GR20170100165A - Electroconductive hydrogels based on poly(pyrrole)-poly(vinylsulfonate sodium) copolymers for bioelectronic applications - Google Patents

Abstract

The invention relates to the composition process of new electro-conductive hydrogels based on the poly-(pyrrole) and poly (vinylsulfonate sodium)polymer conjugate; it is, also, described and claimed herein the use and application of said hydogels in optoelectric-bio-electronic arrangements.

Description

DESCRIPTION

ELECTRICALLY CONDUCTIVE HYDROGELS BASED ON COPOLYMERS

POLY(PYRROLE)-POLY(SODIUM VINYL SULFONATE) FOR

BIOELECTRONIC APPLICATIONS

Subject of the invention

The present invention relates to the development of new electroconductive hydrogels for bioelectronic applications. The specific materials simultaneously combine good mechanical properties due to the existence of a hydrated (high water content) three-dimensional (3D) structure (porous material consisting of a network of crosslinks) with the simultaneous appearance of electronic conductivity (due to the presence of conjugated polymers) and ionic conductivity by adding ions to the chain ends of the conjugated polymers. Until now the most widespread organic material (conjugated polymer) used for the synthesis of electroconductive hydrogels is PEDOT:PSS [poly(ethylenedioxythiophene):poly(styrylsulfonic acid)], known under the trade name Baytron. But the biggest disadvantages for PEDOT:PSS in bioelectronics are its low ionic conductivity and poor mechanical strength. Therefore, the synthesis of electroconductive hydrogel of one component (single component) with the chemical integration of conjugated polymers that will also carry ions to give the required ionic conductivity to a prefabricated three-dimensional (3D) hydrogel network is the research object of the present invention.

Background of the invention

Electrically conductive hydrogels are a class of materials that has begun to develop rapidly in recent years due to their unique properties, combining good mechanical properties with the simultaneous appearance of electronic conductivity due to the presence of conjugated polymers. Such materials have not been developed to date, but are considered ideal materials for application in the rapidly developing scientific field of bioelectronics that effectively connects biology with the field of conventional electronics. Electroconductive hydrogels attract great interest in the field of biomaterials and present a wide range of biomedical applications such as biosensors, drug delivery and tissue engineering. More specifically, electroconductive hydrogels have attracted particular attention as interfacial materials in electrochemical biosensors as they combine a similar electro-response to that of conjugated polymers while maintaining the ability of the hydrogel to retain bioactive molecules. Conjugated polymers facilitate electron transport across interfaces as the porous structure provides a large surface area and shorter diffusion length, and the high water content presented by the hydrogel enhances biocompatibility. Electroconductive hydrogels can also serve as drug delivery response systems that undergo chemical or physical changes under applied electric fields. By changing the redox state of the conjugated polymer, the charge of the polymer main chain can be changed, as well as the bulk of the scaffold. This could result in medication being administered in a controlled manner. Anionically charged drugs could be easily incorporated into the conjugated polymers during synthesis. After the polymerization process, the conjugated polymers are in oxidized form and the main macromolecular chain is positively charged. These positive charges are balanced by anions to maintain electro-neutrality. Thus, negatively charged drugs can serve as counterions and could be introduced during polymerization. Cationally charged drugs could also be introduced into conjugated polymer networks. This could be achieved by electrostatic and hydrophobic interactions between the drug, the polymer backbone and the anionic counterion. Alternatively, the cationically charged drug can be introduced after synthesis and after reduction of the conjugated polymer network. However, the application of electroconductive hydrogels in drug transport systems is limited so far by the low loading efficiency, which could also be achieved by the passive diffusion of the small compensating ions from the network.

A very important application of electrically conductive hydrogels is tissue engineering. These systems are ideal candidates for use as a 3D network for cell seeding and cell regeneration. In this system, the hydrogel provides the required hydrated environment, the desired porosity for nutrient exchange, and the mechanical integrity for cell support and proper adhesion. On the other hand, the conjugated polymer component provides the required electronic conductivity in electroresponsive tissues such as the heart, brain, muscles and nerves. Electroconductive hydrogels have shown promising results in regenerative medicine and as highlighted in the literature, many of the developed electroconductive hydrogels promote cell adhesion and cell proliferation. However, their long-term use remains limited due to the degradation of their electronic properties after incubation at physiological conditions due to the loss of impurities. To date, the synthesis or formation of electrically conductive hydrogels based on conjugated polymers has proven to be particularly difficult. A three-dimensional network of hydrogels consists of cross-linked hydrophilic polymers, with a high water content, while at the same time exhibiting elastic behavior, and having porous internal structures. In contrast, conjugated polymers exhibit: a) high rigidity due to their inherently rigid main chain, which contains conjugation of double bonds, b) quite hydrophobic nature due to aromatic rings in the main chain, and c) undesirable cross-links caused by π- π overlapping of the chains.

Therefore, it initially appears impossible to consider these polymers as suitable precursor materials for the synthesis of conductive hydrogels. There are two main methodologies being investigated for the development of conductive hydrogels. The first is to grow the conjugated polymer from a preformed hydrogel - this route is often referred to as growing hybrid systems. The second is the use of the conjugated polymer as the sole polymeric component (continuous phase) in the hydrogel network, this can be achieved: a) by self-organization of the polymer, b) by introducing water-soluble cross-linked groups into the polymer backbone, c) drying by freezing (freeze drying) solutions of the conjugated polymer, or d) using a low molecular weight gelator (low molecular weight gelator, LMWG). Hybrid hydrogel systems consist of conjugated polymer chains that are physically or ionically entrapped within the conventional hydrogel matrix in such a way as to limit their functionality under physiological conditions. As the hydrogel swells at physiological pH, the naturally entrapped conjugated polymer chains escape, a process that triggers some increase in toxicity and causes a drop in electronic conductivity. The ionically bound chains are neutralized at pH = 7.4 and eventually escape from the 3D network, leading to the degradation of the desired properties. In non-hybrid conductive hydrogels the final product is a hydrogel network with enhanced conductive charge transfer between the conjugated chains due to the absence of the insulating polymer chains from the matrix. However, the chemistry currently used does not allow for the tuning of properties such as desired swelling or the desired mechanical properties of these scaffolds and is not easily modifiable to meet the specific requirements of tissue engineering. In particular, the stability of hydrogels made via self-assembly or via LMWG under physiological conditions has never been tested before. It could be hypothesized that ionic strength has an effect on the physicochemical properties of a three-dimensional network and its composition.

This new strategy will be used in this invention to synthesize new novel electroconductive PEDOT:PSS-type hydrogels that will simultaneously exhibit:

1) Good mechanical properties

2) Hydrated structure so that it can adsorb high water content

3) Electronic conductivity

4) Ionic conductivity

and therefore they will be very attractive materials for application in bioelectronics.

An ideal precursor material for the synthesis of conductive hydrogel is the conjugated polymer of the modified poly(pyrrole) derivative with the following properties: a) water solubility to enhance the capacity during polymer swelling using triethylene glycol side groups, b) functional (vinyl) groups on the side chains that allow cross-linking (triethylene glycol dimethacrylate) to eliminate leaching of the polymer after swelling at pH 7.4 in order to avoid the loss of conjugated polymer chains followed by degradation in electronic properties of the material, c) electronic conductivity due to the nature of the conjugated polymer in physiological buffers, and d) ionic conductivity and hydrate structure due to the presence of sodium ions and sodium poly(vinylsulfonate), respectively.

Detailed Description of the Invention

1. Synthesis of substituted dibromo-monomers of pyrrole The synthesis of the monomers was carried out using common organic synthesis reactions More specifically, the monomers MI and L M3 were synthesized via a Williamson-type etherification reaction from the commercially available monomer 3-chloromethyl pyrrole and 3-butenol-1 for MI or triethylene glycol for M3. Then the dibromo-substituted monomers M2 and M4 were synthesized via bromination reaction of monomers M1 and M3 using either elemental bromine or the reagent N-bromosuccinimide, as shown in Scheme (2). Various spectroscopic techniques including proton (<1>H)-carbon (<13>C) nuclear magnetic resonance (NMR) spectroscopy, elemental analysis, gas chromatography combined with spectrometry were used to certify the successful synthesis of the proposed monomers M1-M4 mass spectrometry (GC-MS) and Fourier Transform Infrared Spectroscopy (FT-IR).

2. Synthesis of poly(pyrrole) producers

At this stage, synthesis of poly(pyrrole) derivatives modified with side chains bearing polar triethylene glycol groups was achieved so that the newly synthesized polymers were compatible with polar solvents, such as tetrahydrofuran, methanol and water as well as side chains bearing vinyl groups to be able to then the produced poly(pyrroles) to be incorporated into more complex polymeric architectures using e.g. of radical polymerization, according to Scheme (3). The poly(pyrrole) derivatives were synthesized via the Grignard Metathesis Method (GRIM) which is based on the treatment of monomers M2 and M4, which were combined in different proportions (M4 from 1% to 10%), μ ' one equivalent of an alkyl- or vinyl- Grignard reagent leading to a magnesium - bromine exchange reaction followed by addition of the catalyst dichloro-1,3-bis(diphenylphosphine)propane nickel(II) [Ni(dppp)CI2], ( dppp=1,3-diphenylphosphinopropane). The ratio between the two monomers was examined to study in the next step what is the optimal density of side chains bearing double bonds for the incorporation of poly(pyrrole) derivatives into more complex polymeric architectures. Various spectroscopic techniques including proton (<1>H)- and carbon (<13>C) nuclear magnetic resonance (NMR) spectroscopy, size exclusion chromatography (SEC), RAMAN spectroscopy and ultraviolet-visible (UV-Vis) absorption spectrometry.

3. Synthesis of poly(pyrrole):poly(sodium vinyl sulfonate) and Hydrogels

The synthesized poly(pyrrole) derivatives modified with polar triethylene glycol groups and vinyl groups were then used to synthesize more complex polymeric architectures and electroconductive hydrogels according to Schemes (4) and (5). More specifically, the modified derivatives of poly(pyrrole) were copolymerized with poly(sodium vinyl sulfonate), via free radical reactions (Scheme 4) using sodium azoisobutylene (AIBN) or benzoyl peroxide (BPO) as polymerization initiators, to give chemically conjugated copolymers of poly(pyrrole) and poly(sodium vinyl sulfonate) that have a similar structure to the commercially available PEDOT:PSS consisting of poly(ethylenedioxythiophene) and poly(styryl sulfonate) chains joined together by electrostatic secondary bonds ( Figure 1). Then finding the optimal copolymerization conditions of poly(pyrrole) and poly(sodium vinyl sulfonate), we proceeded to synthesize the hydrogels using simultaneously the modified derivatives of poly(pyrrole), poly(sodium vinyl sulfonate) and the crosslinking agent which is the dimethacrylate derivative of tertethylene glycol via free radical reactions (Scheme 5) using AIBN or BPO as initiators. The formed hydrogels simultaneously exhibit electronic conductivity due to the poly(pyrrole), ionic conductivity due to the countervailing sodium charges from the poly(sodium vinyl sulfonate), and also mechanical stability and strength due to the crosslinks formed (Figure 5). Briefly, the composition of the electroconductive hydrogel can be varied when the conductive part (conjugated polymer composition) is from 1 to 99% or when the non-conductive-water-soluble part (water-soluble polymer composition) is from 1 to 99%. Various spectroscopic techniques including proton (<1>H)- and carbon (<13>C) nuclear magnetic resonance (NMR) spectroscopy, size exclusion chromatography (SEC), RAMAN spectroscopy and absorption spectrometry in the ultraviolet visible (UV-Vis), since electroconductive hydrogels and their conjugated polymer precursors can be deposited in thin films either by screen printing, drop casting, dr blade, spin coating or spraying.

4. Characterization of Properties of New Electroconductive Hydrogels Emphasis was placed on the characterization of the materials obtained during the synthesis stage and more specifically on the determination of thermal, optical and electrochemical properties as well as electronic and ionic conductivity measurements. Finally, morphological characterization was performed.

Characterization of Thermal, Mechanical and Optical Properties

• The thermal properties of the polymers were examined by means of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). These studies provide initial information on the crystallinity, melting point, glass transition temperature and degradation temperature of the synthesized polymers.

• The absorption and emission spectra of the polymers both in solution and in the solid state were recorded using ultraviolet-visible (UV-Vis) absorption and photoluminescence spectrometry. Based on these results, the absorption maxima and optical energy gap of the polymers as well as their emitting wavelengths were determined.

Electrochemical Characterization and Conductivity Measurements

• The characterization of the electrochemical properties of the polymers and more specifically the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) will be performed through cyclic voltammetry.

· The extraction work of the polymers was determined using the Kelvin probe technique.

• Calculation of the ionic conductivity of the thin films was achieved through impedance (spectroscopy) experiments using micro-electrodes and electrochemical control units, each consisting of a digital potentiostat / galvanostat with resistance analyzer. Instead, the electronic conductivity was calculated through the four probe technique with measurements on thin films.

Morphological Characterization

• To characterize the porosity of the material, e.g. size and distribution of pores within the material, permeability measurements were performed.

• Surface morphology studies were performed with high-resolution scanning electron microscopy (SEM). More specifically, due to the coexistence of hydrophilicity [due to the sodium poly(vinyl sulfonate) part but also the triethylene glycol side groups in the poly(pyrrole)] and hydrophobicity [due to the poly(pyrrole chain)], very interesting, perhaps even unique, solid state morphologies. Then, an attempt was made to correlate these resulting morphologies with the results of both ionic and electronic conductivity to determine if there is any interdependence between them.

Brief Description of Numbered Drawings:

Figure 1: Chemical structure of PEDOT:PSS

[poly(ethylenedioxythiophene) :poly(styrylsulfonic acid)].

Scheme 2: Chemical reaction of synthesis of substituted dibromo-monomers of pyrrole.

Figure 3: Chemical reaction for synthesis of poly(pyrrole) derivatives.

Figure 4: Chemical reaction of synthesis of derivatives of poly(pyrrole):poly(sodium vinyl sulfonate). Figure 5: Chemical reaction of synthesis of Hydrogels.

Claims (8)

CLAIMS 1. Synthesis products of conjugated copolymers based on based on poly(pyrrole) and poly(sodium vinyl sulfonate) copolymers and bearing triethylene glycol side groups as well as side chains bearing vinyl groups through free radical reactions using AIBN or BPO as initiators polymerization, giving chemically linked copolymers of poly(pyrrole) and poly(sodium vinyl sulfonate) as shown in the following chemical formula: 2. The electroconductive hydrogel synthesis products based on poly(pyrrole) and poly(sodium vinyl sulfonate) copolymers and bearing triethylene glycol side groups and vinyl groups according to claim (1), cross-linked with the dimethacrylate derivative of triethylene glycol through free radical reactions using using azoisobutyl sodium (AIBN) or benzoyl peroxide (BPO) as polymerization initiators. 3. The method for the synthesis of conjugated polymers and electroconductive hydrogels mentioned respectively in claims (1) and (2), in which they consist of: the Grignard metathesis method with a catalyst of dichloro-1,3-δLs(diphenylphosphine)propane nickel (II) [Ni (dppp)CI2] and the free radical reactions using azoisobutyl sodium (AIBN) or benzoyl peroxide (BPO) as polymerization initiators. 4. The method of preparing the thin film membrane: (a) the deposition of a thin film from the conjugated polymers and electroconductive hydrogels referred to in claims (1) and (2), either by screen printing, drop casting, dr blade, spin coating or spraying, and (b) the drying process of the deposited polymer film referred to in (a). 5. Any optoelectronic device arrangement (organic transistor arrangements, organic photovoltaics) which consists of one or more surfaces of thin films of the conjugated polymers claimed in (1), which constitutes the active surface. 6. Any bioelectronic device assembly consisting of one or more thin film surfaces of the electroconductive hydrogels claimed in (2), which constitutes the active surface. 7. The composition of electroconductive poly(pyrrole) and poly(sodium vinyl sulfonate) copolymer hydrogel bearing triethylene glycol side groups and vinyl groups, cross-linked with the dimethacrylate derivative of triethylene glycol according to claim (2), when the conductive part [poly(pyrrole) ] is from 1 to 99%. 8. The composition of the electroconductive poly(pyrrole) and poly(sodium vinyl sulfonate) copolymer hydrogel bearing triethylene glycol side groups and vinyl groups, cross-linked with the dimethacrylate derivative of triethylene glycol according to claim (2), when the non-conductive-water-soluble part [ poly(sodium vinyl sulfonate)] is from 1 to 99%.