research, we develop and examine oil in water emulsions surrounded by unmodified cellulose as microreactors for the process of transformation of cellulose into valuable chemicals such as biodiesel. This study presents morphological characterization of cellulose-coated emulsions that can be used for such purposes. Cryogenic-scanning electron microscopy imaging along with light microscopy and light scattering reveals a multi-layer inner structure: an oil core surrounded by a porous cellulose hydrogel shell, coated by an outer shell of regenerated cellulose. Measurements of small-angle X-ray scattering provide quantification of the nano-scale structure within the porous cellulose hydrogel inner shell of the emulsion particle. These characteristics are relevant to utilization of cellulose-coated emulsions in various applications such as controlled release and as hosts for enzymatic biotechnological reactions.

Enabling Clonal Analyses of Yeast in Outer Space by Encapsulation and Desiccation in Hollow Microparticles.

Studying microbes at the single-cell level in space can accelerate human space exploration both via the development of novel biotechnologies and via the understanding of cellular responses to space stressors and countermeasures. High-throughput technologies for screening natural and engineered cell populations can reveal cellular heterogeneity and identify high-performance cells. Here, we present a method to desiccate and preserve microbes in nanoliter-scale compartments, termed PicoShells, which are microparticles with a hollow inner cavity. In PicoShells, single cells are confined in an inner aqueous core by a porous hydrogel shell, allowing the diffusion of nutrients, wastes, and assay reagents for uninhibited cell growth and flexible assay protocols. Desiccated PicoShells offer analysis capabilities for single-cell derived colonies with a simple, low resource workflow, requiring only the addition of water to rehydrate hundreds of thousands of PicoShells and the single microbes encapsulated inside. Our desiccation method results in the recovery of desiccated microparticle morphology and porosity after a multi-week storage period and rehydration, with particle diameter and porosity metrics changing by less than 18% and 7%, respectively, compared to fresh microparticles. We also recorded the high viability of Saccharomyces cerevisiae yeast desiccated and rehydrated inside PicoShells, with only a 14% decrease in viability compared to non-desiccated yeast over 8.5 weeks, although we observed an 85% decrease in initial growth potential over the same duration. We show a proof-of-concept for a growth rate-based analysis of single-cell derived colonies in rehydrated PicoShells, where we identified 11% of the population that grows at an accelerated rate. Desiccated PicoShells thus provide a robust method for cell preservation before and during launch, promising a simple single-cell analysis method for studying heterogeneity in microbial populations in space.

Spatial confinement of multi-enzyme for cascade catalysis in cell-inspired all-aqueous multicompartmental microcapsules

Biocatalytic reaction networks in eukaryotic cells is realized by the immobilized and compartmental multi-enzymatic system. Inspired by the spatial localization of natural cells, multiple enzymes were confined within the multicompartmental microcapsules, which were created using a gas-shearing method coupled with surface-triggered in situ gelation strategy. Heterogeneous multicompartmental (two-, three-, four-, six-, or eight-faced) core particles, due to their capacity for positional assembly, were encapsuled in alginate hydrogel shells. The generated microcapsules integrate logic network to access complex digital design through a three-step convergent enzymatic cascade reaction as a model, and the capsules with high stability, recyclability and cytocompatibility are ideal enzymatic reactor systems to be used for biomimetic biocatalysis process.

Soft and Tough Microcapsules with Double‐Network Hydrogel Shells

AbstractHydrogel‐shelled microcapsules allow communication with the surrounding through molecule‐selective exchanges, serving as microcarriers for cells, drugs, catalysts, and nanoparticle sensors. However, the low mechanical stability of hydrogels has restricted their use in strong shear flows or compressive fields. Here, microcapsules are designed composed of water core and double‐network (DN) hydrogel shell using water‐in‐oil‐in‐water‐in‐oil triple‐emulsion templates to secure high mechanical stability as well as molecular size‐selective permeation. Monodisperse triple‐emulsion droplets are prepared using microfluidic devices. The core water contains divalent ions and the outer water layer contains poly(ethylene glycol)diacrylate (PEGDA) and sodium alginate. The PEGDA is first photocrosslinked by ultraviolet irradiation and the alginate is second ionically crosslinked with an infusion of divalent ions from the core by rupturing the middle oil layer. The resulting DN shells show excellent mechanical stability in comparison with single‐network (SN) shells made of PEGDA only. Enhanced elasticity of the DN enables the microcapsules to elastically deform and fully recover the original state for wide ranges of strain and strain rate. Moreover, the DN shells show a threshold force for the shell rupture almost one order of magnitude larger than the SN and maintain their integrity under violent shear flows.

In vitro proliferation and long-term preservation of functional primary rat hepatocytes in cell fibers

Primary hepatocytes are essential cellular resources for drug screening and medical transplantation. While culture systems have already succeeded in reconstituting the biomimetic microenvironment of primary hepatocytes, acquiring additional capabilities to handle them easily as well as to expand them remains unmet needs. This paper describes a culture system for primary rat hepatocytes, based on cell fiber technology, that brings scalability and handleability. Cell fibers are cell-laden core–shell hydrogel microfibers; in the core regions, cells are embedded in extracellular matrix proteins, cultured three-dimensionally, and exposed to soluble growth factors in the culture medium via the hydrogel shells. By encapsulating primary rat hepatocytes within cell fibers, we first demonstrated their proliferation while maintaining their viability and their hepatic specific functions for up to thirty days of subsequent culture. We then demonstrated the efficiency of proliferating primary rat hepatocytes in cell fibers not only as cell-based sensors to detect drugs that damage hepatic functions and hepatocellular processes but also as transplants to improve the plasma albumin concentrations of congenital analbuminemia. Our culture system could therefore be included in innovative strategies and promising developments in applying primary hepatocytes to both pharmaceutical and medical fields.

Encapsulation of Cells in a Collagen Matrix Surrounded by an Alginate Hydrogel Shell for 3D Cell Culture.

Numerous techniques for mammalian cell culture have been developed to mimic the complex in vivo three-dimensional structure of tissues and organs. Among them, the sole use of proteins to create a matrix where cells are embedded already gives rise to self-organized multicellular assemblies. Loading cells in a controlled extracellular matrix along with cell culture and monitoring through a strategy that is compatible with pipetting tools would be beneficial for high throughput screening applications or simply for a standardized method. Here, we design submillimeter compartments having a thin alginate hydrogel shell and a core made of a collagen matrix where cells are embedded. The process, using a microfluidic device, is based on a high speed co-extrusion in air, leading to a compound jet whose fragmentation is controlled. The resulting core-shell liquid drops are then collected in a gelling bath that triggers a fast hardening of the shell and is followed by a slower self-assembly of collagen molecules into fibers. We show how to formulate the core solution in order to maintain cell viability at physiological conditions that otherwise induce tropocollagen molecules to self-assemble, while being able to prevent flow disturbances that are detrimental for this jetting method. Encapsulated Caco-2 cells, mainly used to model the intestinal barrier, proliferate and form a closed polarized epithelial cell monolayer where the apical membrane faces the continuous medium.

Porous microcapsules encapsulating β cells generated by microfluidic electrospray technology for diabetes treatment

Diabetes mellitus is becoming increasingly prevalent worldwide and needs effective clinical treatment methods. β-Cell replacement therapy has become a safe alternative for diabetes treatment in recent years, and encapsulation methods have been proposed to facilitate this type of therapy. Here, we used coaxial microfluidic electrospray technology to generate microcapsules allowing high cell viability (>90%) with porous alginate shells and β cell-containing cores in less than half an hour. Benefitting from microfluidic electrospray, the sizes of the generated microcapsules were adjustable. The biocompatible porous hydrogel shell not only protected β cells from immune rejection but also allowed the exchange of small molecular nutrients during transplantation, and the liquid core guaranteed the high viability of the encapsulated cells. This constructed living cell biosystem further demonstrated its potential as an artificial islet after transplantation into the omental pouches of diabetic mice to control blood glucose levels and thus treat diabetes. We consider that this system, with an elaborate structure and an abundance of highly viable encapsulated β cells to improve treatment performance, could be applied in a wide range of clinical situations.

Aptamer-Functionalized Barcodes in Herringbone Microfluidics for Multiple Detection of Exosomes.

Tumor-derived exosomes are vital for clinical dynamic and accurate tumor diagnosis, thus developing sensitive and multiple exosomes detection technology has attracted remarkable attention of scientists. Here, a novel herringbone microfluidic device with aptamer-functionalized barcodes integration for specific capture and multiple detection of tumor-derived exosomes is presented. The barcodes with core-shell constructions are obtained by partially replicating the periodically ordered hexagonal close-packaged colloidal crystal beads. As their inverse opal hydrogel shell possesses rich interconnected pores, the barcodes could provide abundant surface area for functionalization of DNA aptamers to realize specific recognition of target exosomes. Besides, the encoded structure colors of the barcodes can be maintained stably during the detection events as their hardish cores are with sufficient mechanical strength. It is demonstrated that by embedding these barcodes in herringbone groove microfluidic device with designed patterns, the specific capture efficiency and synergetic detection of multiple tumor-derived exosomes in peripheral blood can be significantly improved due to enhanced resistance of turbulent flow. These features make the aptamer-functionalized barcodes and herringbone microfluidics integrated platform promising for exosomes extraction and dynamic tumor diagnosis.

Hybrid Core-Shell Polymer Scaffold for Bone Tissue Regeneration.

A great promise for tissue engineering is represented by scaffolds that host stem cells during proliferation and differentiation and simultaneously replace damaged tissue while maintaining the main vital functions. In this paper, a novel process was adopted to develop composite scaffolds with a core-shell structure for bone tissue regeneration, in which the core has the main function of temporary mechanical support, and the shell enhances biocompatibility and provides bioactive properties. An interconnected porous core was safely obtained, avoiding solvents or other chemical issues, by blending poly(lactic acid), poly(ε-caprolactone) and leachable superabsorbent polymer particles. After particle leaching in water, the core was grafted with a gelatin/chitosan hydrogel shell to create a cell-friendly bioactive environment within its pores. The physicochemical, morphological, and mechanical characterization of the hybrid structure and of its component materials was carried out by means of infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and mechanical testing under different loading conditions. These hybrid polymer devices were found to closely mimic both the morphology and the stiffness of bones. In addition, in vitro studies showed that the core-shell scaffolds are efficiently seeded by human mesenchymal stromal cells, which remain viable, proliferate, and are capable of differentiating towards the osteogenic phenotype if adequately stimulated.

Gastroretentive core–shell hydrogel assembly for sustained release of metformin hydrochloride

The metformin hydrochloride is the only oral guanidine anti glycemic agent and is used as the first-line drug for the treatment of type II diabetes. Owing to its high water solubility and short half-life, however, this drug is difficult to be released sustainedly. Here, a core–shell structured hydrogel assembly as gastroretentive carrier is proposed for the sustained release of metformin hydrochloride. The hydrogel assembly can be ingested orally into the stomach. On contact with the gastric juice, the shell rapidly swells to prevent the hydrogel to be expelled from the pylorus, and the core serves as a drug reservoir for loading metformin hydrochloride. The core–shell structure can decrease the driving force of drug release and extend the drug diffusion pathway. As a result, the hydrogel assembly can release metformin hydrochloride sustainedly for 72 h in vitro and maintain stable blood drug concentration for nearly 80 h in vivo. Moreover, the hydrogel assembly can be biodegraded by the gastric environment.

Hollow Filaments Synthesized by Dry-Jet Wet Spinning of Cellulose Nanofibrils: Structural Properties and Thermoregulation with Phase-Change Infills.

We use dry-jet wet spinning in a coaxial configuration by extruding an aqueous colloidal suspension of oxidized nanocellulose (hydrogel shell) combined with airflow in the core. The coagulation of the hydrogel in a water bath results in hollow filaments (HF) that are drawn continuously at relatively high rates. Small-angle and wide-angle X-ray scattering (SAXS/WAXS) reveals the orientation and order of the cellulose sheath, depending on the applied shear flow and drying method (free-drying and drying under tension). The obtained dry HF show Young’s modulus and tensile strength of up to 9 GPa and 66 MPa, respectively. Two types of phase-change materials (PCM), polyethylene glycol (PEG) and paraffin (PA), are used as infills to enable filaments for energy regulation. An increased strain (9%) is observed in the PCM-filled filaments (HF-PEG and HF-PA). The filaments display similar thermal behavior (dynamic scanning calorimetry) compared to the neat infill, PEG, or paraffin, reaching a maximum latent heat capacity of 170 J·g–1 (48–55 °C) and 169 J·g–1 (52–54 °C), respectively. Overall, this study demonstrates the facile and scalable production of two-component core-shell filaments that combine structural integrity, heat storage, and thermoregulation properties.

Dual drug delivery collagen vehicles for modulation of skin fibrosis in vitro

Single molecule drug delivery systems have failed to yield functional therapeutic outcomes, triggering investigations into multi-molecular drug delivery vehicles. In the context of skin fibrosis, although multi-drug systems have been assessed, no system has assessed molecular combinations that directly and specifically reduce cell proliferation, collagen synthesis and transforming growth factor β1 (TGFβ1) expression. Herein, a core–shell collagen type I hydrogel system was developed for the dual delivery of a TGFβ trap, a soluble recombinant protein that inhibits TGFβ signalling, and Trichostatin A (TSA), a small molecule inhibitor of histone deacetylases. The antifibrotic potential of the dual delivery system was assessed in an in vitro skin fibrosis model induced by macromolecular crowding (MMC) and TGFβ1. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and high performance liquid chromatography analyses revealed that ∼50% of the TGFβ trap and ∼30% of the TSA were released from the core and shell compartments, respectively, of the hydrogel system after 10 d (longest time point assessed) in culture. As a direct consequence of this slow release, the core (TGFβ trap)/shell (TSA) hydrogel system induced significantly (p < 0.05) lower than the control group (MMC and TGFβ1) collagen type I deposition (assessed via SDS-PAGE and immunocytochemistry), α smooth muscle actin (αSMA) expression (assessed via immunocytochemistry) and cellular proliferation (assessed via DNA quantification) and viability (assessed via calcein AM and ethidium homodimer-I staining) after 10 d in culture. On the other hand, direct TSA-TGFβ supplementation induced the lowest (p < 0.05) collagen type I deposition, αSMA expression and cellular proliferation and viability after 10 d in culture. Our results illustrate the potential of core–shell collagen hydrogel systems for sustained delivery of antifibrotic molecules.