Synthesizing Thermosensitive Hydrogels for Advanced Biomedical Applications

Abstract

The study focuses on the synthesis of thermosensitive hydrogels from N-isopropylacrylamide (NIPAAm) and 2-hydroxyl ethyl acrylate (2HEA), and their interpolymer complexation with Poly(acrylic acid) (PAA). Investigating the influence of pH, molecular weights, and NaCl on complexation, the research extends to evaluating the hydrogels' swelling behavior in surfactant solutions. This innovation paves the way for versatile biomedical applications, including drug delivery systems and wound care materials.

Introduction

The cooperative reaction of complementary macromolecules in solutions opens up broad prospects for the modification of polymers and obtaining a new type of polymer materials.

Moreover, such processes are widely implemented in nature and play an essential role in living organisms. Due to a set value of physical and chemical properties, interpolymer complexes are highly promising for obtaining various kinds of composite film material. They can be effectively utilized as drug carriers, a new generation of wound dressings, for the treatment of wounds and burn injuries, for the creation of systems with controlled drug release, as separating membranes.

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Several methods have been used to prepare various interpolymer complexes. Many studies have been reported on the interpolymer complex (IPC) between Poly(carboxylic acids) with different non-ionic polymers in solutions, such as polyethene oxide, polyethylene glycol, polyvinylpyrrolidone, polyacrylamide and polyvinyl alcohol. The interaction of various non-ionic homo or copolymers with polycarboxylic acids, in aqueous solution, was studied using viscometry, turbidimetry, conductometry and potentiometry methods.

It is well known that the interpolymer complex formation and stabilization between Polyacids and nonionic polymers is dependent on the different parameters such as nature and concentrations polymers, temperature, pH, solvent nature, ionic strong and molecular weights.

Our research group characterized water-soluble and water swelling thermosensitive copolymer based on N-isopropyl acrylamide by different methods. We studied the effect of the polymer molecular weight and the solution ionic strength on critical pH values of Interpolymercomplex linear thermosensitive copolymer with PAA in aqueous solutions.

In the present work, we have synthesized thermosensitive hydrogels free-radical copolymerization of NIPAAm with 2HEA and studied their interactions with linear poly(acrylic acid) (PAA) and different surfactants.

Materials, methods and Preparation of solutions

N-Isopropylacrylamide (NIPAAm) was purchased from TCI (Tokyo, Japan) and purified by recrystallization from n-hexane. 2-hydroxyethyl acrylate (2HEA), Ammonium persulfate (APS) and N, N-methylene bis(acrylamide) were from Sigma-Aldrich. Polyacrylic acid (PAA) with molecular weights 2 KDa, 250 KDa and 450 KDa was purchased from Sigma-Aldrich and used as received. Surfactants sodium dodecyl sulfate (DDS) and cetyl-pyridinium bromide (CPB) were purchased from Sigma-Aldrich.

Aqueous solutions were prepared by the direct dissolution of known amounts of PAA in distilled water with stirring. The pH of the solution was determined at 250C using Ion Meter 3345 (Jenway, UK).

The swelling ratio V/V0, where V0 and V are the volumes of the polymer network immediately after synthesis and in the moment of measurements, respectively, was used for characterization of the hydrogels swelling in dynamics. The diameter of samples was measured using a V-630 cathetometer (USSR) with the accuracy of measurement 0,01 mm.

Synthesis of Thermosensitive Hydrogel

Hydrogel based on NIPAAm and 2HEA was synthesized with composition ratios M1=30:70, M2=50:50, M3=70:30 respectively using ammonium persulfate as free radical initiator, N, N-methylene-bis-acrylamide as a crosslinking agent. The resulting mixture was poured into the glass ampoule and saturated by argon for 10 minutes to remove oxygen. Thus, the copolymerization was performed in hermetically sealed glass ampoules at 600C for 40 min. The obtained hydrogels were washed several times with distilled water for 10 days.

Results and Discussion

Interpolymer interactions formed at the phase interface between the polymer and linear polymer solution, due to its features attracting the close attention of researchers. The formation of such complexes creates the possibility of modeling of medicinal substances, and changes due to the appearance of the complex can be observed with the naked eye since highly swelling hydrogels are very sensitive and respond quickly to changes in the environment.

Of particular importance is the study of complexes formed between nonionic polymers and linear polyacrylic acid solutions, as such hydrogels can be applied as carriers of medicinal substances. Therefore, to determine the complex formation ability of a cross-linked copolymer based on N-isopropyl acrylamide (NIPAAm) and 2-hydroxyl ethyl acrylate (2HEA) with polyacrylic acid and to study the obtained interpolymer complex (IPC), several different studies have been carried out.

To obtain interpolymer complexes, first, the swollen equilibrium hydrogels were lowered into PAA aqueous solution with molecular weight (MW) 250 KDa (various buffers). The change in relative volume, depending on time, was determined (Fig.1). As shown in Fig 1, the phenomenon of hydrogel samples contracting was observed at pH=4.04, i.e., some decrease of hydrogel volume was detected. Complexation was carried out due to hydrogen bonds between non-ionic PAA groups and hydrogen bond of the carbonyl group of NIPAAm-2HEA, and IPC becomes more hydrophobic in comparison with the initial grid. Hydrogels volume decreased slowly and finally reached the equilibrium amounts. When pH (9,17) of the environment changes towards a decrease in acidity, a swelling and contraction (collapse) of the hydrogel volume was observed.

Kinetics of NIPAAm-2HEA (50:50 mol.%) hydrogel swelling ratio change in 0.01M solution of PAA. MM=250 KDa; рН = 4,04 (1); 6,89 (2); 9,17 (3).

As the pH value of the environment increases, the difference between chemical potentials of linear macromolecules and the environment increases. At this time IPC was also formed in the external area of polymer volume. From the position of diffusion theory16, 17 the formation of IPC in the volume of polyelectrolyte hydrogel should occur, mainly with the hydrogel compression, because the increase in the density of the charge in the internal region practically does not affect the swelling pressure value of the ion component. Thus, the properties of NIPAAm-HEA hydrogels in a solution of a linear ionic polymer PAA are determined mainly by two competing factors: a complete set of macro chains hydrogel and PAA between the nodes of the crosslinking of the polymer network during complexation, which helps to reduce the volume of the hydrogel; at the hydrogel-solution interface, the charge density increases, and an additional swelling of the polymer network occurs.

Thus, depending on which of the two factors prevail, during the complexation of the linear polyelectrolyte polymer, the nonionic gel either swells or undergoes contraction.

Swelling properties of NIPAAm-2HEA hydrogel in aqueous solutions PAA. [NIPAAm-2HEA] = 50-50 mol.%; [PAA] = 0,01mol/L; МW(PAA) = 2 KDa (1); 250 KDa (2); 450 KDa (3).

It is known that the molecular weight of the linear component has a great influence on the complex formation process and swelling parameters of hydrogels. It follows from the results obtained that in diluted solutions with increasing MW of polymer, there is mesh contraception, while the transition amplitude increases with an increased molecular weight of the linear polymer.

Such property of hydrogel complexes with linear PAA macro chains can be explained from the diffusion theory of polyelectrolyte swelling, taking into account various mesh structures formed in the synthesis process. In fact, in many cases, interpolymer complexes are formed in more enriched with carboxylic group parts and accompanied by hydrogel compression as a result, in these regions and on the hydrogel-solution boundary the charge density increases. This leads to an increase in the electrostatic component of swelling and, in the process of interpolymer interaction swelling occurs. And with a significant increase in the molecular weight of PAA, there is an increase in the relative volume of the mesh, and it was found that in comparison with a polymer solution with very low MW, the volume of the mesh with macromolecules with higher MW shifts towards greater amplitude. As can be seen from the above examples, with the increasing length of the linear polymer chain, the conformation transformations sharply change, and their amplitude increases. It is connected with the increase of efficiency of the complex formation process in the gel-linear PAA system.

Besides, the work investigated the influence of the ionic strength of the environment on the interpolymer complex. That inorganic salts, concentrations and molecular weight of polymers (PAA) considerably affecting the possibility of interpolymer complex formation, as well as their stability were studied. It can be seen that as the concentration of low-molecular salt (NaCl) increases, the relative volume of Hydrogel decreases. Such influence of low molecular weight electrolyte is explained by a reduction in thermodynamic quality of the solvent and due to this strengthening of the complex orbited between non - ionic polymer and PAA.

Effect of inorganic salt concentration stability in interpolymercomplex NIPAAm-2HEA with PAA. [NIPAAm-2HEA]= 50-50 мол.%; [PAA; 250 KDa] = 0,01mol/L; [NaCl] = 0.005 (1); 0.05 (2), 0.1 (3) mol/L

Interactions of Hydrogel With Surfactants

Along with the study of interpolymer complexes formed between thermo-sensitive copolymers and polyacrylic acid, the interaction of the thermosensitive polymer with surfactants in an aqueous environment was investigated. Anionic sodium dodecyl sulfate (SDS) and cationic cetyl pyridinium bromide (CPB) were used as surfactants.

To investigate the interaction of NIPAAm-2HEA hydrogels with surfactants, samples of polymers that had swollen in water in equilibrium were lowered into water solutions of SDS and CPB of different concentrations and their relative swelling (V/V0) was observed over time. Fig.-4 and 5 show the parameters of swelling of hydrogels in surfactant solutions of different concentrations.

Kinetics of swelling ratio changes of hydrogels in various concentration of cationic surfactant solution. [ NIPAAm-2HEA] = 50:50 mol.%; in [CPB], mol/L: 2·10-3 (1); 6,2·10-4 (2); 5,0·10-5 (3).

Conclusion

New interpolymer complex based on NIPAAm-2HEA hydrogels with linear PAA, stabilized by hydrogen bonds and hydrophobic interactions, have been obtained. The effect of salt and MW of PAA on the NIPAAm-2HEA with PAA complex was studied. The introduction of surfactant molecules into the network structure of NIPAAm-2HEA copolymers leads to a significant increase in the amplitude of thermally induced collapse.