Hollow Hydrogel Research Articles

Microneedle-based insulin transdermal delivery system: current status and translation challenges.

Diabetes mellitus is a metabolic disease manifested by hyperglycemia. For patients with type 1 and advanced type 2 diabetes mellitus, insulin therapy is essential. Subcutaneous injection remains the most common administration method. Non-invasive insulin delivery technologies are pursued because of their benefits of decreasing patients’ pain, anxiety, and stress. Transdermal delivery systems have gained extensive attention due to the ease of administration and absence of hepatic first-pass metabolism. Microneedle (MN) technology is one of the most promising tactics, which can effectively deliver insulin through skin stratum corneum in a minimally invasive and painless way. This article will review the research progress of MNs in insulin transdermal delivery, including hollow MNs, dissolving MNs, hydrogel MNs, and glucose-responsive MN patches, in which insulin dosage can be strictly controlled. The clinical studies about insulin delivery with MN devices have also been summarized and grouped based on the study phase. There are still several challenges to achieve successful translation of MNs-based insulin therapy. In this review, we also discussed these challenges including safety, efficacy, patient/prescriber acceptability, manufacturing and scale-up, and regulatory authority acceptability.Graphical abstract

Facile Fabrication of Hollow Hydrogel Microfiber via 3D Printing-Assisted Microfluidics and Its Application as a Biomimetic Blood Capillary

Simulating the structure and function of blood capillaries is very important for an in-depth insight into their role in the human body and treatment of capillary-related diseases. Due to the similar composition and structure, hollow hydrogel microfibers are well-recognized as potential biomimetic blood capillaries. In this paper, we report a novel, facile, and reproducible method to fabricate coaxial microfluidic chips via 3D printing-assisted soft lithography and then hollow hydrogel microfibers using the as-prepared coaxial microfluidic chips. Instead of traditional photoresist-based lithography, 3D printing of gelatin hydrogel under various extrusion pressures is used to construct sacrificial templates of coaxial microfluidic chips. Various solid and hollow hydrogel microfibers with complicated and hierarchical structures can be obtained via multitype coaxial microfluidic chips or a combination of coaxial microfluidic fabrication and post-treatment. The as-formed hollow hydrogel microfibers are evaluated in detail as biomimetic blood capillaries, including physicochemical and cytological properties. Our results prove that the hollow hydrogel microfibers exhibit excellent mass transport capacity, hemocompatibility, semipermeability, and mechanical strength, and their barrier function can be further enhanced in the presence of endothelial cells. Overall, our 3D printing-assisted fabrication strategy provides a new technique to construct microfluidic chips with complicated 3D microchannels, and the resulting hollow hydrogel microfibers are promising candidates for blood capillaries.

Flower-inspired bionic sodium alginate hydrogel evaporator enhancing solar desalination performance

Improving the desalination performance of the solar evaporator is the core of promoting the application of sustainable solar desalination technology. In this study, a flower-inspired bionic evaporator was successfully prepared, the bundled of black hollow sodium alginate hydrogel tubes were fixed vertically to form a flower structure with branched hydrogel tubes at the top. The prepared black flower hydrogel evaporator showed the excellent evaporation rate of 3.2 kg m−2 h−1, and the salt crystallization phenomenon during solar desalination was effectively suppressed. Three-dimensional flower configuration of the hydrogel tube with the appropriate length could increase the effective evaporation area and accelerate the evaporation process. Moreover, the hollow hydrogel network structure exhibited the stable water supply capacity to promote salt ions exchange at the evaporation interface, thereby inhibiting salt crystallization phenomenon. This study proved that constructing a 3D-shaped evaporator is an effective way to subversively improve the solar desalination performance for application.

Robust and Antiswelling Hollow Hydrogel Tube with Antibacterial and Antithrombotic Ability for Emergency Vascular Replacement.

Infection and thrombosis are the two major complications in almost any indwelling intravascular catheters, leading to adverse consequences. Here, we report a robust and antiswelling hollow hydrogel tube that is prepared by copolymerizing a hydrogen-bonding (H-bonding) monomer and a zinc methacrylate (ZMA) monomer in the absence of any chemical cross-linker. The strong H-bonding interactions from the side chain of N-acryloylsemicarbazide (NASC) endow the hydrogel with high mechanical strength and swelling stability. Introduction of ZMA affords a superhydrophilic surface, and the release of a zinc ion (Zn2+) from the hydrogel can kill nearly 100% both of Staphylococcus aureus and Escherichia coli, indicating its excellent antibacterial ability. Importantly, the P(NASC-co-ZMA) hydrogel exhibits better antithrombosis ability due to the resistant adhesion of fibrinogen protein and platelets, as well binding calcium ions (Ca2+) from the blood. The hydrogel tube is used to connect the ex vivo arteriovenous shunt circuit or implanted into the left carotid artery in the rabbit model, showing a better patency rate. All of these results suggest that this hydrogel tube may mitigate infection and thrombosis complications, thus holding potential as an artificial blood vessel for emergency vascular replacement.

Magnetic Actuation of Hollow Swarming Spheres for Dynamic Catalysis.

Untethered robots with smart human-machine interactions can execute complex activities such as target cargo delivery or assembly of functional scaffolds. However, it remains challenging for fabricating microscale hollow hydrogel robots that can go with autonomous transformation of their geometric formations to adapt to unstructured environments. We herein report hydrogel-based microscopic hollow swarming spheres (HSSs) with anisotropic/isotropic alignments of Fe3O4 particles in the porous wall that can navigate under complex topography conditions by altering their geometric formation, including passing around or jumping over obstacles, assembling into various formation patterns, and swimming in a high-viscosity system. We introduce HSSs into a catalytic reaction model, in which HSSs as a catalyst can shift between water and oil phases to initiate or terminate the decomposition reaction of H2O2. This dynamic catalysis is expected to construct free-radical "living" polymerization for controlling the reaction rate and polymer dispersity index in the future.

Enzyme hybrid virus-like hollow mesoporous CuO adhesive hydrogel spray through glucose-activated cascade reaction to efficiently promote diabetic wound healing

Diabetic wounds characterized by impaired healing due to uncontrolled and interrelated bacterial infection, reduced vascularization and hypoxia microenvironment, remain a worldwide challenge. Copper ions have been proved to stimulate angiogenesis to improve chronic wound healing, and copper oxide nanoparticles have been widely investigated for bacterial elimination. Herein, we constructed an adhesive hydrogel spray with loading glucose oxidase hybrid virus-like hollow mesoporous CuO nanospheres to efficiently promote diabetic wound healing. Under local hyperglycemia in bacterial biofilm, CuO nanospheres can be decomposed to convert the glucose degradation, produce H2O2 to generate toxic •OH for antibacterial usage, then the simultaneously released Cu2+ can induce the proliferation and migration of keratinocytes and tubule formation of endothelial cells. More importantly, after bacterial eradication within inflammatory phase of wound healing, CuO nanospheres can act as catalase-mimic agents to produce massive O2 by catalyzing intracellular H2O2 for hypoxia alleviation. This glucose-activated cascade reaction hydrogel spray can efficiently promote diabetic wound healing, which might provide a reliable tool for synergistic reconstruction of the chronic non-healing wounds.

Scaling Laws in the Diffusive Release of Neutral Cargo from Hollow Hydrogel Nanoparticles: Paclitaxel-Loaded Poly(4-vinylpyridine).

We study the nonequilibrium diffusive release of electroneutral molecular cargo encapsulated inside hollow hydrogel nanoparticles. We propose a theoretical model that includes osmotic, steric, and short-range polymer-cargo attractions to determine the effective cargo-hydrogel interaction, ueff*, and the effective diffusion coefficient of the cargo inside the polymer network, Deff*. Using dynamical density functional theory (DDFT), we investigate the scaling of the characteristic release time, τ1/2, with the key parameters involved in the process, namely, ueff*, Deff*, and the swelling ratio. This effort represents a full study of the problem, covering a broad range of cargo sizes and providing predictions for repulsive and attractive polymer shells. Our calculations show that the release time through repulsive polymer networks scales with q2eβueff*/Deff* for βueff* ≫ 1. In this case, the cargo molecules are excluded from the shell of the hydrogel. For attractive shells, the polymer retains the cargo molecules on its internal surface and its interior, and the release time grows exponentially with the attraction strength. The DDFT calculations are compared to an analytical model for the mean first passage time, which provides an excellent quantitative description of the kinetics for both repulsive and attractive shells without fitting parameters. Finally, we apply the method to reproduce experimental results on the release of paclitaxel from hollow poly(4-vinylpyridine) nanoparticles and find that the slow release of the drug can be explained in terms of the strong binding attraction between the drug and the polymer.

Coaxial 3D bioprinting of organ prototyps from nutrients delivery to vascularization

Vascular networks inside organs provide the means for metabolic exchange and adequate nutrition. Similarly, vascular or nutrient networks are needed when building tissue constructs >500 µm in vitro due to the hydrogel compact pore size of bioinks. As the hydrogel used in bioinks is rather soft, it is a great challenge to reconstruct effective vascular networks. Recently, coaxial 3D bioprinting was developed to print tissue constructs directly using hollow hydrogel fibers, which can be treated as built-in microchannels for nutrient delivery. Furthermore, vascular networks could be printed directly through coaxial 3D bioprinting. This review summarizes recent advances in coaxial bioprinting for the fabrication of complex vascularized tissue constructs including methods, the effectiveness of varying strategies, and the use of sacrificial bioink. The limitations and challenges of coaxial 3D bioprinting are also summarized.

Coupled thermo-mechanical swelling of a thermo-responsive hydrogel hollow cylinder under extension-torsion: Analytical Solution and FEM

In this article, the mechanical swelling behavior of poly-(N-isopropylacrylamide) hydrogel is scrutinized considering a hollow circular cylinder subjected to temperature variation-extension-torsion. Accordingly, an analytical solution is presented to consider the general combined loading on temperature-sensitive hydrogel cylinder for two approaches, considering same temperature for whole structure and solving heat equation to compute internal temperature of structure. Additionally, to evaluate the proposed solution, finite element analysis has been conducted for same problem which revealed excellent conformity for various case studies. Therefore, a user-material subroutine, UHYPER, is implemented to be employed in finite element analysis in order to define swelling of PNIPAM hydrogels. This subroutine was validated using free swelling and constraint swelling with previous and their analytical solutions. Regarding the complexity of material and loading namely, nonlinear finite behavior of hydrogel as well as combined cooling-extension-torsional loading, various factors, cross-linked density, axial stretch, torsional twist and temperature variation, were investigated to clarify the swelling behavior of hydrogel. Solving heat equation, in the second approach, enables us to apply various thermal conditions on this structure, while in previous studies, the temperature of whole structure is considered to vary simultaneously with the same function. This approach can help researchers to examine diverse thermo-mechanicals problem for temperature-sensitive hydrogels.

Macromolecular Phase-Transition-Driven Motility of Hollow Hydrogel Tubes

The research emphasis and novelty of this work focus on the phase-transition effects on the structural deformation of hollow hydrogel tubes in an aqueous system, where the cross-linking poly(N-isop...

Controlled release of anti-cancer drug from the shell and hollow cavities of poly(N-isopropylacrylamide) hydrogel particles synthesized via reversible addition-fragmentation chain transfer polymerization

Temperature-responsive poly(N-isopropylacrylamid) (PNIPAAm) hydrogels with two different crosslinking densities were coated on silica nanoparticles via surface-initiated reversible addition-fragmentation chain transfer network formation method in an inverse emulsion medium. The temperature-responsive hollow hydrogel particles were also prepared by etching of the silica cores using hydrofluoric acid. The hybrid and hollow hydrogel particles were used as doxorubicin (DOX) delivery systems. The synthesis process was evaluated by proton magnetic nuclear resonance and Fourier-transform infrared spectroscopies, thermogravimetric analysis, and scanning and transmission electron microscopies. Dynamic light scattering and turbidimetry by UV–vis spectroscopy were also used to study responsivity of the hybrid and hollow PNIPAAm hydrogels to temperature. Gel collapse temperature (GCT) of the hydrogels was studied using UV transmittance curves. UV transmittance and the GCT value of the hollow hydrogels were higher than the hybrid samples. The hollow hydrogel particles with higher crosslinking density showed higher hydrodynamic diameter (Dh) at temperatures of above the GCT, whereas the hollow cavity and lower crosslinking densities resulted in higher Dh at temperatures below GCT. Release of DOX from the hybrid and hollow hydrogel particles with two different crosslinking densities was investigated by using UV–vis spectroscopy at below and above GCT of the hydrogel particles (25 and 45 °C, respectively). The hollow particles with low crosslinking density showed the lowest release percent due to its higher loading capacity. In addition, the DOX release percent was reduced by increasing temperature from 25 to 40 °C.

Hollow polypyrrole/cellulose hydrogels for high-performance flexible supercapacitors

A lightweight, flexible, and highly efficient energy management strategy is a requisite for future flexible electronics. Herein, hollow polypyrrole/cellulose hybrid hydrogels featured with biphase porous structures, are firstly designed by in-situ implanting a hollow and continuous polypyrrole conducting network into porous cellulose hydrogels. Such hollow hybrid hydrogels show good mechanical strength and flexibility, enabling its ability to bear severe mechanical deformation without structural damage. Within the hybrid hydrogel, cellulose hydrogel acts as an interior electrolyte reservoir to host movable ions, biphase porous structure offers path for electrolyte ions transportation, and hollow polypyrrole network is responsible for the electrochemical contribution. As a result, a symmetrical supercapacitor assembled with the hollow hybrid hydrogels delivers optimized capacitive properties with a high specific capacitance, a good rate capability, and an enhanced cycling stability. Moreover, no evident loss in capacitance of the device is observed even bended at 180°. This work provides a design of flexible, low-cost, environmental-friendly and high-performance electrode materials for energy conversion and storage systems.

C-Stem, a new technology fro scale up of cell therapy production

Background & Aim Most stem cells, including Human pluripotent stem cells (hPSCs) are adherent cells. The historical standard of culture is in 2D at the bottom of Petri dishes. This technology allowed for the first trials in cell therapy but is limited by: i) reproducibility issues, ii) scalability, iii) high cost due to labor intensive manipulation of the cells, and iv) genomic instability. For cell therapy applications, cell quality reflects the culture process and large quantities of cells are required for allogenic strategies. 2D automation enables reproducible clinical batch production but commercial batch sizes will require further scale up. Suspension culture in bioreactors is a straightforward choice for scale up with two main techniques: i) microcarriers, where the cells grow attached to their surface or ii) spheroids, where cells grow in 3D aggregates. In both culture conditions the cells’ exposure to shear stress in the bioreactors limits further scale up. Methods, Results & Conclusion The C-Stem™ technology addresses this challenge by encapsulating cells within hollow alginate hydrogel capsules, 250 µm in diameter with 30 µm thick walls. Capsules both protect cells form shear stress and let small molecules (smaller than 150 kDa), gas, nutrients and waste in and out. Inside the capsule, hPSCs are seeded in extracellular matrix to mimic in vivo conditions. The capsules are produced at high throughput (5000 per second) with proprietary microfluidics. The C-Stem™ technology allows for 100x fold expansion per week of hPSCs and their differentiation in traditional bioreactors. At the PSC stage, C-Stem™ significantly improves cell viability as compared to standard 2D PSC culture. C-Stem™ promotes pluripotency, yields biomimetic hPSC “epiblastoids” and maintains state of the art genomic integrity. Addressing current manufacturing issues, the process is fully integrated from seeding to harvest, scalable, single use, closed and aligned with cGMP requirements. Most 2D and 3D protocols can be transposed in C-Stem™. Preclinical results will be presented for Parkinson's disease cell therapy. Fully mature dopaminergic neuronal microtissues are differentiated from hPSCs within capsules. They are then engrafted in Parkinson's disease rat model striata. This results in behavioral correction of rats within 6 weeks of surgery, thereby reducing by a factor 2-3 the recovery time as compared to standard progenitor engraftment.

Ionic Strength and Thermal Dual-Responsive Bilayer Hollow Spherical Hydrogel Actuator.

As one of the most promising intelligent materials, polymeric hydrogel actuators could produce reversible shape change upon external stimuli. Although complex shape deformation from 2D to 3D have been achieved, the realization of actuating behavior from 3D to 3D is still a significant challenge. Herein, an effective strategy to develop a novel bilayer hollow spherical hydrogel actuator is proposed. Through immersing a Ca2+ incorporated gelatin core into alginate solution, an ionic-strength-responsive alginate layer will be formed along the gelatin core via alginate-Ca2+ crosslinks, and then another thermo-responsive alginate-poly(2-(dimethylamino)ethyl methacrylate)(Alg-PDMAEMA) layer is introduced to achieve a bilayer hydrogel with ionic strength and temperature dual responsiveness. A hollow hydrogel capsule could be obtained if a spherical gelatin core is applied, and it could produce complex shape deformations from 3D to 3D upon the trigger of ionic strength and temperatures changes. The present work may offer new inspirations for the development of novel intelligent polymeric hydrogel actuators.

Facile Method for Fabrication of Meter-Long Multifunctional Hydrogel Fibers with Controllable Biophysical and Biochemical Features.

Hydrogel structures with microscale morphological features have extensive application in tissue engineering owing to their capacity to induce desired cellular behavior. Herein, we describe a novel biofabrication method for fabrication of grooved solid and hollow hydrogel fibers with control over their cross-sectional shape, surface morphology, porosity, and material composition. These fibers were further configured into three-dimensional structures using textile technologies such as weaving, braiding, and embroidering methods. Additionally, the capacity of these fibers to integrate various biochemical and biophysical cues was shown via incorporating drug-loaded microspheres, conductive materials, and magnetic particles, extending their application to smart drug delivery, wearable or implantable medical devices, and soft robotics. The efficacy of the grooved fibers to induce cellular alignment was evaluated on various cell types including myoblasts, cardiomyocytes, cardiac fibroblasts, and glioma cells. In particular, these fibers were shown to induce controlled myogenic differentiation and morphological changes, depending on their groove size, in C2C12 myoblasts.

Supramolecular Fabrication of Complex 3D Hollow Polymeric Hydrogels with Shape and Function Diversity.

Inspired by the high importance of hollow structures in nature such as blood vessels and bamboos in matter transportation, properties enhancement, or even survival of living creatures, the creation of hollow materials remains of considerable interest. However, constructing hollow unique living-like soft and wet polymeric hydrogels with desirable structures and functionalities is still a big challenge. Here, we reported a robust and effective strategy to fabricate complex three-dimensional (3D) hollow polymeric hydrogel with designed shape and function diversity on the basis of supramolecular interactions. By placing a Ca2+ included gelatin core into the solution of alginate, hydrogel shell could be formed along with the shape of the gelatin core via coordination between alginate chains and Ca2+ diffused from gelatin. The hollow hydrogel could finally be obtained by dissolving the gelatin core. Various complex 3D hollow structures could be achieved by designing/constructing assembled gelatin core as a building block with adjustable supramolecular metal coordination position and strength. Moreover, hollow hydrogels with function diversity could be developed by introducing functional polymers or nanoparticles into the hydrogel wall. This work has made important progress in developing hollow polymeric hydrogel with desirable structures, shapes, and various functional applications including soft actuators and chemical reaction containers.

Multibioinspired slippery surfaces with wettable bump arrays for droplets pumping

Droplet manipulation is playing an important role in various fields, including scientific research, industrial production, and daily life. Here, inspired by the microstructures and functions of Namib desert beetles, Nepenthes pitcher plants, and emergent aquatic plants, we present a multibioinspired slippery surface for droplet manipulation by employing combined strategies of bottom-up colloidal self-assembly, top-down photolithography, and microstructured mold replication. The resultant multilayered hierarchical wettability surface consists of hollow hydrogel bump arrays and a lubricant-infused inverse opal film as the substrate. Based on capillary force, together with slippery properties of the substrate and wettability of the bump arrays, water droplets from all directions can be attracted to the bumps and be collected through hollow channels to a reservoir. Independent of extra energy input, droplet condensation, or coalescence, these surfaces have shown ideal droplet pumping and water collection efficiency. In particular, these slippery surfaces also exhibit remarkable features including versatility, generalization, and recyclability in practical use such as small droplet collection, which make them promising candidates for a wide range of applications.

Interfacial Diffusion Printing: An Efficient Manufacturing Technique for Artificial Tubular Grafts.

Despite great progresses in bioprinting materials and technologies, immense challenges still remain when printing tubular tissues or organs with satisfying mechanical and chemical properties, such as blood vessel, colon, and trachea. Herein, a promising extrusion system based on an interfacial diffusion printing (IDP) technique for one-step printing of tubular tissue grafts is proposed. Specifically, this technique offers great convenience to prepare hollow hydrogel fibers with excellent mechanical properties and satisfactory biocompatibility. The tubular diameter can be readily adjusted within 6 mm, which renders the possibility of these hydrogel tubes to serve as small-diameter vascular grafts. In the model of animal trials, the hydrogel grafts with the capability of enduring arterial pressure are mechanically stable in rabbit carotid artery replacement. Because of its intrinsic simplicity and generality, the IDP technique is considered to be one of the reliable choices for more complicated bioengineering.

A model of guided cell self-organization for rapid and spontaneous formation of functional vessels.

Most achievements to engineer blood vessels are based on multiple-step manipulations such as manual sheet rolling or sequential cell seeding followed by scaffold degradation. Here, we propose a one-step strategy using a microfluidic coextrusion device to produce mature functional blood vessels. A hollow alginate hydrogel tube is internally coated with extracellular matrix to direct the self-assembly of a mixture of endothelial cells (ECs) and smooth muscle cells (SMCs). The resulting vascular structure has the correct configuration of lumen, an inner lining of ECs, and outer sheath of SMCs. These "vesseloids" reach homeostasis within a day and exhibit the following properties expected for functional vessels (i) quiescence, (ii) perfusability, and (iii) contractility in response to vasoconstrictor agents. Together, these findings provide an original and simple strategy to generate functional artificial vessels and pave the way for further developments in vascular graft and tissue engineering and for deciphering the angiogenesis process.

Antifreezing Heat-Resistant Hollow Hydrogel Tubes.

Hollow hydrogel tubes that are capable of maintaining their flexibility and structural stability in extreme temperature conditions have potential for use in biomedical scaffolds, carriers, and soft robotics over a wide temperature range. However, the preparation of hollow hydrogel tubes still remains challenging because it normally requires templates or complex devices and it is hard to endow the hollow tubes with antifreezing heat-resistant capabilities. We report a protocol that does not require a template or complex devices, in which sodium alginate film strips are immersed in an aqueous mixture of CaCO3, CaCl2, NaHCO3, and HCl, which results in the manufacture of hollow tubes in 30 min. These hollow tubes are functionalized by glycerol and poly(ethylene glycol), which provides the tubes with antifreezing heat-resistant performances and enables them to keep their flexibility and hollow structures from -70 to 120 °C. This is the first report on antifreezing heat-resistant hollow hydrogel tubes, to the best of our knowledge. Such hollow tubes as carriers can control the sublimation of a mothball at a rate of 1.1 mg/h, which is one-tenth of the sublimating rate of an unloaded mothball. This sublimating rate reduces the hazard to environments along with maintaining the repellent effects. As the tube is a honey carrier, it enables the sustainable release of the honey over 800 min with a high efficacy for tricking and capturing ants. The simple applications demonstrate that the antifreezing heat-resistant hollow tubes might be feasible as carriers for the controlled release in extremely cold/hot environments.