Controlled Liposome Delivery from Chitosan-Based Thermosensitive Hydrogel for Regenerative Medicine

This work describes the development of an injectable nanocomposite system based on a chitosan thermosensitive hydrogel combined with liposomes for regenerative medicine applications. Liposomes with good physicochemical properties are prepared and embedded within the chitosan network. The resulting nanocomposite hydrogel is able to provide a controlled release of the content from liposomes, which are able to interact with cells and be internalized. The cellular uptake is enhanced by the presence of a chitosan coating, and cells incubated with liposomes embedded within thermosensitive hydrogels displayed a higher cell uptake compared to cells incubated with liposomes alone. Furthermore, the gelation temperature of the system resulted to be equal to 32.6 °C; thus, the system can be easily injected in the target site to form a hydrogel at physiological temperature. Given the peculiar performance of the selected systems, the resulting thermosensitive hydrogels are a versatile platform and display potential applications as controlled delivery systems of liposomes for tissue regeneration.

Xylitol and Maltitol Improve the Rheological Property of Kappa-Carrageenan

To further extend the use of κ-carrageenan (κ-C) in real food systems (such as beverages), the understanding of gelation properties of κ-C with the presence of food ingredients is critical. The effects of xylitol and maltitol (up to 30 wt %) on the rheological and structural properties of κ-C were inspected by means of rheometer and Fourier transform infrared (FTIR). With the addition of xylitol, the gelation temperature increased from 44.1 to 57.3 °C, while the gelation temperature increased from 44.1 to 61.4 °C in maltitol systems. With the increasing concentration of both xylitol and maltitol, the values of fractal dimension df and complex modulus G* of κ-C increased, while the relaxation exponent n decreased from 0.87 to 0.39 of xylitol and 0.87 to 0.78 of maltitol, respectively. These indicated that the gel networks of aqueous κ-C were improved by the addition of xylitol and maltitol. The FTIR results showed that the interaction between κ-C and these polyols contributed to the increase of hydrogen bonds. The effects of maltitol on κ-C were stronger than those of xylitol because of more equatorial-OH bonds in maltitol. These findings contribute to a better understanding of the gelation processes of κ-C/polyols systems.

Colorimetric quantification of linking in thermoreversible nanocrystal gel assemblies

Nanocrystal gel networks can be responsive, tunable materials, but deliberately designing their structure and controlling their properties have been challenging. By employing reversibly bonded molecular linkers, gelation can be realized under conditions predicted by thermodynamics. But, simulations have offered the only microscopic insights, with no experimental means to monitor linking leading to gelation. Here, we introduce a metal coordination linkage with a distinct optical signature allowing us to quantify linking in situ and establish the structural and thermodynamic basis for assembly. Due to coupling between linked indium tin oxide nanocrystals, their infrared absorption shifts abruptly at a chemically tunable gelation temperature. We quantify bonding spectroscopically and use molecular dynamics simulations to understand bonding motifs as a function of temperature, revealing that gel formation is governed by reaching a critical number of effective links that extend the nanocrystal network. Microscopic insights from our colorimetric linking chemistry enable switchable gels based on equilibrium thermodynamic principles, opening the door to rational design of programmable nanocrystal net-work assemblies.

Factors Affecting Gelation of Lidocaine Hydrochloride-Loaded Polyelectrolyte Complex Thermosensitivity Gel for Dry Socket Treatment

Dry socket disease, a pocket wound caused by the tooth extraction that resulted in severe acute pain which requires a topical analgesic with rapidly pain reduction and suppress the pain until the wound healed. This study aimed to investigate factors affecting gelation temperature and gelation time of lidocaine hydrochloride (LH)-loaded polyelectrolyte complex (PEC) thermosensitivity gel for treating dry socket wound. The first factor was investigated the effects of the ratio of three different types of polymers as chitosan (CS), hyaluronic acid (HA) and poloxamer407 (P407) on the phase transition caused by temperature. The second factor was examined the effects of gel preparation methods. The results showed that increasing concentration of the cationic polymer as CS induced the separation of the solution to gel (sol-to-gel) system due to the charge of CS and the charge of PEC. The ratio of HA:P407 affected the gel forming which high concentration of P407 reduced the gelation temperature while low concentration of HA disturbed the sol-to-gel state causing coagulation. The viscosity, spreadability, and swelling were significantly increased due to the concomitant increased in each polymer, HA and P407. The particle of the formulation observed under microscope was found to be less than 1 µm. Phase inversion from sol-to-gel was found after a min at 23°C. Since gelation temperature of the purposed formula is supposed to form gel below 37°C within a short period of injection. The results of the study indicate the suitable sol-to-gel forming in the appropriate temperature and time which should be used for further investigation in the efficacy and safety.

Poloxamer 407 Based Gel Formulations for Transungual Delivery of Hydrophobic Drugs: Selection and Optimization of Potential Additives

The current study aimed to develop poloxamer 407 (P407) gel for transungual delivery of antifungal hydrophobic drugs with sufficient gel strength and drug loading. Gel strength and drug loading of P407 gel was improved by use of functional additives. Hydration enhancement effect was used to select optimum nail penetration enhancer. Face-centered central composite design (FCCCD) was used to observe the effect of the selected penetration enhancer (thioglycolic acid (TGA)) and cosolvent (ethanol) on gelation behavior to develop formulation with enough loading of hydrophobic drug, i.e., terbinafine HCl (TBN), and its permeation across the nail plate without compromising on gel strength. It was observed that increasing concentration of P407 and TGA significantly reduced gelation temperature and enhanced the gel strength of P407 gel and can be used to improve P407 gel strength. Under the scanning electron microscope, the significant effect of TGA as an ungual penetration enhancer was observed on the morphology of the nail plate. Optimized P407 gel prepared with modified cold method showed a gelation temperature of 8.7 ± 0.16 °C, gel strength of 122 ± 7.5 s and drug loading of 1.2% w/w, which was four times more than the drug loading in the gels prepared with conventional cold method. Rheological behavior was pseudoplastic with 47.75 ± 3.48% of gel erosion after 12 washings and 67.21 ± 2.16% of drug release after 12 h. A cumulative amount of TBN permeated from P407 gel with and without PE after 24 h was 27.30 ± 4.18 and 16.69 ± 2.31 µg/cm2, respectively. Thioglycolic acid can be used as a nail penetration enhancer without the chemical modification or addition of extra additives while retaining the gel strength. Water miscible cosolvents with moderate evaporability such as ethanol, can be incorporated to P407 gel by minor modification in method of preparation to load the required dose of hydrophobic drugs. Developed P407 gel formulation with sufficient gel strength and drug loading will be a promising carrier for transungual delivery of hydrophobic antifungal agents.

Applied Rheology as Tool for the Assessment of Chitosan Hydrogels for Regenerative Medicine

The regeneration of soft tissues that connect, support or surround other tissues is of great interest. In this sense, hydrogels have great potential as scaffolds for their regeneration. Among the different raw materials, chitosan stands out for being highly biocompatible, which, together with its biodegradability and structure, makes it a great alternative for the manufacture of hydrogels. Therefore, the aim of this work was to develop and characterize chitosan hydrogels. To this end, the most important parameters of their processing, i.e., agitation time, pH, gelation temperature and concentration of the biopolymer used were rheologically evaluated. The results show that the agitation time does not have a significant influence on hydrogels, whereas a change in pH (from 3.2 to 7) is a key factor for their formation. Furthermore, a low gelation temperature (4 °C) favors the formation of the hydrogel, showing better mechanical properties. Finally, there is a percentage of biopolymer saturation, from which the properties of the hydrogels are not further improved (1.5 wt.%). This work addresses the development of hydrogels with high thermal resistance, which allows their use as scaffolds without damaging their mechanical properties.

Development of a Cyclodextrin-Based Mucoadhesive-Thermosensitive In Situ Gel for Clonazepam Intranasal Delivery

A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer. Moreover, randomly methylated β-Cyclodextrin (RAMEB) was used to improve the low drug solubility. A screening DoE was applied for a systematic examination of the effect of varying the formulation components proportions on gelation temperature, gelation time and pH. Drug-loaded gels at different clonazepam-RAMEB concentrations were then prepared and characterized for gelation temperature, gelation time, gel strength, mucoadhesive strength, mucoadhesion time, and drug release properties. All formulations showed suitable gelation temperature (29–30.5 °C) and time (50–65 s), but the one with the highest drug-RAMEB concentration showed the best mucoadhesive strength, longest mucoadhesion time (6 h), and greatest release rate. Therefore, it was selected for cytotoxicity and permeation studies through Caco-2 cells, compared with an analogous formulation without RAMEB and a drug solution. Both gels were significantly more effective than the solution. However, RAMEB was essential not only to promote drug release, but also to reduce drug cytotoxicity and further improve its permeability.

Flow behaviour of water-in-oil emulsions stabilized by wax crystals

The large temperature gradients experienced by crude oil emulsions in pipelines found in colder environments can lead to the precipitation, deposition and build-up of wax-like species from the crude oil onto the pipe wall that result in flow assurance problems. The objective of this thesis was to understand the rheological behaviour of model water-in-oil emulsions stabilized by wax crystals. The microstructure, phase transitions and rheology of model emulsions constisting of water, mineral oil, parrafin wax and the emulsifier polyglycerol polyricinoleate (PgPr) were investigated. Changes in emulsion flow begaviour (steady state and dynamic) as a function of composition, termperature and passage through a laboratory-scale flowloop were investigated, with these parameters significantly affecting shear flow, yield stress and viscoelasticity. The gelation temperature of wax-containing ('waxy') oil was slightly lower than that of its equivalent emulsion due to differences in the structure of the gelled emulsion network. Overall, this study successfully showed that there exist significant differences in the microstructure and flow behaviour of model crude oil emulsions when wax and a dispersed aqueous phase are present.

Flow behaviour of water-in-oil emulsions stabilized by wax crystals

The large temperature gradients experienced by crude oil emulsions in pipelines found in colder environments can lead to the precipitation, deposition and build-up of wax-like species from the crude oil onto the pipe wall that result in flow assurance problems. The objective of this thesis was to understand the rheological behaviour of model water-in-oil emulsions stabilized by wax crystals. The microstructure, phase transitions and rheology of model emulsions constisting of water, mineral oil, parrafin wax and the emulsifier polyglycerol polyricinoleate (PgPr) were investigated. Changes in emulsion flow begaviour (steady state and dynamic) as a function of composition, termperature and passage through a laboratory-scale flowloop were investigated, with these parameters significantly affecting shear flow, yield stress and viscoelasticity. The gelation temperature of wax-containing ('waxy') oil was slightly lower than that of its equivalent emulsion due to differences in the structure of the gelled emulsion network. Overall, this study successfully showed that there exist significant differences in the microstructure and flow behaviour of model crude oil emulsions when wax and a dispersed aqueous phase are present.