Phase-separated Hydrogels Research Articles

Temperature-Governed Microstructure of Poly(vinyl alcohol) Hydrogels Prepared through Mixed-Solvent-Induced Phase Separation.

The formation of phase-separated structures in hydrogels plays a crucial role in determining their optical and mechanical properties. Traditionally, phase-separated hydrogels are prepared through a two-step process involving initial hydrogel synthesis followed by post-treatment. In this study, we present an approach for temperature-governed phase separation microstructure modulation in hydrogels, harnessing the cononsolvency effect. This method allows the phase-separated structure to develop during hydrogel synthesis, significantly simplifying the preparation process. Importantly, we found that the preparation temperature has a substantial effect on the internal structure of the phase-separated hydrogel. We systematically investigated how the temperature influences the phase structure, optical properties, and mechanical performance of these hydrogels. The resulting hydrogels demonstrate excellent moisturizing and antifreezing capabilities. Additionally, the incorporation of sodium chloride imparts remarkable electrical conductivity to the hydrogels, making them suitable for strain sensing applications across a wide temperature range.

Microstructure and characteristics of phase-separated gels of Type-A gelatin and hydroxypropyl starch: pH responsiveness

The impact of phase separation behavior on the performance of hydrogels has always been the research focus. This study explored the relationship of “pH-microstructure-hydrogel properties” of phase-separated hydrogels composed of type-A gelatin (GE, 5 wt%) and hydroxypropyl starch (HPS, 3 wt%). The results revealed that changes in the microstructure of the hydrogel at different pHs significantly impacted the gel properties. At pH 4.00 and 11.00, phase separation occurred in the GE/HPS gel with a microstructure of HPS-in-GE. In particular, at pH 5.00, 6.00, 7.00, and 9.00, severe phase separation resulted in the separation of substantial aggregates of HPS and GE, resulting in a continuous phase structure. At pH 2.00 and 3.00, phase separation was suppressed, resulting in a homogeneous microstructure. Compared to the phase-separated gels at pH 4.00–11.00, the homogeneous systems at pH 2.00 and 3.00 displayed a synergistic effect with higher gel strength. Analysis of intermolecular forces in the GE/HPS gel indicated that hydrogen bonding was the primary interaction force. Furthermore, the addition of GE/HPS into hawthorn jelly at about pH 3.00 effectively preserved the structural appearance and exhibited higher levels of hardness, thus improving the sensory properties of hawthorn jelly. In summary, phase separation decreased the storage modulus of GE/HPS gel, but the compatibility of GE/HPS macromolecules exhibited synergistic effects at 2.00 and 3.00 and improved the hydrogel mechanical properties. This work provides some new insights for GE/HPS-based gel foods.

Inducing an LCST in hydrophilic polysaccharides via engineered macromolecular hydrophobicity

Thermoresponsive polysaccharide-based materials with tunable transition temperatures regulating phase-separated microdomains offer substantial opportunities in tissue engineering and biomedical applications. To develop novel synthetic thermoresponsive polysaccharides, we employed versatile chemical routes to attach hydrophobic adducts to the backbone of hydrophilic dextran and gradually increased the hydrophobicity of the dextran chains to engineer phase separation. Conjugating methacrylate moieties to the dextran backbone yielded a continuous increase in macromolecular hydrophobicity that induced a reversible phase transition whose lower critical solution temperature can be modulated via variations in polysaccharide concentration, molecular weight, degree of methacrylation, ionic strength, surfactant, urea and Hofmeister salts. The phase separation is driven by increased hydrophobic interactions of methacrylate residues, where the addition of surfactant and urea disassociates hydrophobic interactions and eliminates phase transition. Morphological characterization of phase-separated dextran solutions via scanning electron and flow imaging microscopy revealed the formation of microdomains upon phase transition. These novel thermoresponsive dextrans exhibited promising cytocompatibility in cell culture where the phase transition exerted negligible effects on the attachment, spreading and proliferation of human dermal fibroblasts. Leveraging the conjugated methacrylate groups, we employed photo-initiated radical polymerization to generate phase-separated hydrogels with distinct microdomains. Our bottom-up approach to engineering macromolecular hydrophobicity of conventional hydrophilic, non-phase separating dextrans to induce robust phase transition and generate thermoresponsive phase-separated biomaterials will find applications in mechanobiology, tissue repair and regenerative medicine.

Mechanochromic luminescence of phase-separated hydrogels that contain cyclophane mechanophores

Phase-separated hydrogels that contain cyclophane mechanophores exhibit mechanochromic luminescence.

Liquid-Liquid Phase-Separated Hydrogel with Tunable Sol-Gel Transition Behavior as a Hotmelt-Adhesive Postoperative Barrier.

Postoperative barriers have been widely used to prevent adhesions. However, there are currently few barriers that satisfy clinical requirements, such as tissue adhesion, operability, and biocompatibility. Inspired by the adhesion system of living organisms, we report a liquid-liquid phase-separated hydrogel as a single-syringe hotmelt-type postoperative barrier. Mixing polyethylene glycol with gelatin formed liquid-liquid phase-separated hydrogels through segregative liquid-liquid phase separation. Incorporation of a liquid-liquid phase-separated system into gelatin can enhance the sol-gel transition temperature to give a hotmelt-adhesive property to hydrogels. Hotmelt-adhesive hydrogels became a sol phase and cohered into tissue gaps when warmed and solidified at body temperature to adhere to soft tissues. The hydrogels exhibited tissue adhesion to large intestine tissues and showed improved mechanical strength, gelation time, and shear-thinning properties. In rat cecum-abdominal adhesion models, it was confirmed that the resulting hydrogels prevented abdominal adhesion and did not prevent tissue regeneration. Hotmelt-adhesive hydrogels with high tissue adhesive properties, operability, and biocompatibility have enormous potential as barriers to prevent postoperative complications.

Fast and Large Shrinking of Thermoresponsive Hydrogels with Phase-Separated Structures.

Thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels have been attracting attention in a variety of functional materials, such as biomaterials, because they exhibit a volume phase transition phenomenon near physiological temperatures. However, the slow kinetics and small volume shrinkage of bulk PNIPAAm hydrogels upon heating greatly limit their practical application. Here, we report PNIPAAm hydrogels with phase-separated structures that exhibited ultrafast shrinking upon heating. The phase separation into a PNIPAAm-rich phase and a water-rich phase was formed through aqueous polymerization in the presence of NaClO4 salt. Through structural analysis of the hydrogels, a topologically heterogeneous and porous structure was observed, which was highly dependent on the NaClO4 concentration in the polymerization step. Compared to conventional PNIPAAm hydrogels, the phase-separated hydrogels exhibited much faster and larger shrinkage upon heating. Simultaneously, the hydrogels quickly released a large amount of water owing to the effective water channels inside them. The present method can be widely applied to general hydrogels, and it can address the numerous limitations of hydrogels in terms of operating programmability and deformation efficiency.

Water dynamics and thermal properties of tyramine-modified hyaluronic acid - Gelatin hydrogels

A new family of injectable hydrogels, enzymatically crosslinked from mixtures of tyramine conjugates of hyaluronic acid (HA) and gelatin (Gel) are characterized in terms of their molecular morphology, miscibility and water sorption ability by employing Field Emission Scanning Electron Microscopy, water sorption/desorption measurements and differential scanning calorimetry technique. The hydrogels were chemically crosslinked by reaction of the phenol groups of the tyramine in the presence of the enzyme horseradish peroxidase and a small amount of hydrogen peroxide. The water fraction in the microporous hydrogels, hw, was up to 0.68 being achieved by equilibration in environment of saturated water vapor. Our measurements reveal good miscibility between HA and Gel components in the whole hydration range studied and that the HA/Gel mixtures exhibit glass transition characteristics, water diffusion dynamics and equilibrium water contents that are independent of the composition. The intermolecular interactions have been found to be dependent on the hydration level and the mixtures behave like the Gel component for hw < 0.20 and like the HA for higher hydration levels. On the other hand, the appearance of gel-sol like transition in all mixtures, like in neat Gel component, points to nanoscale heterogeneities in the hydrogels and the existence of Gel-rich nanodomains. Calorimetric measurements on hydrogels at high hydration levels (hw > 0.40) show that they become partially crystallized at subzero temperatures and reveal that absorbed water molecules form, at least, two discrete forms of ice crystals. In the phase separated hydrogels, next to ice phase, a second phase of polymer/water homogeneous mixture with constant water fraction about 0.25 has been identified.

Hierarchically structured phase separated biopolymer hydrogels create tailorable delayed burst release during gastrointestinal digestion

The on demand delivery of novel peptide actives, traditional pharmaceuticals, nutrients and/or vitamins is a ever present challenge due to the digestive and metabolic degradation of the active and the delivery vehicle. Biodegradable biopolymer hydrogels have long held promise as candidates for creating tailored release profiles due to the ability to control gel porosity. The present study describes the creation of novel hierarchical biopolymer hydrogels for the controlled release of lipids/lipophilic actives pharmaceutical ingredients (APIs), and mathematically describes the mechanisms that affect the timing of release. The creation of phase separated protein/polysaccharide core (6.6 wt% gelatin, 40 wt% Oil in water emulsion) shell structures (7 g/L xanthan with 70–140 g/L β-lactoglobulin) altered enzyme mass transport processes. This core shell structure enabled the creation of a tailorable burst release of API during gastrointestinal digestion where there is a delay in the onset of release, without affecting the kinetics of release. The timing of the delay could be readily programmed (with release of between 60 and 240 min) by controlling either the thickness or protein concentration (between 70 g/L and 140 g/L β-lactoglobulin) of the outer mixed biopolymer hydrogel shell (7 g/L xanthan with 70–140 g/L β-lactoglobulin). Enzyme diffusion measurements demonstrated that surface erosion was the main degradation mechanism. A kinetic model was created to describe the delayed burst release behaviour of APIs encapsulated within the core, and successfully predicted the influence of shell thickness and shell protein density on the timing of gastro-intestinal release (in vitro). Our work highlights the creation of a novel family of core-shell hydrogel oral dosage forms capable of programmable delivery of lipids/lipophilic APIs. These findings could have considerable implications for the delivery of peptides, poorly soluble drugs, or the programmed delivery of lipids within the gastrointestinal tract.

An Insight on the Swelling, Viscoelastic, Electrical, and Drug Release Properties of Gelatin–Carboxymethyl Chitosan Hydrogels

ABSTRACTThe present study reports the in-depth analysis of the gelatin–carboxymethyl chitosan hydrogels. The composite system formed phase-separated hydrogels, which is confirmed by scanning electron microscopy. The swelling of the carboxymethyl chitosan-containing hydrogels was lower than the gelatin hydrogel. Macroscale deformation study using a static mechanical tester indicated a viscoelastic nature of the hydrogels. A decrease in the impedance of the hydrogels was observed with an increase in the carboxymethyl chitosan content. The drug release from the hydrogels was predominantly Fickian diffusion mediated and was released in its active form. The results suggested the potential use of the hydrogels as drug delivery matrices.

Thermoresponsive Toughening with Crack Bifurcation in Phase-Separated Hydrogels under Isochoric Conditions.

Thermoresponsive Toughening with Crack Bifurcation in Phase-Separated Hydrogels under Isochoric Conditions.

Gelatin and amylopectin-based phase-separated hydrogels: An in-depth analysis of the swelling, mechanical, electrical and drug release properties

The current study delineates the development of gelatin–amylopectin-based phase-separated hydrogels for drug delivery applications. Gelatin and amylopectin were used as the representative protein and polysaccharide phases, respectively. The hydrogels were prepared by adding different proportions of amylopectin to gelatin solutions and subsequently cross-linking the mixture using glutaraldehyde. Microscopic analysis showed formation of phase-separated hydrogels. Secondary structure of gelatin was conserved within the hydrogels. The presence of amylopectin drastically reduced the rate of water absorption by the hydrogels. Viscoelastic analysis using stress relaxation study suggested an increase in the viscous component of the hydrogels with the increase in the amylopectin content. After incorporating amylopectin within the gelatin hydrogel, even though the bulk resistance remained unaltered, there was a corresponding variation in the capacitive elements of the equivalent electrical models. The release of the drug from the hydrogels was diffusion mediated. Suitable mathematical models were used for the analysis of the swelling (Peleg’s model), viscoelastic (Weichert model), electrical (RQQ model) and drug release (Korsmeyer–Peppas and Peppas–Sahlin models) properties. The drug retained its antimicrobial activity within the hydrogels. An analysis of the results suggested that the developed hydrogels may be explored as matrices for controlled drug delivery applications.

Thermoresponsive Toughening with Crack Bifurcation in Phase-Separated Hydrogels under Isochoric Conditions.

A novel mode of gel toughening displaying crack bifurcation is highlighted in phase-separated hydrogels. By exploring original covalent network topologies, phase-separated gels under isochoric conditions demonstrate advanced thermoresponsive mechanical properties: excellent fatigue resistance, self-healing, and remarkable fracture energies. Beyond the phase-transition temperature, the fracture proceeds by a systematic crack-bifurcation process, unreported so far in gels.

An In-depth Analysis of the Mechanical, Electrical, and Drug Release Properties of Gelatin–Starch Phase-Separated Hydrogels

ABSTRACTGelatin–starch-based phase-separated hydrogels were prepared in this study. Corn starch, soluble starch, and hydrated starch were used as the representative starches for the preparation of the hydrogels. Bright field microscopy suggested the formation of phase-separated hydrogels. An increase in the hydrophilic nature of the starch molecules resulted in decrease in the agglomeration of the starch particles within the gelatin matrices. Fourier transform infrared study confirmed the presence of starch particles within the hydrogels. X-ray diffraction studies suggested that the higher degree of crystallinity of corn starch and soluble starch was responsible for the comparative hydrophobic nature of these starch particles. Hydrated starch was found to be amorphous in nature and can be explained by the destruction of the intramolecular associative forces. Stress relaxation and creep recovery studies indicated predominant elastic nature of the hydrogels. Hydrated starch-containing hydrogels were firmer than corn starch and soluble starch because of the better miscibility of the hydrated starch particles within the gelatin matrices. The bulk resistance of the starch-containing hydrogels was higher. This was because of the capability of the starch particles to behave as dielectric medium. Incorporation of starch particles within the gelatin matrix was found to increase the polymer relaxation-mediated drug diffusion. Metronidazole-loaded hydrogels were found to have good antimicrobial activity.

Development and characterization of gelatin-tamarind gum/carboxymethyl tamarind gum based phase-separated hydrogels: a comparative study

The purpose of this research was to synthesize and characterize gelatin and tamarind gum (TG)/carboxymethyl tamarind (CMT) gum-based phase-separated hydrogels. The hydrogels were thoroughly characterized using bright-field microscope, FTIR spectroscope, differential scanning calorimeter, mechanical tester, and impedance analyzer. The mucoadhesivity, biocompatibility, and swelling property of the hydrogels were also evaluated. The antimicrobial efficiency of ciprofloxacin (model antimicrobial drug) loaded hydrogels was studied against E. coli. The in vitro drug release was carried out in both gastric and intestinal pHs. Microstructural analysis suggested the formation of phase-separated hydrogels. FTIR studies suggested that CMT gum altered the secondary structure of the gelatin molecules. Presence of the polysaccharides within the hydrogels resulted in the increase in the enthalpy and entropy for evaporation of the moisture from the hydrogels. The mechanical studies indicated viscoelastic nature of the hydrogels. Electrical analysis suggested an increase in the impedance of the hydrogels in the presence of the TG. The presence of CMT gum resulted in the decrease in the impedance of the hydrogels. The hydrogels exhibited good mucoadhesivity, biocompatibility, and pH-dependent swelling behavior. The drug-loaded hydrogels showed good antimicrobial activity and the drug release from the hydrogels was pH dependent and diffusion mediated.

Effect of Processed Starches on the Properties of Gelatin-based Physical Hydrogels: Characterization, in vitro Drug Release and Antimicrobial Studies

Sols of starches have been reported to form phase-separated systems when mixed with the gelatin solution. This has been attributed to the thermodynamic incompatibility of the starch-gelatin systems. The current work has been designed to study the effect of processed starches on the properties of the gelatin-starch based phase-separated physical hydrogels. The hydrogels were prepared using corn starch, soluble starch and boiled starch. The hydrogels were characterized by FTIR spectroscopy, thermal studies, textural studies and impedance spectroscopy. Metronidazole was incorporated within the hydrogels. The drug-loaded gels have shown good antimicrobial activity against Escherichia coli and Bacillus subtilis.

Crack blunting and the strength of soft elastic solids

When a material is so soft that the cohesive strength (or adhesive strength, in the case of interfacial fracture) exceeds the elastic modulus of the material, we show that a crack will blunt instead of propagating. Large–deformation finite–element model (FEM) simulations of crack initiation, in which the debonding processes are quantified using a cohesive zone model, are used to support this hypothesis. An approximate analytic solution, which agrees well with the FEM simulation, gives additional insight into the blunting process. The consequence of this result on the strength of soft, rubbery materials is the main topic of this paper. We propose two mechanisms by which crack growth can occur in such blunted regions. We have also performed experiments on two different elastomers to demonstrate elastic blunting. In one system, we present some details on a void growth mechanism for ultimate failure, post–blunting. Finally, we demonstrate how crack blunting can shed light on some long–standing problems in the area of adhesion and fracture of elastomers.

Hydrogels based on poly(ethylene oxide) and poly(tetramethylene oxide) or poly(dimethyl siloxane). III. In vivo biocompatibility and biostability.

To investigate the effects of polymer chemistry and topology (linear or graft copolymer) on in vivo biocompatibility and biostability based on cage implant system, various hydrogels, composed of short hydrophilic [polyethylene oxide (PEO)] and hydrophobic block, were prepared by polycondensation reaction. Poly(tetramethylene oxide) (PTMO) or poly(dimethyl siloxane) (PDMS) was chosen as a hydrophobic block because of their wide utilization as a biomaterial. By using the specimens retrieved from rats killed after 1, 2, 3, 5, and 7 weeks' implantation, cellular and material responses were assessed. Most hydrogels showed a comparable value of macrophage density to Pellethane(R), control polymer, whereas they did significantly lower foreign body giant cell (FBGC) density and coverage because of the presence of PEO. However, PEO block length and polymer topology did not affect macrophage adhesion and FBGC formation in our polymer composition. The hydrogel based on PDMS alone showed significantly lower macrophage density and FBGC density than Pellethane(R), indicating that PDMS plays a role in inhibiting cellular adhesion. The results obtained from gel permeation chromatography curve and Fourier transform infrared spectra exhibited that all the polymers were susceptible to oxidative degradation in vivo. Although Pellethane(R) revealed surface degradation by 5 weeks in vivo, hydrogels showed rapid degradation in the bulk within 2 weeks because of the penetration of oxidative chemicals released from phagocytic cells into PEO domain of phase-separated hydrogels. The more significant degradation was observed in the hydrogels with longer PEO block and PTMO as a hydrophobic block instead of PDMS. It was evident that the minor degradation could be achieved by grafting PEO and adopting PDMS as a hydrophobic block in the hydrogel.