Bilayer Hydrogel Research Articles

Tough Interfacial Adhesion of Bilayer Hydrogels with Integrated Shape Memory and Elastic Properties for Controlled Shape Deformation.

The weak adhesion between two hydrogel layers may lead to the delamination of bilayer hydrogels or low force transfer efficiency during deformation. Here, tough interfacial adhesive bilayer hydrogels with rapid shape deformation and recovery were prepared by simple attachment-heating of two gel layers. The bilayer hydrogels, composed of a shape memory gel (S-gel) and an elastic gel (E-gel), exhibited extremely tough interfacial adhesion between two layers (Γ ∼ 2200 J/m2). The shape deformation and shape recovery of the bilayer hydrogels, tuned by "heating-stretching" mode and "stretching-heating-stretching" mode, were rapid (<5 s) and no delamination between two gel layers was detected during shape deformation. Based on the fast shape deformation and recovery, the bilayer hydrogels could mimic the flower and hand, and a gel gripper could be fabricated to catch the object in the hot water. This work provides a simple method to prepare tough adhesive bilayer hydrogels with controlled shape deformation.

Biologically controlled gelatin actuators

Gelatin is a natural and environment-friendly polymer that can be cross-linked to various degrees with glutaraldehyde (GTA) and swollen with water to form a hydrogel. As the gelatin cross-link density increases, gel stiffness increases and swelling in water decreases with the cross-link density saturating at about 0.01 mol of GTA. Forming gelatin hydrogel bilayers with layers of differing cross-link densities results in a gelatin actuator that bends toward the layer of higher cross-link density when swollen in water. The extent of bilayer bending is dependent on the difference between the volume swelling ratio of the layers, which is directly determined by the cross-link density difference. When the gelatin bilayers are close in swell ratio or when the swell ratios are significantly different, no bending occurs. The highest bending is found when the higher cross-linked passive layer swells to about 60% of the swelling of the lower cross-linked active layer. Filling the active layer with pre-gelatinized starch increases the bilayer curvature, but it returns to its original shape after hydrolyzing the starch with α-amylase, demonstrating shape change in response to a biochemical reaction. The results show that simple gelatin bilayers can serve as actuators when stimulated with water or sugar and enzyme.

Graphene Oxide-Doped Gellan Gum-PEGDA Bilayered Hydrogel Mimicking the Mechanical and Lubrication Properties of Articular Cartilage.

Articular cartilage (AC) is a specialized connective tissue able to provide a low-friction gliding surface supporting shock-absorption, reducing stresses, and guaranteeing wear-resistance thanks to its structure and mechanical and lubrication properties. Being an avascular tissue, AC has a limited ability to heal defects. Nowadays, conventional strategies show several limitations, which results in ineffective restoration of chondral defects. Several tissue engineering approaches have been proposed to restore the AC's native properties without reproducing its mechanical and lubrication properties yet. This work reports the fabrication of a bilayered structure made of gellan gum (GG) and poly (ethylene glycol) diacrylate (PEGDA), able to mimic the mechanical and lubrication features of both AC superficial and deep zones. Through appropriate combinations of GG and PEGDA, cartilage Young's modulus is effectively mimicked for both zones. Graphene oxide is used as a dopant agent for the superficial hydrogel layer, demonstrating a lower friction than the nondoped counterpart. The bilayered hydrogel's antiwear properties are confirmed by using a knee simulator, following ISO 14243. Finally, in vitro tests with human chondrocytes confirm the absence of cytotoxicity effects. The results shown in this paper open the way to a multilayered synthetic injectable or surgically implantable filler for restoring AC defects.

Swelling-Induced Interface Crease Instabilities at Hydrogel Bilayers

Two dissimilar hydrogel layers bonded together become unstable when the compressive stresses due to diffusion-driven swelling of the layers reach a critical point and creases form at the interface. Although creasing instabilities observed on surfaces of soft solids subjected to large compressions are well studied, the transient nature and critical conditions for the emergence of interface creases as a result of swelling behavior of hydrogels remain elusive. Here, we investigate the formation and transient growth of interface creases in bilayer hydrogels through experimental and computational approaches. Equipped with a mixed isogeometric analysis that accounts for large swelling deformations along with dissipative fluid transport phenomena, we show that both the equilibrium and the transient characteristics of interface creases can be tuned by controlling the material properties, in contrast to the reported material-independent behavior of creases in elastomers. The effects of material parameters on the onset and growth of interface creases are quantified in terms of the critical swelling ratio and critical chemical potential, and these values are compared to the critical conditions for the emergence of wrinkling instabilities. In agreement with our experimental observations of swelling bilayer hydrogels, our computational results demonstrate that the formation of creases is energetically more favorable than wrinkle formation at the interface.

Heterogenous hydrogel mimicking the osteochondral ECM applied to tissue regeneration.

Inspired by the intricate extracellular matrix (ECM) of natural cartilage and subchondral bone, a heterogenous bilayer hydrogel scaffold is fabricated. Gelatin methacrylate (GelMA) and acryloyl glucosamine (AGA) serve as the main components in the upper layer, mimicking the chondral ECM. Meanwhile, vinylphosphonic acid (VPA) as a non-collagen protein analogue is incorporated into the bottom layer to induce the in situ biomineralization of calcium phosphate. The two heterogenous layers are effectively sutured together by the inter-diffusion between the upper and bottom layer hydrogels, together with chelation between the calcium ions and alginate added to separate layers. The interfacial bonding between the two different layers was thoroughly investigated via rheological measurements. The incorporation of AGA promotes chondrocytes to produce collagen type II and glycosaminoglycans and upregulates the expression of chondrogenesis-related genes. In addition, the minerals induced by VPA facilitate the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). In vivo evaluation confirms the biocompatibility of the scaffold with minor inflammation and confirms the best repair ability of the bilayer hydrogel. This cell-free, cost-effective and efficient hydrogel shows great potential for osteochondral repair and inspires the design of other tissue-engineering scaffolds.

Computational Stability Analysis of Diffusion‐Deformation Processes at Finite Strains

AbstractIn the present work, we investigate the onset of structural instabilities occuring in soft hydrophilic elastomers undergoing geometrically constrained swelling, which is characterized by large elastic deformations coupled with transient fluid diffusion. We model this phenomenon using a minimization‐based variational formulation having the deformation map and the fluid flux as the independent variables [1,3]. The space‐time‐discrete form of the variational problem is implemented using a conforming Raviart–Thomas‐type finite element formulation, which yields a symmetric and positive definite global tangent matrix for a stable deformation state. The onset of instability is captured as the point where the tangent matrix loses its positive definiteness [4,5]. To validate the proposed theoretical framework, we consider the surface wrinkling phenomenon observed in constrained hydrogel bilayers subjected to fluid diffusion. Variations in the critical buckling load and the corresponding mode number with respect to the geometry and material parameters of the bilayer are studied. These studies could, for instance, serve as potential design guidelines for applications of such materials in microsensors or in the fabrication of soft microgears for actuators, where the buckling modes are exploited to produce a desired mechanical output [8].

Multiple-Stimuli-Responsive and Cellulose Conductive Ionic Hydrogel for Smart Wearable Devices and Thermal Actuators.

Stimulus-responsive hydrogels, such as conductive hydrogels and thermoresponsive hydrogels, have been explored extensively and are considered promising candidates for smart materials such as wearable devices and artificial muscles. However, most of the existing studies on stimulus-responsive hydrogels have mainly focused on their single stimulus-responsive property and have not explored multistimulus-responsive or multifunction properties. Although some works involved multifunctionality, the prepared hydrogels were incompatible. In this work, a multistimulus-responsive and multifunctional hydrogel system (carboxymethyl cellulose/poly acrylic-acrylamide) with good elasticity, superior flexibility, and stable conductivity was prepared. The prepared hydrogel not only showed excellent human motion detection and physiological signal response but also possessed the ability to respond to environmental temperature changes. By integrating a conductive hydrogel with a thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) hydrogel to form a bilayer hydrogel, the prepared bilayer also functioned as two kinds of actuators owing to the different degrees of swelling and shrinking under different thermal stimuli. Furthermore, the different thermochromic properties of each layer in the bilayer hydrogel endowed the hydrogel with a thermoresponsive "smart" feature, the ability to display and conceal information. Therefore, the prepared hydrogel system has excellent prospects as a smart material in different applications, such as ionic skin, smart info-window, and soft robotics.

Highly Bidirectional Bendable Actuator Engineered by LCST-UCST Bilayer Hydrogel with Enhanced Interface.

Thermoresponsive hydrogel-based actuators are highly important for fundamental research and industrial applications, while the preparation of temperature-driven bilayer hydrogel actuators with rapid response to bend and recover properties remains a challenge. To date, most temperature-driven bilayer hydrogel actuators are based on polymers only with a lower critical solution temperature (LCST) or with an upper critical solution temperature (UCST), which need more time to bend and recover just in a small range of bending angle. Herein, we propose a new strategy to design and synthesize a fully temperature-driven bilayer hydrogel actuator, which consists of a poly(N-acryloyl glycinamide) (NAGA) layer with a UCST-type volume phase change and a poly(N-isopropyl acrylamide) (NIPAM)-Laponite nanocomposite layer with an LCST-type volume phase change. Due to the complementary UCST and LCST behavior of the two selected polymers, both layers have opposite thermoresponsive swelling and shrinkage properties at low and high temperatures; this imbues the hydrogel actuator with rapid thermoresponsive bending and recovery ability, as well as a large bending angle. In addition, the incorporation of Laponite nanosheets in PNIPAM layer not only improves the mechanical property of actuators but also provides the excellent bonding ability of the two-layer interface, which prevents delamination caused by excessive local stress on the interface during the bending process. Thanks to high-performance behavior, the actuator can act as an effective and sensitive actuator, such as a gripper to capture, transport, and release an object, or as an electrical circuit switch to turn on and off a light-emitting diode (LED). Overall, such hydrogel actuator may provide new insights for the design and fabrication of artificial intelligence materials.

Cell-Free Bilayered Porous Scaffolds for Osteochondral Regeneration Fabricated by Continuous 3D-Printing Using Nascent Physical Hydrogel as Ink.

Cartilage is difficult to self-repair and it is more challenging to repair an osteochondral defects concerning both cartilage and subchondral bone. Herein, it is hypothesized that a bilayered porous scaffold composed of a biomimetic gelatin hydrogel may, despite no external seeding cells, induce osteochondral regeneration in vivo after being implanted into mammal joints. This idea is confirmed based on the successful continuous 3D-printing of the bilayered scaffolds combined with the sol-gel transition of the aqueous solution of a gelatin derivative (physical gelation) and photocrosslinking of the gelatin methacryloyl (gelMA) macromonomers (chemical gelation). At the direct printing step, a nascent physical hydrogel is extruded, taking advantage of non-Newtonian and thermoresponsive rheological properties of this 3D-printing ink. In particular, a series of crosslinked gelMA (GelMA) and GelMA-hydroxyapatite bilayered hydrogel scaffolds are fabricated to evaluate the influence of the spacing of 3D-printed filaments on osteochondral regeneration in a rabbit model. The moderately spaced scaffolds output excellent regeneration of cartilage with cartilaginous lacunae and formation of subchondral bone. Thus, tricky rheological behaviors of soft matter can be employed to improve 3D-printing, and the bilayered hybrid scaffold resulting from the continuous 3D-printing is promising as a biomaterial to regenerate articular cartilage.

Actuating Supramolecular Shape Memorized Hydrogel Toward Programmable Shape Deformation.

Inspired by nature, diverse biomimetic hydrogel actuators are fabricated and become one of the most essential components of bionics research. Usually, the anisotropic structure of a hydrogel actuator is generated at the early fabrication process, only a specific shape transformation behavior can be produced under external stimuli, and thus has limited the development of hydrogel actuators toward the biomimetic shape deformation behavior. Herein, a novel bilayer hydrogel having a thermoresponsive actuating layer and a metal ion-responsive memorizing layer is proposed, therefore, a 2D hydrogel film can be fixed into various 3D shapes via supramolecular metal-ligand coordination, with further realizing programmable 4D shape deformation under the stimulus of temperature. By manipulating the temporary shapes via shape memory behavior, various temporary anisotropic structures can be obtained via the bilayer hydrogel, thus producing diverse reversible shape deformation performances, which is expected to promote the development of intelligent polymeric materials.

Thermally triggered soft actuators based on a bilayer hydrogel synthesized by gamma ray irradiation

Hydrogel soft actuators, which have a bilayer structure consisting of a temperature-responsive active layer and a passive layer, were prepared by a gamma ray radiation-induced polymerization and cross-linking process. We synthesized single layer hydrogels of poly(N-isopropyl acrylamide) (PNIPAAm), poly(N-isopropyl acrylamide-co-acrylic acid) (PNIPAAm-PAAc), or poly(acrylamide) (PAAm) and bilayer hydrogels of PNIPAAm/PAAm and PNIPAAm-PAAc/PAAm with a range of cross-link densities. It was confirmed that PNIPAAm-based hydrogels could be synthesized without any additives through effective polymerization and cross-linking reactions under a gamma ray irradiation dose >20 kGy. Most hydrogels had a gel fraction >80%, which gradually increased with gamma ray irradiation dose and cross-linker content. All PNIPAAm-based hydrogels showed a high equilibrium water content (EWC) of >90%. As the cross-link density within the hydrogel matrix increased, the EWC gradually decreased, while the mechanical strength tended to increase linearly. It was found that the temperature-responsive bending actuation of the PNIPAAm-based hydrogel with a bilayer structure could be controlled by monomer composition, cross-link density, and the geometrical parameters of hydrogel. In addition, all A549 cells exposed to the extracts of PNIPAAm/PAAm and PNIPAAm-PAAc/PAAm hydrogels exhibited >77% cell viability. This gamma ray radiation-induced hydrogel with bilayer structure provides a new strategy for the construction of stimuli-responsive and shape-transformable hydrogel actuators for various applications including biomimetic robotics, wearable devices, medical devices, and environmental sensors.

A 3D, Dynamically Loaded Hydrogel Model of the Osteochondral Unit to Study Osteocyte Mechanobiology.

Osteocytes are mechanosensitive cells that orchestrate signaling in bone and cartilage across the osteochondral unit. The mechanisms by which osteocytes regulate osteochondral homeostasis and degeneration in response to mechanical cues remain unclear. This study introduces a novel 3D hydrogel bilayer composite designed to support osteocyte differentiation and bone matrix deposition in a bone-like layer and to recapitulate key aspects of the osteochondral unit's complex loading environment. The bilayer hydrogel is fabricated with a soft cartilage-like layer overlaying a stiff bone-like layer. The bone-like layer contains a stiff 3D-printed hydrogel structure infilled with a soft, degradable, cellular hydrogel. The IDG-SW3 cells embedded within the soft hydrogel mature into osteocytes and produce a mineralized collagen matrix. Under dynamic compressive strains, near-physiological levels of strain are achieved in the bone layer (≤ 0.08%), while the cartilage layer bears the majority of the strains (>99%). Under loading, the model induces an osteocyte response, measured by prostaglandin E2, that is frequency, but not strain, dependent: a finding attributed to altered fluid flow within the composite. Overall, this new hydrogel platform provides a novel approach to study osteocyte mechanobiology in vitro in an osteochondral tissue-mimetic environment.

Soft elastic hydrogel couplants for ultrasonography

Couplants play significant roles in ultrasonography. To ensure imaging quality, it is critical to maintain conformal contact of the couplant with both the skin surface and the ultrasound probe in clinical applications. In addition, either the probe or the couplant should not deform the skin surface significantly, which will result in an overestimated modulus of the tissue for elastography imaging. However, existing liquid gel couplants cannot bear external compressive force, while existing solid gel couplants cannot maintain a conformal contact with skin surface. Especially, the nonconformal contacts and deformation become more severe on body parts of locally high curvatures such as skin tumors, fingers, and elbows. Here we report a bilayer design of couplant for ultrasonography, composing of a stiff layer and a compliant layer of hydrogels. The bilayer hydrogel pad enables it to bear external compression, allowing the probe to move smoothly, conforming high curvature parts and releasing stress concentration. Our clinical experiments further show high quality imaging of thyroid nodules, skin tumors in elbows and fingers using the bilayer hydrogel pad, which represents a promising alternative for a range of applications in ultrasonic diagnosis.

Controlled Cooperative Wetting Enabled Heterogeneous Structured 3D Morphing Transducers

AbstractA unique microfluidics approach for functional hydrogel patterning with multilayered heterogeneous structures is presented. Prepolymer solution droplets with differentiated sodium acrylate concentrations are dispensed/printed in a wetting‐controlled “two‐parallel plate” (TPP, like a Hele‐Shaw Cell) system. The gelation within the system enables hydrogel bilayer structures with reconfigurable 3D deformations driven by in‐plane and through‐thickness heterogeneity under stimuli‐responsive mask‐less swelling/deswelling. The cooperation between swelling mismatch of functional groups results in a higher complexity of 3D reconfiguration in responding to discrete levels of stimulation inputs. This facile patterning technology with an in‐built ionic hierarchy can be scaled up/down with advanced transducing functionalities in various fields.

Smart Bilayer Polyacrylamide/DNA Hybrid Hydrogel Film Actuators Exhibiting Programmable Responsive and Reversible Macroscopic Shape Deformations.

As a crucial instinct for the survival of organisms, adaptive smart deformation has been well shown via profusely astounding examples within biological morphogenesis in nature, which inspired the construction of biomimetic shape-morphing materials with controlled actuating behaviors. Herein, the construction of nature-inspired bilayer hydrogel film actuators, composed of a polyacrylamide hydrogel passive layer and a polyacrylamide-DNA hybrid hydrogel active layer, which exhibited programmable stimuli-responsive and reversible macroscopic shape deformations directed by the sequence of DNA crosslinking units in the active layer, is reported. As a proof-of-concept, the introduction of DNA i-motif based crosslinking structures into the active layer, which can undergo pH-stimulated formation and dissociation of crosslinking between polymers and therefore change the crosslinking density of the active layer, lead to the redistribution of the internal stresses within the bilayer structure, and result in the pH-stimulated shape deformations. By programming the sequence of DNA units in the active layer, a Ag+ /Cysteamine-stimulated bilayer DNA hybrid hydrogel film actuator is further constructed and exhibits excellent actuation behaviors. Thanks to the micrometer-scale thickness of the films, these actuators exhibit a high degree of macroscopic and reversible shape deformations at high speed, which may find use in future smart biosensing and biomedical applications.

Bilayer wound dressing based on sodium alginate incorporated with curcumin-β-cyclodextrin inclusion complex/chitosan hydrogel

The aim of this study was to fabricate and characterize curcumin-β-cyclodextrin inclusion complex loaded sodium alginate/chitosan (CMx-loaded SA/CS) bilayer hydrogels for use as wound dressing materials. Various concentrations of calcium chloride (CaCl2) including 0.05, 0.10, and 0.20% w/v was directly added to SA layer for crosslinking hydrogels. The morphology, Attenuated total reflection-Fourier transform infrared (ATR-FTIR) analysis, thermal properties, mechanical properties, moisture absorption, mucoadhesion, water swelling and weight loss, release characteristics, antibacterial activity, and indirect cytotoxicity of the bilayer hydrogels were investigated. The results showed that the SA and CS layers were successfully attached through electrostatic force. Increasing CaCl2 concentration caused the mechanical properties to increase but the moisture absorption, water swelling, and weight loss to decrease. Moreover, the high content of CaCl2 tended to decrease maximum detachment force. For the release study, the hydrogels showed similar release behavior of CM. The CMx-loaded SA/CS bilayer hydrogels exhibited inhibition against both Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). All CMx-loaded SA/CS bilayer hydrogels were non-toxic to NCTC clone 929 cells and normal human dermal fibroblast cells. Therefore, these bilayers might be a good candidate for use in wound dressing application.

Skin-Contactable and Antifreezing Strain Sensors Based on Bilayer Hydrogels

Currently, most hydrogel sensors require an isolation layer to prevent current from damaging the skin. However, the mismatch of mechanical property between the isolation layer and the hydrogel sens...

Synthesis, test, calibration and modeling of a temperature-actuated hydrogel bilayer

Smart structures such as temperature-sensitive actuators made of soft hydrogels can be useful for designing biomedical devices. In this study, free swelling and force generation behavior of a bilayer actuator based on thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) hydrogel and an elastomer under various loading profiles has been investigated. The thermo-sensitive hydrogel was synthesized by redox-initiated radical polymerization. We then prepared a bilayer actuator made of temperature-sensitive PNIPAM hydrogel, and examined its behavior under different loading conditions such as free swelling and force generation to study different aspects of the response of the hydrogel, including homogeneous free swelling and confined swelling using two approaches for (monolayer) hydrogel. Experiments on free swelling and force generation swelling of the bilayer actuator were also performed. After implementing an appropriate hydrogel constitutive model within a finite element framework, material parameters (of both the hydrogel and an elastomer) required in fabrication of the bilayer were calibrated. Using these calibrated material parameters, the same test conditions were simulated, and the numerical results were compared to those of experiments; a good agreement was observed between the experimental tests and numerical outcomes. The results show that the material model parameters are reliable, and the finite element method can be used for designing more complicated structures based on thermo-sensitive hydrogels.

4D-bioprinted silk hydrogels for tissue engineering

Recently, four-dimensional (4D) printing is emerging as the next-generation biofabrication technology. However, current 4D bioprinting lacks biocompatibility or multi-component printability. In addition, suitable implantable targets capable of applying 4D bioprinted products have not yet been established, except theoretical and in vitro study. Herein, we describe a cell-friendly and biocompatible 4D bioprinting system including more than two cell types based on digital light processing (DLP) and photocurable silk fibroin (Sil-MA) hydrogel. The shape changes of 3D printed bilayered Sil-MA hydrogels were controlled by modulating their interior or exterior properties in physiological conditions. We used finite element analysis (FEA) simulations to explore the possible changes in the complex structure. Finally, we made trachea mimetic tissue with two cell types using this 4D bioprinting system and implanted it into a damaged trachea of rabbit for 8 weeks. The implants were integrated with the host trachea naturally, and both epithelium and cartilage were formed at the predicted sites. These findings demonstrate that 4D bioprinting system could make tissue mimetic scaffold biologically and suggest the potential value of the 4D bioprinting system for tissue engineering and the clinical application.

Inhomogeneous swelling behavior of a bi-layered spherical hydrogel containing a hard core

Hydrogels can absorb a significant amount of water and swell greatly. When the swelling is constrained, hydrogels exhibit inhomogeneous deformation, stress, and water concentration fields. This paper studies the swelling behavior of a bi-layered spherical hydrogel containing a hard core after imbibing sufficient water. By adopting a continuum field theory of hydrogels, the governing differential equation of the hydrogel radial deformation is derived, which is further solved numerically at proper mixed boundary conditions and inner field continuity conditions across the hydrogel interface. Effects of material properties and the presence of the hard core on the deformation, stress, and water concentration fields of the hydrogels are examined. It shows that the inner hard core can remarkably reduce the water concentration near the core surface and simultaneously induce large stresses. In addition, the water concentration in the bi-layered hydrogel heavily depends upon the stiffness of the individual hydrogel. The study offers a rational route to design and regulate hydrogels with tailorable swelling behavior for practical applications in drug delivery, leakage blocking, etc.