Grafting solution

Abstract

An aqueous grafting solution comprising monomers for obtaining a polymer grafted onto a substrate, the monomers comprising: sodium styrene sulfonate (NaSS), methacrylic acid (MA) or acrylic acid (AA), and hydroxyethyl methacrylate (HEMA). "No figure"

Description

Title of the invention: Grafting solution

[0001] The present invention relates to an aqueous grafting solution comprising monomers for the purpose of obtaining a grafted polymer on a substrate. The invention also relates to a substrate coated with the grafted polymer, as well as a grafting method.

[0002] Cell adhesion or cell adhesion is an essential function of the organism that occurs naturally during the formation of tissues or organs. Cell adhesion can occur between cells and is then referred to as intercellular adhesion, i.e. between cells and a substrate. Cell-substrate adhesion occurs as soon as a cell is in contact with a natural surface such as a membrane or the extracellular or synthetic matrix such as a medical device.

[0003] Cell adhesion can occur under in vitro conditions in the laboratory or in vivo during implantation of a medical device. This step is crucial for the subsequent interactions between cells and the surface of a medical device.

[0004] Cell proliferation is a natural phenomenon during which cells multiply to form tissues; it follows cell adhesion.

[0005] The chemical, physicochemical or physical nature of the substrate surface very strongly modifies the interactions that develop between the cells and the substrate during cell adhesion and proliferation. In order to modulate cell adhesion and proliferation, different surface treatments have been developed; among these are treatments to reduce or even inhibit cell adhesion and proliferation.

[0006] In the prior art, techniques are already known for covering or coating substrates with highly hydrophilic natural or synthetic molecules or macromolecules or with hydrogels to prevent interactions between cells and these substrates and consequently reduce cell adhesion and proliferation. Also known is the modification of substrates by coating or fixing cytotoxic agents such as quaternary ammoniums or silver salts to prevent any adhesion and consequently any cell proliferation. Simpler "mechanical" methods have also been proposed to create a physical barrier to prevent cells from reaching a surface.

[0007] These prior art techniques are not satisfactory for the following reasons: coating with very hydrophilic molecules or with hydrogels can reduce the adhesion of cells to a substrate, however the coating is rarely obtained by covalent grafting, and it is weakened and its integrity is difficult to maintain. easily controllable during the drying, sterilization and more simply preservation and storage stages.

[0008] Another major problem with grafted coatings lies in the grafting rate, which is often insufficient.

[0009] The present invention aims to remedy the aforementioned drawbacks of the prior art by defining an aqueous grafting solution combining several monomers capable of generating a polymer grafted onto a substrate, with a greatly improved grafting rate.

[0010] According to the invention, this aqueous grafting solution comprises the following monomers: - sodium styrene sulfonate (NaSS), - methacrylic acid (MA) or acrylic acid (AA), and - hydroxyethylmethacrylate (HEMA).

[0011] Sodium styrene sulfonate (NaSS) has properties to provide glycosaminoglycan-like character and a controlled biological response of the modified surface.

[0012] Methacrylic acid (MA) or acrylic acid (AA) has properties that, when combined with NaSS, reduce cell adhesion and proliferation. It also contributes to providing the glycosaminoglycan-like character to the surface.

[0013] As for hydroxyethylmethacrylate (HEMA), it has hydrophilic properties which improve the wettability of the substrate and, depending on the quantity of “hydroxyl” groups introduced, allows the inflammatory response to be modulated.

[0014] Advantageously, the aqueous grafting solution comprises 1 to 30 mol% of hydroxyethylmethacrylate (HEMA). Preferably, it comprises approximately 1 to 10 mol% of HEMA.

[0015] According to an advantageous embodiment, the mixture of sodium styrene sulfonate (NaSS) and methacrylic acid (MA) or acrylic acid (AA) comprises 10 to 90 mol% of sodium styrene sulfonate (NaSS) and 10 to 90 mol% of methacrylic acid (MA) or acrylic acid (AA).

[0016] According to another advantageous embodiment, the aqueous grafting solution may comprise 30 to 80 mol% of sodium styrene sulfonate (NaSS), 30 to 80 mol% of methacrylic acid (MA) or acrylic acid (AA) and 1 to 10 mol% of hydroxyethyl methacrylate (HEMA).

[0017] The invention also defines a substrate coated with the polymer obtained by grafting the aqueous grafting solution as defined above, in which the substrate is chosen from polyesters, vinyl polymers, polyacrylics and polymethacrylics, PEEK, silicones, natural polymers - natural or artificial celluloses ficial - collagens and glycopolymers - ceramics, metals and metal alloys: Ti and its alloys, stainless steels, Ni-Ti alloys (known for stents). In addition to a very high grafting rate with HEMA between 1 and 10 mol%, the grafted polymer is a copolymer capable of minimizing or even inhibiting the cellular adhesion of eukaryotic cells, such as osteoblasts, fibroblasts, keratinocytes, endothelial, epithelial cells on the substrate and of minimizing or inhibiting the proliferation of adherent cells on this same substrate.

[0018] The invention also defines a grafting method for applying a polymer obtained by grafting the aqueous grafting solution as defined above onto a substrate as defined above, the grafting being radical grafting or electrografting.

[0019] The grafting step itself is preferably preceded by a surface activation step. On titanium, for example, the grafting process may be of the radical type with a surface activation step carried out by anodic oxidation, as described in document WO2017068272. This preliminary activation step is followed by polymerization initiated thermally or by UV. For other types of substrate, a surface activation step is also recommended, otherwise it will be difficult to polymerize from the surface.

[0020] The spirit of the invention lies in the choice of the statistical copolymerization of three monomers, carrying defined chemical groups and chosen for their specificity and for the properties that they will bring to the surface. In other words, the copolymerization of NaSS, MA and HEMA in defined proportions makes it possible to increase the grafting rate, but also to control cell adhesion and proliferation on these surfaces while maintaining control of the inflammatory response.

[0021] Thus, grafting a copolymer of NaSS, MA and HEMA onto titanium or a titanium alloy makes it possible to inhibit the adhesion of osteoblast and fibroblast cells and to prevent the adhesion of cells and tissues to the osteosynthesis plates intended to be explanted.

[0022] Grafting rate measurements were carried out in the laboratory under precise and controlled conditions on different Ti alloy pellets. Ti pellets could also have been used.

[0023] First, a mixture of NaSS and MA (without HEMA) was grafted onto a PO base pellet. A base grafting rate T0 was thus measured.

[0024] Then, three other pellets PI, P2 and P3 were coated by grafting with a mixture of NaSS, MA and HEMA of the invention: - Pellet 1: grafted with a solution containing NaSS, MA and 1% HEMA, with a measured grafting rate Tl, - Pellet 2: grafted with a solution containing NaSS, MA and 5% HEMA, with a measured grafting rate T2, - Pellet 3: grafted with a solution containing NaSS, MA and 10% HEMA, with a measured grafting rate T3.

[0025] It was thus possible to observe that T1 is approximately 1.5 times greater than T0, that T2 is approximately 3 times greater than T0 and that T2 is approximately 5 times greater than T0.

[0026] It can therefore be concluded that a very low percentage of HEMA, namely 1%, is sufficient to significantly increase (50%) the grafting rate of a mixture of NaSS and MA. And with a still low percentage of 10%, the grafting rate is quintupled.

[0027] This amplified grafting rate of course has a significant influence on the inhibition of cell adhesion and proliferation.

[0028] It should be noted that MA (methacrylic acid) can be replaced by AA (acrylic acid) in the mixture of NaSS and HEMA, with equivalent results.

Claims

Claims

1. An aqueous grafting solution comprising monomers for the purpose of obtaining a polymer grafted onto a substrate, the monomers comprising a mixture of sodium styrene sulfonate (NaSS), and methacrylic acid (MA) or acrylic acid (AA), the aqueous grafting solution further comprising hydroxyethylmethacrylate (HEMA), characterized in that: the mixture of sodium styrene sulfonate (NaSS) and methacrylic acid (MA) or acrylic acid (AA) comprises 10 to 90 mol% of sodium styrene sulfonate (NaSS) and 10 to 90 mol% of methacrylic acid (MA) or acrylic acid (AA), and the aqueous grafting solution comprises 1 to 10 mol% of hydroxyethylmethacrylate (HEMA).

2. An aqueous grafting solution according to claim 1, comprising 5 mol% hydroxyethylmethacrylate (HEMA).

3. An aqueous grafting solution according to claim 1, comprising 1 mol% of hydroxyethylmethacrylate (HEMA).

4. Substrate coated with the polymer obtained by grafting the aqueous grafting solution according to any one of the preceding claims, in which the substrate is chosen from polyesters, vinyl polymers, polyacrylics and polymethacrylics, PEEK, silicones, natural polymers, natural or artificial celluloses, collagens, glycopolymers, ceramics, metals and metal alloys, and in particular Ti and its alloys and Ni-Ti alloys.

5. 11. A grafting method for applying a polymer obtained by grafting the aqueous grafting solution according to any one of claims 1 to 3 onto a substrate, the grafting being a radical grafting.

6. A grafting method for applying a polymer obtained by grafting the aqueous grafting solution according to any one of claims 1 to 3 onto a substrate, the grafting being electrografting. * * *