Thermo- and pH-Responsive Gelatin/Polyphenolic Tannin/Graphene Oxide Hydrogels for Efficient Methylene Blue Delivery.

Gelatin (GE), amino-functionalized polyphenolic tannin derivative (TN), and graphene oxide (GO) were associated to yield thermo- and pH-responsive hydrogels for the first time. Durable hydrogel assemblies for drug delivery purposes were developed using the photosensitizer methylene blue (MB) as a drug model. The cooling GE/TN blends provide brittle physical assemblies. To overcome this disadvantage, different GO contents (between 0.31% and 1.02% wt/wt) were added to the GE/TN blend at 89.7/10.3 wt/wt. FTIR and RAMAN spectroscopy analyses characterized the materials, indicating GO presence in the hydrogels. Incorporation studies revealed a total MB (0.50 mg/mL) incorporation into the GE/TN-GO hydrogel matrices. Additionally, the proposed systems present a mechanical behavior similar to gel. The GO presence in the hydrogel matrices increased the elastic modulus from 516 to 1650 Pa. SEM revealed that hydrogels containing MB present higher porosity with interconnected pores. Dissolution and swelling degree studies revealed less stability of the GE/TN-GO-MB hydrogels in SGF medium (pH 1.2) than SIF (pH 6.8). The degradation increased in SIF with the GO content, making the polymeric matrices more hydrophilic. MB release studies revealed a process controlled by Fickian diffusion. Our results point out the pH-responsible behavior of mechanically reinforced GE/TN-GO-MB hydrogels for drug delivery systems purposes.

Dual-Crosslink Physical Hydrogels with High Toughness Based on Synergistic Hydrogen Bonding and Hydrophobic Interactions.

Constructing dual or multiple noncovalent crosslinks is highly effective to improve the mechanical and stimuli-responsive properties of supramolecular physical hydrogels, due to the synergistic effects of different noncovalent bonds. Herein, a series of tough physical hydrogels are prepared by solution casting and subsequently swelling the films of poly(ureidopyrimidone methacrylate-co-stearyl acrylate-co-acrylic acid). The hydrophobic interactions between crystallizable alkyl chains and the quadruple hydrogen bonds between ureidopyrimidone (UPy) motifs serve as the dual crosslinks of hydrogels. Synergistic effects between the hydrophobic interactions and hydrogen bonds render the hydrogels excellent mechanical properties, with tensile breaking stress up to 4.6 MPa and breaking strain up to 680%. The UPy motifs promote the crystallization of alkyl chains and the hydrophobic alkyl chains also stabilize UPy-UPy hydrogen bonding. The resultant hydrogels are responsive to multiple external stimuli, such as temperature, pH, and ion; therefore, they show the thermal-induced dual and metal ion-induced triple shape memory behaviors.

Physical Polyurethane Hydrogels via Charge Shielding through Acids or Salts.

Physical hydrogels with tunable stress-relaxation and excellent stress recovery are formed from anionic polyurethanes via addition of acids, monovalent salts, or divalent salts. Gel properties can be widely adjusted through pH, salt valence, salt concentration, and monomer composition. We propose and investigate a novel gelation mechanism based on a colloidal system interacting through charge repulsion and chrage shielding, allowing a broad use of the material, from acidic (pH 4-5.5) to pH-neutral hydrogels with Young's moduli ranging from 10 to 140 kPa.

Self-Assembled Liquid-Crystalline Membranes Form Supramolecular Hydrogels via Hydrogen Bonding.

Developing simple methods to organize nanoscale building blocks into ordered superstructures is a crucial step toward the practical development of nanotechnology. Bottom-up nanotechnology using self-assembly bridges the molecular and macroscopic, and can provide unique material properties, different from the isotropic characteristics of common substances. In this study, a new class of supramolecular hydrogels comprising 40 nm thick linear polymer layers sandwiched between nanolayers of self-assembled amphiphilic molecules are prepared and studied by nuclear magnetic resonance spectroscopy, scanning electronic microscopy, small angle X-ray diffraction, and rheometry. The amphiphilic molecules spontaneously self-assemble into bilayer membranes when they are in liquid-crystal state. The hydrogen bonds at the interface of the nanolayers and linear polymers serve as junctions to stabilize the network. These hydrogels with layered structure are facile to prepare, mechanically stable, and with unique temperature-dependent optical transparency, which makes it interesting in applications, such as soft biological membranes, drug release, and optical filters.

Tuning the underwater adhesiveness of antibacterial polysaccharides complex coacervates.

HYPOTHESIS: Adjusting the water content and mechanical properties of polyelectrolyte coacervates for optimal underwater adhesion requires simultaneous control of the macromolecular design and the type and concentration of the salt used. Using synthetic or bio-inspired polymers to make coacervates often involves complicated chemistries and large variations in salt concentration. The underwater adhesiveness of simple, bio-sourced coacervates can be tuned with relatively small variations in salt concentration. Bio-sourced polymers can also impart beneficial biological activities to the final material. EXPERIMENTS: We made complex coacervates from charged chitosan (CHI) and hyaluronic acid (HA) with NaCl as the salt. Their water content and viscoelastic properties were investigated to identify the formulation with optimal underwater adhesion in physiological conditions. The coacervates were also studied in antibacterial and cytotoxicity experiments. FINDINGS: As predicted by linear rheology, the CHI-HA coacervates at 0.1 and 0.2 M NaCl had the highest pull-off adhesion strengths of 44.4 and 40.3 kPa in their respective supernatants. In-situ physical hardening of the 0.2 M coacervate upon a salt switch in 0.1 M NaCl resulted in a pull-off adhesion strength of 62.9 kPa. This material maintained its adhesive properties in physiological conditions. Finally, the optimal adhesive was found to be non-cytotoxic and inherently antimicrobial through a chitosan release-killing mechanism.

Mechanically strong and on-demand dissoluble chitosan hydrogels for wound dressing applications.

Physical hydrogels of pure chitosan preserve the natural properties of chitosan, and therefore are ideal candidates for wound dressing applications, however, their poor mechanical strength severely limits their application. In addition, chitosan dressings tend to adhere to the wounds, making their change difficult. Here physical hydrogels of pure chitosan were prepared by first dissolving chitosan in an alkaline aqueous solution, followed by thermal gelling and solvent change. The gels exhibited better mechanical properties than the gels prepared previously. They were soluble in diluted acetic acid, making them on-demand dissoluble. When used as wound dressing and changed by mechanical debridement, the gels achieved a faster wound closure than gauze. An even faster wound closure was achieved when they were changed by dissolution with acetic acid solution. Besides a faster healing, the on-demand dissoluble dressing could also reduce the formation of scars and reestablish the normal anatomy and function of the skin.

Super Tough and Intelligent Multibond Network Physical Hydrogels Facilitated by Ti3C2Tx MXene Nanosheets.

Stretchable and conductive hydrogels have emerged as promising candidates for intelligent and flexible electronic devices. Herein, based on a multibond network (MBN) design rationale, super tough and highly stretchable nanocomposite physical hydrogels are prepared, where 2D Ti3C2Tx MXene nanosheets serve as multifunctional cross-linkers and effective stress transfer centers. Further MXene-poly(acrylic acid) (PAA)-Fe3+ MBN physical hydrogels fabricated through controlled permeation of Fe3+ exhibit prominent and well-balanced mechanical properties (e.g., the tensile strength can reach 10.4 MPa and elongation at break can be as high as 3080%), attributed to the dual cross-linking network with dense Fe3+-mediated coordination cross-links between MXene nanosheets and PAA chains and sparse carboxy-Fe3+ cross-links between PAA chains. Moreover, both conductive MXene nanosheets and numerous ions endow the hydrogels with superior conductivity (up to 3.8 S m-1), strain sensitivity (high gauge factor of 10.09), and self-healing performance, showing great prospect as intelligent flexible electronics.

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.

Role of rheological properties on physical chitosan aerogels obtained by supercritical drying.

Chitosan aerogels were obtained after using supercritical carbon dioxide to dry physical hydrogels, studying the effect of the rheological behavior of hydrogels and solutions on the final aerogels properties. An increase on the solutions pseudoplasticity increased the subsequent hydrogels physical entanglement, without showing a significant effect on aerogels morphology (nanoporous) and textural properties (pores of about 10 nm). However, an increase of hydrogel physical entanglement promoted the formation of aerogels with a higher compressive strength (from 0.2 to 0.80 MPa) and higher thermal decomposition range, while decreasing the porosity (from 90 % to 94 %). Aerogels stress-strain responses were also successfully fitted using a hyperelastic equation with three adjustable parameters (Yeoh), showing that this type of models must be taken into account when large stresses are studied.

Embedment of liposomes into chitosan physical hydrogel for the delayed release of antibiotics or anaesthetics, and its first ESEM characterization.

This work describes the characterization of an original liposomes/hydrogel assembly, and its application as a delayed-release system of antibiotics and anaesthetics. This system corresponds to drug-loaded liposomes entrapped within a chitosan (CS) physical hydrogel. To this end, a suspension of pre-formed 1,2-dipalmitoyl-sn-glycero-3-phosphocoline liposomes loaded with an antibiotic (rifampicin, RIF), an anaesthetic (lidocaine, LID), or a model fluorescent molecule (carboxyfluorescein, CF), was added to a CS solution. The CS gelation was subsequently carried out without any trace of chemical cross-linking agent or organic solvent in the final system. Liposomes within the resulting gelled CS matrix were characterized for the first time by environmental scanning electron microscopy. The release of drugs from the assembly was investigated by fluorescence or UV spectroscopy. The cumulative release profiles of RIF and LID (and also CF for comparison) were found to be lower from the "drug-in-liposomes-in-hydrogel" (DLH) assembly in comparison to "drug-in-hydrogel" (DH) system.

Affinity-Triggered Assemblies Based on a Designed Peptide-Peptide Affinity Pair.

Affinity-triggered assemblies rely on affinity interactions as the driving force to assemble physically crosslinked networks. WW domains are small hydrophobic proteins binding to proline-rich peptides that are typically produced in the insoluble form. Previous works attempted the biological production of the full WW domain in tandem to generate multivalent components for affinity-triggered hydrogels. In this work, an alternative approach is followed by engineering a 13-mer minimal version of the WW domain that retains the ability to bind to target proline-rich peptides. Both ligand and target peptides are produced chemically and conjugated to multivalent polyethylene glycol, yielding two components. Upon mixing together, they form soft biocompatible affinity-triggered assemblies, stable in stem cell culture media, and display mechanical properties in the same order of magnitude as for those hydrogels formed with the full WW protein in tandem.

Hydrogels for Hydrophobic Drug Delivery. Classification, Synthesis and Applications.

Hydrogels have been shown to be very useful in the field of drug delivery due to their high biocompatibility and ability to sustain delivery. Therefore, the tuning of their properties should be the focus of study to optimise their potential. Hydrogels have been generally limited to the delivery of hydrophilic drugs. However, as many of the new drugs coming to market are hydrophobic in nature, new approaches for integrating hydrophobic drugs into hydrogels should be developed. This article discusses the possible new ways to incorporate hydrophobic drugs within hydrogel structures that have been developed through research. This review describes hydrogel-based systems for hydrophobic compound delivery included in the literature. The section covers all the main types of hydrogels, including physical hydrogels and chemical hydrogels. Additionally, reported applications of these hydrogels are described in the subsequent sections.

Preparation and characterization of chitosan physical hydrogels with enhanced mechanical and antibacterial properties.

The chitosan physical hydrogels formed under gaseous ammonia atmospheres usually have poor mechanical properties and low antibacterial activities, which limit its application as biomaterials. In the current study, CTS-Ag+/NH3 physical hydrogels with great comprehensive properties were prepared by the gelation of chitosan in the presence of AgNO3 under a gaseous ammonia atmosphere. Compared with the previously reported hydrogels made with chitosan and AgNO3, the CTS-Ag+/NH3 hydrogels were more homogeneous and transparent. In addition, the AgNO3 content in the hydrogels was decreased to 0.064-0.424wt.%. The formation mechanism and the influence of reaction conditions on the structures and properties of CTS-Ag+/NH3 physical hydrogels were characterized by FT-IR, SEM, XPS, XRD and rheological measurement. Tensile testing suggested that CTS-Ag+/NH3 physical hydrogels had a higher tensile strength than the CTS/NH3 hydrogel. Moreover, the CTS-Ag+/NH3 physical hydrogels showed excellent antibacterial activities against both gram positive and negative bacteria.

Synthesis, mechanical and thermal rheological properties of new gellan gum derivatives.

New derivatives of gellan gum (GG) were prepared by covalent attachment of octadecylamine (C18-NH2) to polysaccharide backbone via amide linkage by using bis(4-nitrophenyl) carbonate (4-NPBC) as a coupling agent. The effect of the alkyl chain grafted onto hydrophilic backbone of high molecular weight GG was investigated in terms of physicochemical properties and ability of new derivatives to form hydrogels. A series of hydrogels was obtained in solutions with different kind and concentration of ions and their stability and mechanical properties were evaluated. The obtained derivatives resulted soluble at temperature lower than starting GG and physicochemical properties of obtained hydrogels suggested their potential use in biomedical field.

DESIGN AND CHARACTERIZATION OF A BIOCOMPATIBLE PHYSICAL HYDROGEL BASED ON SCLEROGLUCAN FOR TOPICAL DRUG DELIVERY.

Physical hydrogels of a high-carboxymethylated derivative of scleroglucan (Scl-CM300) were investigated as potential systems for topical drug delivery using three different therapeutic molecules (fluconazole, diclofenac and betamethasone). Rheological tests were carried out on drug-loaded hydrogels along with in-vitro release studies in a vertical Franz cell, in order to investigate if and how different drugs may influence the rheological and release properties of Scl-CM300 hydrogels. Experimental results and theoretical modeling highlighted that, in the absence of drug/polymer interactions (as for fluconazole and betamethasone) Scl-CM300 matrices offer negligible resistance to drug diffusion and a Fickian transport model can be adopted to estimate the effective diffusion coefficient in the swollen hydrogel. The presence of weak drug/hydrogel chemical bonds (as for diclofenac), confirmed by frequency sweep tests, slow down the drug release kinetics and a non-Fickian two-phase transport model has to be adopted. In-vivo experiments on rabbits evidenced optimal skin tolerability of Scl-CM300 hydrogels after topical application.

Liposome-loaded chitosan physical hydrogel: toward a promising delayed-release biosystem.

This work deals with the elaboration of an original biosystem in view of its application as drug delayed-release device in biomedical area. This innovative "hybrid" system is composed of phosphatidylcholine liposomes entrapped within a chitosan physical hydrogel (only constituted of polymer and water). To this end, pre-formed liposomes were suspended into chitosan solutions, and the polymer gelation process was subsequently carried out following particular experimental conditions. This liposome incorporation did absolutely not prevent the gel formation as shown by rheological properties of the resulting tridimensional matrix. The presence of liposomes within the hydrogel was confirmed by fluorescence and cryo-scanning electron microscopies. Then, the expected concept of delayed-release of this "hybrid" system was proved using a model water soluble molecule (carboxyfluorescein, CF) encapsulated in liposomes, themselves incorporated into the chitosan hydrogel. The CF release was assayed after repeated and intensive washings of hydrogels, and was found to be higher in the CF-in-hydrogel systems in comparison with the CF-in-liposomes-in-hydrogel ones, demonstrating a CF delayed-release thanks to lipid vesicles.

Physicochemical modulation of chitosan-based hydrogels induces different biological responses: interest for tissue engineering.

Polysaccharide-based hydrogels are remarkable materials for the development of tissue engineering strategies as they meet several critical requirements for such applications and they may partly mimic the extracellular matrix. Chitosan is widely envisioned as hydrogel in biomedical fields for its bioresorbability, biocompatibility, and fungistatic and bacteriostatic properties. In this study, we report that the modulation of the polymer concentration, the degree of acetylation, the gelation processes [or neutralization routes (NR)] in the preparation of different chitosan-based hydrogels lead to substantially and significantly different biological responses. We show that it is possible to tune the physicochemical characteristics, mechanical properties, and biological responses of such matrices. Physical hydrogels prepared from highly acetylated chitosan were softer, degraded quickly in vivo, and were not suitable for in vitro culture of human mesenchymal stem and progenitor derived endothelial cells. In contrast, for a same chitosan concentration and obtained by the same processing route, a low degree of acetylation chitosan hydrogel provided a more elastic material, better cell adhesion on its surface and tissue regeneration, and restored tissue neo-vascularization as well. This work offers promising and innovative perspectives for the design of hydrogel materials with tunable properties for tissue engineering and regenerative medicine.