Bilayer Hydrogel Research Articles

Anomalous fracture behavior of soft layered materials

Soft layered material systems are ubiquitous in nature and engineering – from natural biological tissues to engineered devices. However, from the mechanics perspective, why soft layered materials are favored by natural selection and engineering design remains largely unexplored. Here we study the fracture mechanics of heterogeneous soft layered materials. We develop a theoretical framework for analyzing the co-evolving channel cracking and interfacial delamination in soft film/substrate systems, which is then applied on investigating the fracture of bilayer hydrogels – a representative soft layered material. Through both experiment investigation, theoretical analysis and numerical modeling, we find that the heterogeneous soft layered materials exhibit anomalous size-independent fracture behaviors with fracture strains independent of the flaw size and overall structural dimensions, in stark contrast to ordinary homogeneous materials whose stretch at break reduces undesirably with increasing flaw size and structural dimensions. The size-independent fracture behavior leads to notable toughening of soft layered materials. The findings hold for a broad range of hyperelastic soft materials, from biological materials to hydrogels and elastomers, opening potentially new avenues for the development of fracture-resistant soft materials, and motivating new investigations of the development and applications of heterogeneous soft materials.

Composite Spheroid-Laden Bilayer Hydrogel for Engineering Three-Dimensional Osteochondral Tissue.

A combination of hydrogels and stem cell spheroids has been used to engineer three-dimensional (3D) osteochondral tissue, but precise zonal control directing cell fate within the hydrogel remains a challenge. In this study, we developed a composite spheroid-laden bilayer hydrogel to imitate osteochondral tissue by spatially controlled differentiation of human adipose-derived stem cells. Meticulous optimization of the spheroid-size and mechanical strength of gelatin methacryloyl (GelMA) hydrogel enables the cells to homogeneously sprout within the hydrogel. Moreover, fibers immobilizing transforming growth factor beta-1 (TGF-β1) or bone morphogenetic protein-2 (BMP-2) were incorporated within the spheroids, which induced chondrogenic or osteogenic differentiation of cells in general media, respectively. The spheroids-filled GelMA solution was crosslinked to create the bilayer hydrogel, which demonstrated a strong interfacial adhesion between the two layers. The cell sprouting enhanced the adhesion of each hydrogel, demonstrated by increase in tensile strength from 4.8 ± 0.4 to 6.9 ± 1.2 MPa after 14 days of culture. Importantly, the spatially confined delivery of BMP-2 within the spheroids increased mineral deposition and more than threefold enhanced osteogenic genes of cells in the bone layer while the cells induced by TGF-β1 signals were apparently differentiated into chondrocytes within the cartilage layer. The results suggest that our composite spheroid-laden hydrogel could be used for the biofabrication of osteochondral tissue, which can be applied to engineer other complex tissues by delivery of appropriate biomolecules.

3D printing sequentially strengthening high-strength natural polymer hydrogel bilayer scaffold for cornea regeneration.

3D printing of high-strength natural polymer biodegradable hydrogel scaffolds simultaneously resembling the biomechanics of corneal tissue and facilitating tissue regeneration remains a huge challenge due to the inherent brittleness of natural polymer hydrogels and the demanding requirements of printing. Herein, concentrated aqueous solutions of gelatin and carbohydrazide-modified alginate (Gel/Alg-CDH) are blended to form a natural polymer hydrogel ink, where the hydrazides in Alg-CDH are found to form strong hydrogen bonds with the gelatin. The hydrogen-bonding-strengthened Gel/Alg-CDH hydrogel demonstrates an appropriate thickened viscosity and shear thinning for extrusion printing. The strong hydrogen bonds contribute to remarkably increased mechanical properties of Gel/Alg-CDH hydrogel with a maximum elongation of over 400%. In addition, sequentially Ca2+-physical crosslinking and then moderately chemical crosslinking significantly enhance the mechanical properties of Gel/Alg-CDH hydrogels that ultimately exhibit an intriguing J-shaped stress-strain curve (tensile strength of 1.068 MPa and the toughness of 677.6 kJ/m2). The dually crosslinked Gel-Alg-CDH-Ca2+-EDC hydrogels demonstrate a high transparency, physiological swelling stability and rapid enzymatic degradability, as well as suturability. The growth factor and drug-loaded biomimetic bilayer hydrogel scaffold are customized via a multi-nozzle printing system. This bioactive bilayer hydrogel scaffold considerably promotes regeneration of corneal epithelium and stroma and inhibits cornea scarring in rabbit cornea keratoplasty.

Bilayer hydrogel with a protective film and a regenerative hydrogel for effective diabetic wound treatment.

Diabetic foot ulcers (DFUs) are one of the most serious complications of diabetes, often leading to necrosis and amputation. DFU is caused by the intricate diabetic microenvironment, including ischemia, hypoxia, hyperinflammation, reduced angiogenesis, and persistent infection. Traditional wound dressings made of single or mixed materials often struggle to meet all the requirements for effective diabetic wound healing. In contrast, multilayer dressings comprising more than single layers have the potential to address these challenges by combining their diverse chemical and physical properties. In this study, we developed a bilayer hydrogel comprising a GelMA-ALG-nano-ZnO protective film and a COL1-PRP regenerative hydrogel for facilitating diabetic wound healing. We demonstrated the protective properties against bacterial infection of the protective film, while highlighting the regenerative potential of the COL1-PRP hydrogel in promoting fibroblast and MUVEC migration, extracellular matrix secretion and deposition, and angiogenesis. Importantly, the bilayer hydrogel exhibited superior efficacy in promoting full-thickness wound healing in a diabetic rat model compared to its single-layer hydrogel counterparts. This multi-layer approach offers a promising strategy for addressing the complexities of diabetic foot treatment and improving clinical outcomes.

Next-gen biomimetic actuators: bilayer hydrogel evolution in the 21st century and its advancements from a post-2020 perspective

Bilayer hydrogel actuators, consisting of two hydrogel layers with differing rates or proportions of swelling, have emerged as an encouraging category of intelligent materials.

Development OF pH-sensitive wound dressings using PVA/PAA hydrogels and bioactive glass nanoparticles doped with cerium and cobalt

Proper management of chronic wounds is critical to promoting healing and improving patients' quality of life by reducing pain, preventing infection, and restoring function to affected areas. As a result, multifunctional dressings that reduce the need for systemic medications have been investigated in recent years. In this study, we developed a responsive nanocomposite based on a bilayer hydrogel of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) loaded with bioactive glass nanoparticles containing cerium and cobalt. Tensile tests showed that the mechanical strength of the prepared materials depends on the mechanical behavior of PVA and the amount of BG added to the hydrogel. The obtained samples exhibited high hydrophilicity, pH responsiveness with greater absorption at alkaline pH, water vapor permeability, and fluid handling capacity similar to commercial dressings. In addition, flow cytometry indicated cell viability and the prepared hydrogels exhibited antimicrobial activity against Staphylococcus aureus. These materials have potential as biomaterials for wound care due to their pH-responsive behavior, which allows for the controlled release of therapeutic ions.

Preparation of a Dual-Functional Active Film Based on Bilayer Hydrogel and Red Cabbage Anthocyanin for Maintaining and Monitoring Pork Freshness.

In this study, a composite film was created with the dual goal of prolonging pork shelf life and showing freshness. Hydrogel materials as solid base films were selected from gelatin (G), sodium alginate (SA) and carboxymethyl cellulose (CMC) based on their antioxidant activity, water vapor permeability, mechanical properties, as well as their stability, antimicrobial activity, and freshness, which indicates effectiveness when combined with anthocyanins. Furthermore, the effects of several concentrations of red cabbage anthocyanin (R) (3%, 6%, 12%, and 24%) on freshness indicators and bacteriostasis were investigated. The antimicrobial activity of the composite films was evaluated against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. Likewise, the freshness indicates effectiveness was evaluated for NH3. Considering the mechanical properties, antibacterial ability, freshness indicator effect, and stability of the composite film, CS film combined with 12% R was selected to prepare a dual-functional intelligent film for pork freshness indicator and preservation. By thoroughly investigating the effect of composite film on pork conservation and combining with it KNN, the discriminative model of pork freshness grade was established and the recognition rate of the prediction set was up to 93.3%. These results indicated that CSR film can be used for the creation of active food packaging materials.

Cellulose-based bi-layer hydrogel evaporator with a low evaporation enthalpy for efficient solar desalination

Interfacial evaporation through hydrogel-based evaporators is emerging as a sustainable and cost-effective strategy for drinkable water production. Herein, a specially designed bi-layer hydrogel evaporator was fabricated and used for efficient solar water desalination. With cotton linter as cellulose precursor, it was dispersed in a highly concentrated ZnCl2 (65 %) solution, and cross-linked by epichlorohydrin to prepare cellulose composite hydrogel. After removing inorganic salts by salt-leaching, polyaniline (PANi) with broadband and wide-range light absorption was then integrated into the top surface of hydrogel through in situ polymerization to construct a bi-layer evaporator. As a solar evaporator, the water could be evaporated with a low-energy demand, and the heat from the sunlight could be confined at the interface to achieve efficient water evaporation. Therefore, the hydrogel evaporator demonstrates an optimal water evaporation rate of 3.02 kg m−2 h−1 and photothermal conversion efficiency of 89.09 % under 1 sun (1 kW m−2) irradiation. This work provides new possibilities for efficient solar water purification systems with assured water quality.

Mechanical properties of three N-isopropylacrylamide-based semi-interpenetrating network bilayer hydrogels and their effects on multi-stimuli responsiveness

Mechanical properties of three N-isopropylacrylamide-based semi-interpenetrating network bilayer hydrogels and their effects on multi-stimuli responsiveness

3D printed β-sheet-reinforced natural polymer hydrogel bilayer tissue engineering scaffold

3D printed β-sheet-reinforced natural polymer hydrogel bilayer tissue engineering scaffold

Biomimetic injectable and bilayered hydrogel scaffold based on collagen and chondroitin sulfate for the repair of osteochondral defects

The simultaneous regeneration of articular cartilage and subchondral bone is a major challenge. Bioinspired scaffolds with distinct regions resembling stratified anatomical architecture provide a potential strategy for osteochondral defect repair. Here, we report the development of an injectable and bilayered hydrogel scaffold with a strong interface binding force. In this bilayer hydrogel, composed of carbonyl hydrazide grafted collagen (COL-CDH) and oxidized chondroitin sulfate (OCS), which are derivatives of osteochondral tissue components, in combination with poly (ethylene glycol) diacrylate (PEGDA), functions as a cartilage layer; while zinc-doped hydroxyapatite acts as a subchondral bone layer that is based on the cartilage layer. The strong interface between the two layers involves dynamic amide bonds formed between COL-CDH and OCS, and permanent CC bonds formed by PEGDA radical reactions. This bilayer hydrogel can be used to inoculate adipose mesenchymal stem cells which can then differentiate into chondrocytes and osteoblasts, secreting glycosaminoglycan, and promoting calcium deposition. This accelerates the regeneration of cartilage and subchondral bone. Micro-CT and tissue staining revealed an increase in the amount of bone present in new subchondral bone, and new tissues with a structure similar to normal cartilage. This study therefore demonstrates that injectable bilayer hydrogels are a promising scaffold for repairing osteochondral defects.

Polymer Hydrogel Sheets with Perpendicular Cross-Linking Gradient: Non-Monotonic Actuation and Ion-Specific Effects on the Actuation Kinetics.

Non-monotonous actuation, that is, different kinds of motion in response to a single stimulus, is observed in some natural materials but difficult to implement in synthetic systems. Herein, polymer hydrogel sheets made from polyacrylamide (PAAm) or poly(dimethylacrylamide) (PDMAA) with a cross-linking gradient along the sheet thickness are reported. These are obtained by thermally initiated free radical polymerization using a specially designed Teflon mold with a glass lid. The resulting PAAm hydrogels undergo non-monotonous actuation (rolling into a tube and re-opening) when exposed to aqueous media as a single external stimulus. Their actuation kinetics is tuned with anions that have specific ion effects in their interaction with the surrounding solvent and the polymer itself: structure-breaking chloride enhances the hydration of the polymer backbone, structure-making sulfate decreases it, and is thus slowing down the actuation kinetics of the PAAm hydrogels. The PDMAA gel rolls up instantaneously in aqueous NaCl and only re-opens after 24h. PDMAA actuation in aqueous Na2 SO4 is only moderate as the gel didnot swell in that solvent. Bilayer hydrogels made from PAAm and PDMAA (without gradient) show monotonic actuation, closing in NaCl solution and re-opening in Na2 SO4 .

Construction and Properties of High-Toughness Soft-Soft Interfaces Based on the Adhesion of Natural Polyphenols.

Artificial joint replacement is the most effective way to treat osteoarthritis. However, these artificial joints are too stiff with high interfacial contact stress and poor surface lubrication, resulting in stress shielding and severe wear and tear lead to an extremely high failure rate. At present, hydrogels are considered the most promising substitute for artificial joint prostheses owing to their good biocompatibility, adjustable mechanical properties, and excellent flexibility. Nevertheless, a traditional single-layer hydrogel has poor bearing capacity and lubrication, which are far from the properties of natural articular cartilage. The high strength and low friction properties of natural articular cartilage are based on its own multilayer fibrous structure. Therefore, by simulating the multilayer structure of natural cartilage, a bilayer bionic cartilage hydrogel was prepared; that is, the upper hydrogel realized excellent lubrication and the lower hydrogel realized high load-bearing capacity. However, the interface binding of bilayer hydrogels is a challenge at present. Therefore, the interfacial adhesion of the bilayer hydrogel is improved by adding tannic acid (TA) based on the adhesion of the natural polyphenol structure. The average interfacial toughness reaches 3650 J/m2, and the average interfacial shear force reaches 800 kPa. In the preparation of the bilayer hydrogel, taking advantage of the coordination reaction between TA and metal cations, Fe3+ is further added to endow the bilayer hydrogel with excellent mechanical properties and good sliding friction performance. Therefore, this work opens up a new way to construct cartilage-like materials with high toughness and a soft-soft interface.

Novel 3D-printing bilayer GelMA-based hydrogel containing BP, β-TCP and exosomes for cartilage–bone integrated repair

The integrated repair of cartilage and bone involves the migration and differentiation of cells, which has always been a difficult problem to be solved. We utilize the natural biomaterial gelatin to construct gelatin methacryloyl (GelMA), a hydrogel scaffold with high cell affinity. GelMA is mixed with different components to print a bi-layer porous hydrogel scaffold with different modulus and composition in upper and lower layers through three-dimensional (3D) printing technology. The upper scaffold adds black phosphorus (BP) and human umbilical cord mesenchymal stem cells (hUMSCs) exosomes (exos) in GelMA, which has a relatively lower elastic modulus and is conducive to the differentiation of BMSCs into cartilage. In the lower scaffold, in addition to BP and hUMSCs exos, β-tricalcium phosphate (β-TCP), which has osteoconductive and osteoinductive effects, is added to GelMA. The addition of β-TCP significantly enhances the elastic modulus of the hydrogel scaffold, which is conducive to the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs). In vitro experiments have confirmed that the bi-layer scaffolds can promote osteogenesis and chondrogenic differentiation respectively. And in the rabbit cartilage–bone injury model, MRI and micro-CT results show that the 3D printed bi-layer GelMA composite scaffold has a repair effect close to normal tissue.

Reactive Cell Electrospinning of Anisotropically Aligned and Bilayer Hydrogel Nanofiber Networks.

Structured hydrogels that incorporate aligned nanofibrous morphologies have been demonstrated to better replicate the structures of native extracellular matrices and thus their function in guiding cell responses. However, current techniques for nanofiber fabrication are limited in their ability to create hydrogel scaffolds with tunable directional alignments and cell types/densities, as required to reproduce more complex native tissue structures. Herein, we leverage a reactive cell electrospinning technique based on the dynamic covalent cross-linking of poly(ethylene glycol methacrylate (POEGMA) precursor polymers to fabricate aligned hydrogel nanofibers that can be directly loaded with cells during the electrospinning process. The scaffolds were found to support high C2C12 myoblast viabilities greater than 85% over 14 days, with changes in the electrospinning collector allowing for the single-step fabrication of nonaligned, aligned, or cross-aligned nanofibrous networks. Cell aspect ratios on aligned scaffolds were found on average to be 27% higher compared to those on nonaligned scaffolds; furthermore, cell-loaded bilayer scaffolds with perpendicular fiber alignments showed evidence of enabling localized directional cell responses to individual layer fiber directions while avoiding delamination between the layers. This fabrication approach thus offers potential for better mimicking the structure and thus function of aligned and multilayered tissues (e.g., smooth muscle, neural, or tendon tissues).

A Biomimetic Follicle‐Based Design for Engineering Reproductive Technologies

AbstractIn the field of assisted reproductive technologies, oocyte in vitro maturation (IVM) has emerged as a potential alternative to overcome the limitations associated with standard ovarian stimulation treatments. However, current IVM protocols lack standardization and yield oocytes of inferior quality compared to those matured in vivo. To address this issue, novel biomaterials like hydrogels offer distinct advantages in cell culture by providing a 3D cellular environment and facilitating easy adjustment and characterization of mechanical properties, such as hydrogel stiffness. Herein, a novel and reusable bilayer hydrogel system is presented that accurately mimics the mechanical properties of the microenvironment surrounding oocyte maturation. The system comprises an outer layer fabricated from either a 3D‐printed synthetic polymer (2‐vinyl‐4,6‐diamino‐1,3,5‐triazine, (VDT)) or a natural polymer (chitosan), along with an inner layer composed of alginate. By faithfully replicating the mechanical properties of native tissue within a 3D culture environment, this system significantly improves the quality and developmental capacity of oocytes, thus resulting in successful embryo development. Overall, this innovative system holds great potential for future medical research and applications in cell culture, thus representing a significant advancement in assisted reproductive technologies.

Microgel-Modified Bilayered Hydrogels Dramatically Boosting Load-Bearing and Lubrication.

Hydrogel-based articular cartilage replacement materials are promising candidates for their potential to provide both high load-bearing capacity and low friction performance, similar to natural cartilage. Nevertheless, the design of these materials presents a significant challenge in reconciling the conflicting demands of the load-bearing capacity and lubrication. Despite extensive research in this area, there is still room for improvement in the creation of hydrogel-based materials that effectively meet these demands. Herein, a facile strategy is provided to realize simultaneously high load-bearing and low friction properties on the proposed hydrogel by modifying the surface of mechanically strong annealled PVA-PAAc hydrogel with a high hydration potential PAAm-co-PAMPS microgel. Consequently, a bilayer hydrogel with a porous surface and a compact substrate has been obtained. Compressive experiments confirmed that the bilayer hydrogel exhibited excellent mechanical strength with a compressive strength of 32.23 MPa at 90% strain. A high load-bearing (applied load up to 30 N), extremely low friction coefficiency (0.01-0.05) and excellent wear resistance (COF low to 0.03 after a 4 h test at 10 N using a steel ball as the contact pair) are successfully achieved. These findings provide new perspectives for the design of articular cartilage materials.

Design of an anti-scald photothermal hydrogel for rapid bacteria removal and hemostasis

Applying hydrogels as medical dressing in treating wounds has become a research hotspot in recent years. Photothermal hydrogels with antibacterial properties and favorable biocompatibility offer great potential for treating infected wounds. However, the risks associated with photosensitizer leakage and excessive heat cause edema and vascular damage, cutting off the nutrients and oxygen supply and slowing the wound healing rate. Herein, a bilayer hydrogel (AuDG2) containing the photothermal and heat-absorbing hydrogel layers is developed to generate adequate heat for quick bacteria removal and tissue protection. In this system, Au nanoparticles are firmly fixed to the nano-hydroxyapatite and coated in the photothermal hydrogel layer, effectively avoiding the leakage of the photosensitizer. Near-infrared imaging shows AuDG2 hydrogel maintains 48–50 °C at the wound by heat exchange between the two layers of it. This property enables AuDG2 to have an 89.68 % clearance rate against Staphylococcusaureus (S. aureus) and a 73.03 % removal efficiency of Escherichia coli (E. coli) within 5 min, increasing the healing area of infected wounds by 26.45 % compared to the normal saline treatment group, without adverse effects from burns, and evaporate water from the blood to stop blooding in a very short time. This anti-scald photothermal hydrogel structure is simple in preparation, offering the possibility to mitigate the side effects of photothermal therapy.

Fabrication of flexible accelerated-wound-healing chitosan/dopamine-based bilayer hydrogels for strain sensors

Flexible conductive hydrogels have great potential for healthcare and human motion sensing. However, it is difficult to simultaneously achieve conductive hydrogel epidermal sensors with reliable adhesion capabilities and excellent sensing properties, as well as accelerated wound healing performance in wearable hydrogels. Here, an epidermal sensor with excellent adhesion (0.6 kPa) and tensile strain (218.0 %) properties was assembled from an easy-to-prepare bilayer antimicrobial hydrogel, which effectively accelerates wound healing, as well as for human motion sensing. The upper hydrogel layer was composed of PVA, which could effectively enhance the mechanical properties of the bilayer hydrogel. The lower hydrogel layer consisted of polyacrylamide (PAm) and chitosan-dopamine (CC-DA). PAm with good adhesion properties adhered effectively to the skin surface. CC-DA not only had adhesion properties, but also has good antibacterial effects. It inhibited the growth of bacteria, which assisted in wound healing and infection prevention. Therefore, the design of the bilayer hydrogel combined the mechanical enhancement of PVA with the adhesion properties and antimicrobial effect of PAm and CC-DA to provide better wound repair. In addition, the double-layer hydrogel with good electrical conductivity (1.65 S·m−1) could sensitively monitor the tiny electrophysiological signals emitted by the human body during exercise rehabilitation training.

Thermoresponsive double-network hydrogel/elastomer hybrid bilayer laminates with high interfacial toughness and controllable shape deformations

Thermoresponsive hydrogel-based actuators have shown great potential in tissue engineering, biosensors and soft robots, while the preparation of temperature-driven bilayer hydrogel actuators with rapid responseness and recovery properties remains a challenge. Inspired by the layered heterostructure of human skin, we developed a Janus bilayer structure actuator consisting of thermoresponsive double network (TDN) hydrogel and polydimethylsiloxane (PDMS) elastomer with tough interface adhesion. Specifically, PNaAMPS/P(NIPAM-co-AAm) TDN hydrogel via photocopolymerization of N-isopropyl acrylamide (NIPAM) and acrylamide (AAm) and reinforced by microgel poly(2-acrylamide-2-methylpropane sulfonate sodium salt) (PNaAMPS) was in situ grafted onto benzophenone-activated PDMS surface, exhibiting strong interface adhesion (628 Jm-2 adhesion energy). The thermoresponsive shape deformations of the double-layer structure actuator were controllable by adjusting hydrogel/elastomer thickness ratio and introduction of metal ions, taking advantage of the different swelling and shrinkage characteristics of the hydrogel layer and the elastomer layer. The TDN/PDMS bilayer structure actuator, which integrates the "Janus" structure, thermal responsiveness and photothermal conversion, provides new ideas for the application and remote control of soft robots and soft actuators.