Elastic Hydrogel Research Articles

Engineering Tough, Injectable, Naturally Derived, Bioadhesive Composite Hydrogels.

Engineering mechanically robust bioadhesive hydrogels that can withstand large strains may open new opportunities for the sutureless sealing of highly stretchable tissues. While typical chemical modifications of hydrogels, such as increasing the functional group density of crosslinkable moieties and blending them with other polymers or nanomaterials have resulted in improved mechanical stiffness, the modified hydrogels have often exhibited increased brittleness resulting in deteriorated sealing capabilities under large strains. Furthermore, highly elastic hydrogels, such as tropoelastin derivatives are highly expensive. Here, gelatin methacryloyl (GelMA) is hybridized with methacrylate-modified alginate (AlgMA) to enable ion-induced reversible crosslinking that can dissipate energy under strain. The hybrid hydrogels provide a photocrosslinkable, injectable, and bioadhesive platform with an excellent toughness that can be tailored using divalent cations, such as calcium. This class of hybrid biopolymers with more than 600% improved toughness compared to GelMA may set the stage for durable, mechanically resilient, and cost-effective tissue sealants. This strategy to increase the toughness of hydrogels may be extended to other crosslinkable polymers with similarly reactive moieties.

Injectable Therapeutic Organoids Using Sacrificial Hydrogels

SummaryOrganoids are becoming widespread in drug-screening technologies but have been used sparingly for cell therapy as current approaches for producing self-organized cell clusters lack scalability or reproducibility in size and cellular organization. We introduce a method of using hydrogels as sacrificial scaffolds, which allow cells to form self-organized clusters followed by gentle release, resulting in highly reproducible multicellular structures on a large scale. We demonstrated this strategy for endothelial cells and mesenchymal stem cells to self-organize into blood-vessel units, which were injected into mice, and rapidly formed perfusing vasculature. Moreover, in a mouse model of peripheral artery disease, intramuscular injections of blood-vessel units resulted in rapid restoration of vascular perfusion within seven days. As cell therapy transforms into a new class of therapeutic modality, this simple method—by making use of the dynamic nature of hydrogels—could offer high yields of self-organized multicellular aggregates with reproducible sizes and cellular architectures.

Highly elastic superabsorbent collagen/PVP/PAA/PEO hydrogels crosslinked via e-beam radiation

In this work, highly elastic and superabsorbent hydrogels of collagen-poly(vinyl pyrrolidone) (PVP)-poly(acrylic acid) (PAA)-poly(ethylene oxide) (PEO) quaternary copolymer were obtained using e-beam crosslinking reaction to be used for soft tissue engineering. This study is focused on the evaluation of rheological, swelling and stability properties under different pH media, offering in the same time an insight on the hydrogel network parameters. Rheological studies confirm that collagen/PVP/PAA/PEO hydrogels present solid behaviour similar with that of most soft tissue as human abdominal fat, skin and dermis and even more of breast gland or brain and liver. Hydrogels revealed superabsorbent capacity, both in deionized water and in simulated biological buffers, 1600% and 4000%. The stability and physical form of hydrogels were maintained for more than 50 h in environments that simulate both the pH of the healthy skin and that of an infected wound. The elastic modulus and the parameters of the network structure of hydrogels showed the formation of hydrogel with permanent network.

Use of a crosslinked casein micelle hydrogel as a carrier for jaboticaba (Myrciaria cauliflora) extract

Casein micelle hydrogels were developed using transglutaminase (Tgase) as a crosslink agent in order to encapsulate anthocyanins from jaboticaba fruit (Myrciaria cauliflora). Spray dried casein micelles (CMs) powder was rehydrated in ultrapure water at a concentration of 4.5% w/w, and Tgase was added at 3 units/g of casein. The suspensions were incubated at 45 °C for 1 h, followed by enzyme deactivation at 85 °C for 5 min. Jaboticaba extract (JE), obtained from jaboticaba peel, was added to the suspensions at a concentration of 2% (w/w) at 25 °C. In the suspensions, Tgase promoted a reduction in CMs size and an increase in the degree of casein polymerization. The presence of JE did not affect CMs size or charge. The hydrogel samples were produced by acidification of the suspensions using 2% w/w of glucono – δ – lactone until pH 4.5 at 30 °C. The hydrogels were analyzed using small deformation rheology and confocal laser scanning microscopy. Tgase treatment promoted the formation of a more compact protein matrix compared to the samples without the enzyme. The presence of JE decreased hydrogel elasticity and increased hydrogel pore size. The JE release profile was evaluated by immersing the hydrogels in three buffer solutions at pH 2.0, 4.5 and 7.0. The release rates for the hydrogels with Tgase were lower for all pH values. Solutions with higher pH values induced faster release rates. These findings can be applied to specific delivery systems, such as the transport of JE in an intestinal environment.

Effect of interpolymer complex formation between chondroitin sulfate and chitosan-gelatin hydrogel on physico-chemical and rheological properties

The present study focuses on the fabrication of three-dimensional (3D) natural polymeric hydrogel containing chitosan (C), gelatin (GE) and chondroitin sulfate A (CS) to surpass the drawbacks of chitosan-gelatin (C-GE) hydrogel. Hydrogels were prepared using dual gelling agents in the form of β-glycerol phosphate (β-GP) and sodium hydrogen carbonate (SHC) and failed to gel in the absence of either gelling agent. All the hydrogels showed the ability to self-heal when broken into two parts. The addition of CS resulted in the formation of elastic hydrogels during the entire range of applied shear strain (0.001–100 %) compared to hydrogel without CS. CS containing hydrogels resulted in 25–41 % bovine serum albumin in vitro release compared to 77 % in hydrogel without CS at the end of 16 days. The addition of VEGF165 to hydrogel improved cell proliferation drastically in C-GE hydrogel. C-GE-CS hydrogels exhibited better cell growth compared to C-GE hydrogel with or without the addition of VEGF165.

Non-linear rheological study of hydrogel sliding friction in water and concentrated hyaluronan solution

Studying sliding friction of hydrogels in liquid is important for understanding biological friction. This work applies the non-linear rheology approach to study the friction of elastic hydrogels against adhesive glass in water and in concentrated hyaluronan (HA) solution. Using a rheometer in parallel plate geometry, stress-strain Lissajous curves are obtained from the oscillatory strain sweep test. Non-linearity and energy dissipation are characterized the strain-hardening ratio S, and “energy dissipation occupancy” κ, respectively. For friction in water, a clear transition from a linear viscoelastic to non-linear viscoelastic response occurs at a critical strain amplitude. Whereas, in HA solution, significant friction reduction and non-linear viscoelastic response occurs, related to the rheological behaviors of HA film intercalated at the gel/glass interface.

Independent Tuning of Viscous and Elastic Properties of Protein Biomaterials

The composition and mechanical features of the extracellular matrix (ECM) determine cell behavior. Many mechanistic studies have used synthetic, purely elastic hydrogels to examine how ECM stiffness affects cell differentiation, proliferation and migration. However, the ECM is a viscoelastic material, and it has recently become evident that cells also sense and react to its viscous component, which cannot be probed using traditional elastic hydrogels. Hence, there is a need to develop designer viscoelastic materials whose elastic and viscous properties can be tuned independently. Here, we produce hydrogels with tailored viscoelasticity by exploiting fundamental protein unfolding and refolding transitions under force. Our materials are based on engineered titin domain polyproteins, which are casted into hydrogels by photocatalytic crosslinking of exposed tyrosine residues. To modulate the stiffness of the hydrogels, we have increased the length of the random coil regions between the domains of the polyproteins, leading to reduced elastic modulus. Consistent with the anisotropy of protein mechanical unfolding, we have also found that energy dissipation can be tuned by modifying the geometry in which force is applied to the protein domains. Importantly, the modulation of the viscoelastic properties that we engineer takes place at the same protein concentration and crosslink density. Hence, our platform emerges as a unique tool to dissect how specific elastic and viscous cues cooperate to steer cell behavior.

The interplay between network morphology and degradation kinetics of polymers: Theoretical and experimental analysis by means of a 2D model system

ABSTRACTNetwork formation by cross-linking is a common method to incorporate functions like elastic deformability, shape-memory capability or hydrogel formation into polymer materials for medical applications. Since these materials are often intended to degrade, their design would benefit from a quantitative prediction of the interdependence between network architecture and degradation behavior. Here, we introduce a quantitative description of the degradation behavior of polymer networks. A simplified model was developed under the assumption of having an ideal network, where all network strands are terminated by network nodes and each node is connected to the same number of strands. To describe the degradation of real networks, the model was modified by allowing for a varying connectivity of network nodes, which also included free chain-ends. The models were validated by comparison with Langmuir monolayer degradation data from 2D networks formed by cross-linking oligo(ε-caprolactone)diols with dialdehydes. We found that both the ideal network hypothesis and the real network model were in excellent agreement with the experimental data, with the ideal network hypothesis requiring longer network strands than the real network to result in the same degradation behavior. The models were further used to calculate the degradation curves of the corresponding, non cross-linked molecules. By comparison, it was found that the network formation increases the time required to reach 50% degradation of oligo(ε-caprolactone)diols by only 20%. This difference mainly arises from attaching free chain ends to network points.

Fabrication of morphologically modified strong supramolecular nanocomposite antibacterial hydrogels based on sodium deoxycholate with inverted optical activity and sustained release

Low Molecular Weight (LMWG) gelators are small molecules that form supramolecular self-assembly involving physical forces and are highly biocompatible. However, fragility of these physical gels restricts their applicability where gels of higher mechanical strength are required. Herein, we have developed two different types of 2-D carbon nanomaterials viz. graphene oxide (GO) and carbon nanosheet (CNS) embedded sodium deoxycholate (NaDC) hydrogels. XRD, scanning electron microscopy (SEM), rheology and CD studies suggest significant modification of morphological, mechanical, viscoelastic and optical properties of the nanocomposite gels which is ascribed to the presence of the 2D nanotemplates and participation of different surface functionalities of GO and CNS in the gelation process. The overall shear resistance of both the nanocomposite hydrogels upto a shear rate of 300 shears/s−1 and above reveals tremendously improved mechanical stability with respect to the pure gels. The increased shear strength of the GO/NaDC and CNS/NaDC hydrogels is attributed to their 3–4 times broader and longer ribbon like structures in comparison to the fibrous structure of pure gels. The intact ribbon like morphology and greater entanglement impart 10 folds greater viscosity to GO-NaDC hydrogels as compared to better elasticity of CNS-NaDC hydrogels possessing broken ribbon edges. Most interestingly both GO and CNS influence the optical activity of the gels and presence of GO results in inversion of optical activity. The GO-NaDC gels are also found to demonstrate antibacterial activity against E. coli, and S. aureus. Thus, these extraordinarily modified mechanically strong gels have enhanced potential for use in tissue engineering, enantioselective and sustained drug delivery, topical antibiotics and other biomedical applications.

On the role of flexibility in linker-mediated DNA hydrogels.

Three-dimensional DNA networks, composed of tri- or higher valent nanostars with sticky, single-stranded DNA overhangs, have been previously studied in the context of designing thermally responsive, viscoelastic hydrogels. In this work, we use linker-mediated gels, where the sticky ends of two trivalent nanostars are connected through the complementary sticky ends of a linear DNA duplex. We can design this connection to be either rigid or flexible by introducing flexible, non-binding bases. The additional flexibility provided by these non-binding bases influences the effective elasticity of the percolating gel formed at low temperatures. Here we show that by choosing the right length of the linear duplex and non-binding flexible joints, we obtain a completely different phase behaviour to that observed for rigid linkers. In particular, we use dynamic light scattering as a microrheological tool to monitor the self-assembly of DNA nanostars with linear linkers as a function of temperature. While we observe classical gelation when using rigid linkers, the presence of flexible joints leads to a cluster fluid with a much-reduced viscosity. Using both the oxDNA model and a coarse-grained simulation to investigate the nanostar-linker topology, we hypothesise on the possible structure formed by the DNA clusters. Moreover, we present a systematic study of the strong viscosity increase of aqueous solutions in the presence of these DNA building blocks.

Super-stretchable, elastic and recoverable ionic conductive hydrogel for wireless wearable, stretchable sensor

A super-stretchable and self-recoverable ionic conductive hydrogel was designed and used as a wearable stretchable sensor to monitor human body motions.

Highly Stretchable, Elastic, and Sensitive MXene-Based Hydrogel for Flexible Strain and Pressure Sensors.

Electronic skin is driving the next generation of cutting-edge wearable electronic products due to its good wearability and high accuracy of information acquisition. However, it remains a challenge to fulfill the requirements on detecting full-range human activities with existing flexible strain sensors. Herein, highly stretchable, sensitive, and multifunctional flexible strain sensors based on MXene- (Ti3C2Tx-) composited poly(vinyl alcohol)/polyvinyl pyrrolidone double-network hydrogels were prepared. The uniformly distributed hydrophilic MXene nanosheets formed a three-dimensional conductive network throughout the hydrogel, endowing the flexible sensor with high sensitivity. The strong interaction between the double-network hydrogel matrix and MXene greatly improved the mechanical properties of the hydrogels. The resulting nanocomposited hydrogels featured great tensile performance (2400%), toughness, and resilience. Particularly, the as-prepared flexible pressure sensor revealed ultrahigh sensitivity (10.75 kPa−1) with a wide response range (0-61.5 kPa), fast response (33.5 ms), and low limit of detection (0.87 Pa). Moreover, the hydrogel-based flexible sensors, with high sensitivity and durability, could be employed to monitor full-range human motions and assembled into some aligned devices for subtle pressure detection, providing enormous potential in facial expression and phonation recognition, handwriting verification, healthy diagnosis, and wearable electronics.

Investigation on the Structure and Mechanical Properties of Highly Tunable Elastomeric Silk Fibroin Hydrogels Cross-Linked by γ-Ray Radiation.

Silk fibroin (SF) is a natural polymer with low immunogenicity and good biocompatibility. However, most silk-based hydrogels formed through chemical or physical cross-linking are brittle, the preparation of which also inevitably introduces cytotoxic cross-linking agents. Herein, a simple strategy is presented for synthesizing SF hydrogels with tunable mechanical properties by combining γ-ray radiation with ethanol treatment. Neither toxic initiators nor chemical agents are utilized during the whole preparation procedure. For "soft" hydrogels, the compressive moduli are less than 29 kPa (SF-S hydrogels), while for "tough" hydrogels, the compressive moduli are between 1.21 and 2.41 MPa (SF-D hydrogels). Specifically, γ-ray radiation makes SF form uniform and stable chemical cross-linking sites within and between molecular chains, resulting in "soft" and highly elastic SF hydrogels. The physical cross-linking via ethanol treatment leads to the self-assembly of fibroin chains, transforming those soft hydrogels to tough hydrogels. These double cross-linked SF hydrogels (SF-D hydrogels) exhibit excellent mechanical strength. Effects of various cross-linking conditions on the secondary structure, pore structure, mechanical properties, gelation degree, swelling, and in vitro degradation properties are explored. A series of cell experiments demonstrate that the SF hydrogels with different mechanical strength can stimulate the expression of specific genes of rat bone marrow mesenchymal stem cells (BMSCs) in various differentiation directions. These results also show the application prospects in tissue engineering by customizing hydrogels for the mechanical strength of different tissues.

Preparation and properties of a highly elastic galactomannan- poly(acrylamide- N, N-bis (acryloyl) cysteamine) hydrogel with reductive stimuli-responsive degradable properties

An oxidation-reduction responsive degradable highly elastic galactomannan hydrogel was synthesized from galactomannan (GA), N,N-bis (acryloyl) cysteamine (BAC) and acrylamide by grafting polymerization in aqueous solution. The microstructure, degradability and mechanical properties of the hydrogels were emphatically investigated using Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), ultraviolet spectroscopy and differential scanning calorimetry (DSC). The mechanical properties of hydrogels can be improved by adjusting the content of GA. Continuous cyclic compression tests showed that the hydrogel did not rupture under 60 %,70 %,80 % strain and quickly recovered to its original shape. The degradation rate and drug release rate of hydrogel can be adjusted by the concentration of the reductant and the reduction time. These hydrogels broaden the scope of application of GA and can be tuned with a broad range of mechanical, degradation and release properties and therefore hold potential applications in drug carriers, tissue engineering scaffolds, extracellular matrix and other fields.

Highly Stretchable and Tough Physical Silk Fibroin-Based Double Network Hydrogels.

Regenerated silk fibroin (RSF) is a promising biomedical material, but the poor mechanical properties of RSF hydrogels may hinder the use as structural components. Herein, an equilibrium RSF hydrogel is prepared and optimized based on the double network (DN) concept. After sufficient soaking in water and removal of small molecules, the equilibrium RSF DN hydrogels prove stable in water, strong, highly extensible, and tough with 0.26-0.44 MPa tensile strength, 500-900% elongation, and 2 MJ m-3 work of extension. The combination of high strength and extensibility is attributed to the homogeneous morphology and the hydrophobic interactions and hydrogen bonding between the two networks. The strategy in this work overcomes the previous issue of swelling and eventual fracture of as-prepared RSF/SDS DN hydrogels in water. In addition, such mechanically superior RSF DN hydrogels also display low cytotoxicity. It concludes that the elastic and tough RSF DN hydrogels could be engineered by introducing widely used polymer networks, and the hydrogels from inexpensive, environmentally friendly, and biocompatible silk fibroin may hold great potential in biomedical applications.

In vitro and in vivo evaluation of 3D bioprinted small-diameter vasculature with smooth muscle and endothelium

The ability to fabricate perfusable, small-diameter vasculature is a foundational step toward generating human tissues/organs for clinical applications. Currently, it is highly challenging to generate vasculature integrated with smooth muscle and endothelium that replicates the complexity and functionality of natural vessels. Here, a novel method for directly printing self-standing, small-diameter vasculature with smooth muscle and endothelium is presented through combining tailored mussel-inspired bioink and unique ‘fugitive-migration’ tactics, and its effectiveness and advantages over other methods (i.e. traditional alginate/calcium hydrogel, post-perfusion of endothelial cells) are demonstrated. The biologically inspired, catechol-functionalized, gelatin methacrylate (GelMA/C) undergoes rapid oxidative crosslinking in situ to form an elastic hydrogel, which can be engineered with controllable mechanical strength, high cell/tissue adhesion, and excellent bio-functionalization. The results demonstrate the bioprinted vascular construct possessed numerous favorable, biomimetic characteristics such as proper biomechanics, higher tissue affinity, vascularized tissue manufacturing ability, beneficial perfusability and permeability, excellent vasculoactivity, and in vivo autonomous connection (∼2 weeks) as well as vascular remodeling (∼6 weeks). The advanced achievements in creating biomimetic, functional vasculature illustrate significant potential toward generating a complicated vascularized tissue/organ for clinical transplantation.

Spatiotemporal Control of Viscoelasticity in Phototunable Hyaluronic Acid Hydrogels.

Viscoelasticity has emerged as a critical regulator of cell behavior. However, there is an unmet need to develop biomaterials where viscoelasticity can be spatiotemporally controlled to mimic the dynamic and heterogeneous nature of tissue microenvironments. Toward this objective, we developed a modular hyaluronic acid hydrogel combining light-mediated covalent and supramolecular cross-linking to afford spatiotemporal control of network viscoelastic properties. Covalently cross-linked elastic hydrogels or viscoelastic hydrogels combining covalent and supramolecular interactions were fabricated to match healthy and fibrotic liver mechanics. LX-2 human hepatic stellate cells cultured on viscoelastic hydrogels displayed reductions in spreading, actin stress fiber organization, and myocardin-related transcription factor A (MRTF-A) nuclear localization compared to cells on elastic hydrogels. We further demonstrated the dynamic capabilities of our hydrogel system through photo-mediated secondary incorporation of either covalent or supramolecular cross-links to modulate viscoelastic properties. We used photopatterning to create hydrogels with well-controlled patterned regions of stiff elastic mechanics representing fibrotic tissue nodules surrounded by regions of soft viscoelastic hydrogel mimicking healthy tissue. Cells responded to the local mechanics of the patterned substrates with increased spreading in fibrosis-mimicking regions. Together, this work represents an important step forward toward the creation of hydrogel models with spatiotemporal control of both stiffness and viscoelastic cell-instructive cues.

In Situ Crosslinking Temperature-Responsive Hydrogels with Improved Delivery, Swelling, and Elasticity for Endovascular Embolization

Endovascular embolization of cerebral aneurysms is a common approach for reducing the risk of often-fatal hemorrhage. However, currently available materials used to occlude these aneurysms provide incomplete filling (coils) or require a complicated, time-consuming delivery procedure (solvent-exchange precipitating polymers). The objective of this work was to develop an easily deliverable in situ forming hydrogel that can occlude the entire volume of an aneurysm. The hydrogel is formed by mixing a solution of a temperature-responsive polymer containing pendent thiol groups with a solution of poly(ethylene glycol) diacrylate. Incorporation of hydrophilic grafts of Jeffamine® M-1000 acrylamide (JAAm) in the temperature-responsive polymer caused weaker physical crosslinking, facilitated faster and more complete chemical crosslinking, and increased gel swelling. One formulation (30 wt% PNCJ20+PEGDA) could be delivered for over 220 seconds after mixing, formed a strong and elastic hydrogel (G' > 6000 Pa) within 30 minutes and maintained its shape and volume in a model aneurysm under flow. This gel represents a promising candidate water-based material utilizing both physical and chemical crosslinking that warrants further investigation as an embolic agent for saccular aneurysms.

Adaptable boronate ester hydrogels with tunable viscoelastic spectra to probe timescale dependent mechanotransduction

Cells are capable of sensing the differences in elastic and viscous properties (i.e., the ‘viscoelasticity’) of their tissue microenvironment and responding accordingly by changing their transcriptional activity and modifying their behaviors. When designing viscoelastic materials to mimic the mechanical properties of native tissue niches, it is important to consider the timescales over which cells probe their microenvironment, as the response of a viscoelastic material to an imposed stress or strain is timescale dependent. Although the timescale of cellular mechano-sensing is currently unknown, hydrogel substrates with tunable viscoelastic spectra can allow one to probe the cellular response to timescale dependent mechanical properties. Here, we report on a cytocompatible and viscoelastic hydrogel culture system with reversible boronate ester cross-links, formed from pendant boronic acid and vicinal diol moieties, where the equilibrium kinetics of esterification were leveraged to tune the viscoelastic spectrum. We found that viscoelasticity increased as a function of the boronic acid and vicinal diol concentration, and also increased with decreasing cross-linker concentration, where the maximal loss tangent achieved with this system was 0.55 at 0.1 rad s−1. Additionally, we found that the cis-vicinal diols configuration altered the viscoelastic spectra, where a tan δ peak occurred at ~1 rad s−1 for hydrogels functionalized with boronic acid, while an additional peak formed at ≥10 rad s−1 for hydrogels functionalized with both boronic acid and cis-vic-diols. In experiments with NIH-3T3 fibroblasts cultured on these hydrogels, the projected cell area and nuclear area, focal adhesion tension, and subcellular localization of YAP/TAZ were all found to be lower for cells cultured on the viscoelastic hydrogels compared to elastic hydrogels with a similar storage modulus. Despite these differences, there was not a statistically significant relationship between the frequency dependent viscoelastic material properties characterized in this study and cellular morphologies, focal adhesion tension, or the subcellular localization of YAP. While these results demonstrate that mechanotransduction pathways are affected by viscoelasticity, they also suggest that these mechanotransduction pathways are not particularly sensitive to the frequency dependent viscoelastic material properties from 0.1 to 10 rad s−1.

Salt-induced thermal gelation of xyloglucan in aqueous media

The influence of Na2SO4 as a kosmotropic salt on the thermogelation of xyloglucan (XG) solutions was measured by rheology. The gelation occurred at lower temperatures and shorter times when the salt concentration was increased above 0.5 mol.L−1. For Na2SO4 concentrations equal to 1 mol.L−1, a not thermoreversible elastic hydrogel was obtained. Salts containing various types of anions were used, and it was observed that SO42−, HPO42− and H2PO4− promoted the formation of a gelled network. The gel structure was observed using confocal laser scanning microscopy and scanning electron microscopy. In XG containing SO42 at 1 mol.L−1aggregates and gels were formed by interconnected sub-micrometer XG particles. Increasing the concentration of SO42− led to conformation changes in the XG, from a twisted/helical to an extended/flat conformation, as observed using circular dichroism. The naturally occurring hydrophobic sequences promoted an economically feasible XG gelling that may produce thermo and kosmo-sensitive hydrogels.