RU2806060C1 - Method of obtaining surgical suture materials with antibacterial properties by atomic layer deposition - Google Patents

Abstract

FIELD: application of atomic layer deposition (ALD) nanotechnology in medicine and veterinary medicine.

SUBSTANCE: invention relates to the development of a method for producing surgical sutures with an antibacterial nanocoating. A method of producing surgical suture materials with antibacterial properties is proposed, the said method includes applying an antibacterial functional nanomaterial, a titanium-vanadium oxide nanofilm (TiVO_x), 12 nm thick, to the surface of a polypropylene surgical suture by atomic layer deposition (ALD). Titanium tetrachloride (TiCl₄), vanadium oxytrichloride (VOCl₃) and water (H₂O) are used as precursors for ACO TiVO_x. The temperature at which ASO is carried out is 80°C.

EFFECT: developed method makes it possible to obtain an antibacterial coating on the surface of surgical suture materials with good adhesion.

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Description

The invention relates to the field of application of atomic layer deposition (ALD) nanotechnology in medicine and veterinary medicine, and more precisely to the development of a method for producing surgical suture materials with antibacterial nanocoating. The invention can be most effectively used to combat infections in the area of surgical interventions.

The essence of the invention : to obtain surgical sutures with antibacterial properties, a titanium-vanadium oxide (TiVO _x ) nanofilm 12 nm thick is applied to polypropylene suture material using the atomic layer deposition method. Previously, aluminum oxide (Al ₂ O ₃ ) with a thickness of 5 nm is applied to the polypropylene suture material using the ALD method for improved adhesion of the antibacterial nanomaterial to its surface. Trimethylaluminum (TMA, Al(CH ₃ ) ₃ ) and water (H ₂ O) are used as precursors for this process. Titanium tetrachloride (TiCl ₄ ), vanadium oxotrichloride (VOCl ₃ ) and water (H ₂ O) are used as precursors for the production of titanium-vanadium oxide nanofilm (TiVO _x ). ALD is carried out in a vacuum installation for atomic and molecular layer deposition at a temperature of 80°C.

The technical result of the invention is a method for improving the functional properties of surgical suture materials by applying antibacterial nanomaterials based on titanium-vanadium oxide (TiVO _x ) nanofilm to them. A TiVO _x nanofilm 12 nm thick is applied to the suture material using the atomic layer deposition method using titanium tetrachloride (TiCl ₄ ), vanadium oxotrichloride (VOCl ₃ ) and water (H ₂ O) at a temperature of 80 °C. This coating has strong adhesion to the suture material due to the gradual growth of the film using surface chemical reactions, which provides advantages such as safety (stability), durability and high efficiency of the coating.

Analogues

Medical suture materials often contribute to the spread of surgical site infections (SSIs), so surgical suture materials with antibacterial coating are becoming increasingly common in surgical practice. Traditional materials used in clinical settings often cause secondary complications such as infection, foreign body reaction, or chronic inflammation. Coating suture materials with broad-spectrum antiseptics can make a significant contribution to solving the problem of surgical site infections (SSIs).

Suture materials are divided into absorbable and non-absorbable. The tissue reaction to its implantation depends on the quality, chemical composition and structure of the suture material. They are made using a variety of materials, including animal derivatives (collagen), synthetic polymers (polyglactin 910), woven (silk) and monofilament (nylon) [1]. Non-absorbable sutures can contribute to the accumulation of infection at the surgical site, and prolonged exposure of such sutures in the body can lead to chronic bacterial complications that cannot be treated with conventional antibiotics (D.J. Hess et al., 2011; Balasubramaniam B. et al., 2021 ) [2-3].

The global antibacterial coatings market size was valued at $8.1 billion in 2020 and is expected to grow at a CAGR of 13.1% from 2021 to 2028. And the volume of consumption of surgical suture materials on the Russian market in 2011 amounted to about 1.6 million packages.

There are two methods of coating surgical suture material with an antibacterial agent:

1) placing in a solution containing an antimicrobial agent until it binds or is absorbed into the product;

2) coating with a polymer matrix containing antimicrobial agents.

In the field of suture surgical materials, the most widely used and proven antimicrobial agent is the broad-spectrum antiseptic triclosan. It acts on gram-positive and gram-negative flora, as a result of which it also exhibits fungicidal activity. However, due to the ecotoxicity of its oxidation products, there is currently a tendency to create suture materials with a low triclosan content.

The most common method for producing antibacterial suture materials is described in a patent (US patent 20040185250). This method includes two stages. First, absorbable surgical suture material based on lactomer 9-1 is treated with a 2% triclosan solution. Then dry at 65°C for 2 minutes. Next, triclosan-treated suture materials are impregnated with a mixture containing equal parts of glycolide-lactide with calcium stearate with different concentrations of triclosan. Dichloromethane is used as a solvent. The disadvantages of this method are the high concentration of triclosan in the solution, the impossibility of controlling its content in the resulting suture material, the use of an organic solvent, which complicates maintaining the concentration of the working solution and the impregnation process, as well as the use of glycolide-lactide in the impregnation composition, which increases the rigidity of the thread (changes initial properties of the thread).

There is a known method for producing fibers and woven materials containing triclosan by treating them with triclosan esters - acetate, propionate, benzoate, nitrobenzoate, triclosan hexanoate (US Patent 6299651). The disadvantages of this method are the high consumption of triclosan and the impossibility of its controlled introduction into the material.

Surgical suture material with antibacterial properties is known, obtained by impregnation with an antimicrobial agent followed by application of a polyurethane sheath (US patent 4024871). The disadvantage of this surgical suture material is the use of polyurethane as a sheath, since it is a relatively expensive polymer. In addition, when such surgical suture materials with antibacterial properties are used, their activity decreases faster than the wound healing process.

Recently, as an alternative to triclosan, the antiseptic chlorhexidine has been successfully tested, which is active against most pathogens that cause infections at the site of surgical interventions. To date, there are many studies on the introduction of chlorhexidine into suture materials (Andreas Obermeier et al., 2014). Obermeier A. et al. impregnated suture materials made from polyglycolic acid with an antimicrobial solution prepared by dissolving fatty acids (palmitic and lauric) and chlorhexidine in 99.8% ethanol. Two types of solutions were used as impregnation: chlorhexidine diacetate containing lauric acid and chlorhexidine diacetate containing palmitic acid. Suture materials were impregnated with the resulting solutions of chlorhexidine laurate and palmitate. The disadvantages of this method are the long impregnation and drying time of products [4].

There is a known method for producing medical products containing triclosan by treating them with a multicomponent solution containing up to 5% triclosan, up to 5% chlorhexidine and up to 5% polyurethane necessary for the controlled release of an antimicrobial agent (US patent 20010024661). The disadvantages of this method are the long impregnation and drying time of products (up to 60 minutes and 3 days, respectively), the use of methanol, which is toxic, as one of the solvents, and the need for a high concentration of triclosan.

There is a known method of imparting antibacterial properties to surgical suture materials (RF patent No. 2278693), the essence of which is to impregnate the surgical suture material with a solution of silver nitrate, followed by chemical reduction of the compound that has impregnated the suture material to metallic silver in an alkaline solution of formaldehyde. Then the suture material is washed to remove residual reagents. Despite the fact that the remaining reagents are washed off after the recovery process, formaldehyde (hazard group II (highly hazardous substances)) is released from the resulting suture material when placed in an aquatic environment in a concentration of up to 0.1 mg/l, which is almost twice its maximum permissible concentration. Also, metallic silver reduced from silver nitrate has a lesser antibacterial effect compared to silver nanoparticles.

The prototype and its shortcomings

RF patent 2517121C2 is given as a prototype of the proposed method. This method consists of a suspension prepared by mixing powdered silver with particle sizes of 300-500 microns and powdered titanium dioxide in a ratio of 1:30 with distilled water to the concentration of the TiO complex₂-Ag 2.5-3 mg/kg, surgical suture material is treated in an ultrasonic bath (WUC-A06H) with an oscillation frequency of 20-30 kHz for 30-60 minutes and dried for 6-8 hours at a temperature of 50-70°C in an oven. 70-80 mg of suspension is applied to one meter of surgical suture material. The method eliminates the development of postoperative complications due to the long-term preservation of the antibacterial properties of the suture material.

To test the antibacterial properties of suture material impregnated with a suspension containing the TiO ₂ -Ag complex, a suspension of microorganisms of the genus Streptococcus was prepared in a physiological solution with a concentration of 500 million CFU/ml. Pieces of the test suture material 5 cm long were placed into the prepared suspension. After 5 min. the suture material was removed from the suspension of microorganisms and dried in sterile Petri dishes. Then the suture material under study was placed in test tubes with 5 ml of meat peptone agar (MPA). An MPA solution was used as a control. The tubes were placed in a thermostat (t=37 °C). After 24 hours from the start of the experiment, the results of changes in the optical density of MPA were recorded on a Multiskan spectrophotometer. The maximum antibacterial effect was observed in surgical suture material coated with a suspension of silver nanoparticles with titanium dioxide, and a thread coated with metallic silver, studied for comparison, showed insignificant antibacterial properties.

Criticism of the prototype

The method for producing surgical suture material with antibacterial properties to reduce purulent-inflammatory processes at the site of surgical interventions, which is proposed for the prototype, is that the surgical suture material in an ultrasonic bath is treated with a suspension containing silver nanoparticles and submicron particles of titanium dioxide.

The disadvantages of this method compared to the atomic layer deposition technology we offer:

1. Poor adhesion to the substrate, leading to the fragility of the coating (not stable coating), in contrast to ACO, which is based on the technology of step-by-step film growth using surface chemical reactions, which provides such advantages as durability (stability) and high coating efficiency ;

2. Insecurity. Due to the lack of adhesion of the material to the substrate, over time, particles of heavy metals will begin to desorb from such suture material and penetrate into the body. This can be avoided when using ASO technology, since a uniform nanofilm is formed on the surface of the polypropylene suture material, which does not degrade over time and the likelihood of metal ions entering the tissue (diffusion into the body) undergoing surgical intervention is minimized here;

3. Unevenness and non-conformity of the coating due to impregnation of the suture material with a suspension of titanium dioxide containing silver nanoparticles (TiO ₂ -Ag). In ALD, uniform deposition (100% coating conformality) of nanofilms onto the suture material occurs with control of their composition and thickness at the atomic level;

4. Expensive. The use of silver nanoparticles to increase the antibacterial activity of TiO ₂ is not economically profitable due to the high cost of silver. Our proposed approach of precision doping of titanium oxide with vanadium atoms based on ASO allows us to activate its antibacterial properties in sunlight by shifting the activation region of TiO ₂ to the visible region of the spectrum, and the precursors used for this (TiCl ₄ , VOCl ₃ and H ₂ O) are commercially available more accessible and can be synthesized in the laboratory.

The purpose of this invention is to develop a method for improving the functional properties of surgical suture materials by applying antibacterial nanomaterials based on titanium vanadium oxide (TiVO) to them._x) nanofilm obtained by atomic layer deposition method in order to prevent infections in the surgical area.

An example of a specific implementation of the method

The method for producing titanium-vanadium oxide ASO film with antibacterial properties on polypropylene surgical suture material consists of the following steps:

1. Cleaning and degreasing the surface of the suture material with isopropanol;

2. Placing the suture material in the chamber of a vacuum ASO installation (Fig. 1) and heating it to a temperature of 80 °C;

3. Atomic layer deposition of Al ₂ O ₃ using trimethylaluminum (TMA) and H ₂ O;

Preliminary application of an Al ₂ O ₃ ALD film on a polypropylene suture material makes it possible to achieve better adhesion of TiVO _x to its surface due to the creation of additional reaction groups and better film growth on them. The process of atomic layer deposition of Al ₂ O ₃ , consisting of repeated surface reactions between TMA and H ₂ O, can be represented as follows:

Reaction A: ](–OH) _x ^* + Al(CH ₃ ) ₃ (g) → ](–O) _x –Al(CH ₃ ) _3-x ^* + xCH ₄ (g)

Reaction B: ](–O) _x –Al(CH ₃ ) _3-x ^* + H ₂ O (g) → ](–O) _x –Al(OH) _x ^* + (3-x)CH ₄ (g ),

where ] is the surface; *—surface reactive groups; x is the proportion of ligands remaining after dosing the precursors; CH ₄ is the gaseous product of reactions.

The time of injection and purging of precursors during one cycle of atomic layer deposition of Al ₂ O ₃ was denoted as: t ₁ /t ₂ /t ₃ /t ₄ , where t ₁ is the time of TMA injection; t ₂ , t ₄ purge time; t ₃ H ₂ O infusion time. To deposit 5 nm Al ₂ O ₃ ALD, 50 cycles with time parameters of 2/30/2/30 seconds were used.

5. Atomic layer deposition of antibacterial TiVO _x nanofilm using TiCl ₄ , VOCl ₃ and H ₂ O.

The process of supplying reagents for this process, which amounted to one ALD supercycle, is shown in Figure 2. According to this deposition scheme, after injecting TiCl ₄ a monolayer of titanium chloride groups is formed on the surface, and injecting H ₂ O vapor leads to the replacement of chlorine ions (Cl ^– ) by hydroxyl groups (OH) ^- , which subsequently react with VOCl ₃ . After this, a monolayer of vanadium oxochloride groups is formed on the surface, and the injection of H ₂ O vapor leads to the regeneration of surface hydroxyl groups. This supercycle is repeated a specified number of times, depending on the required film thickness. To obtain an ALD TiVO _x film 12 nm thick, 50 ALD supercycles were performed with process time parameters of 2/30/2/30/2/30/2/30 seconds. The time of injection and purging of precursors during one supercycle of atomic layer deposition of TiVO _x was denoted as: t ₁ /t ₂ /t ₃ /t ₄ / t ₅ / t ₆ / t ₇ /t ₈ , where t ₁ is the time of injection of TiCl ₄ ; t ₂ , t ₄ , t ₆ , t ₈ purge time; t ₅ - VOCl ₃ injection time; t ₃ , t ₇ – H ₂ O injection time.

To test the antibacterial properties of surgical suture materials, a suspension of E.Coli microorganisms was prepared in a physiological solution with a concentration of 500 million CFU/ml. 5 ml of this suspension was sown on meat peptide agar (MPA) in sterile Petri dishes. Pieces of the test suture material 2 cm long were placed in the prepared media. After this, the Petri dishes were placed in a thermostat (t=37 °C). After 24 hours, the growth zone around the suture material was observed. In the case of a surgical thread with an antibacterial coating, the zone of no growth (zone of suppression of bacterial colonization) was larger than that of an uncoated thread, which indicates the antibacterial effect of this suture material, compared to the sample where there was no coating.

1. Infection after spinal surgery and procedures / A. Di Martino, R. Papalia, E. Albo [et al.] // Eur. Rev. Med. Pharmacol. Sci. – 2019 – No. 23 – P. 173–178. – URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469318/ (access date: 11/07/2022).

2. Gentamicin promotes Staphylococcus aureus biofilms on silk suture / D.J. Hess, M.J.H. Stanley, C.L. Wells [et al.] // J. Surg. Res. – 2011 – No. 2 – P. 302–308. – URL: https://pubmed.ncbi.nlm.nih.gov/21816417/ (access date: 11/07/2022).

3. Antibacterial and antiviral functional materials: Chemistry and biological activity toward tackling COVID-19-like pandemics / V. Balasubramaniam, Prateek, S. Ranjan [et al.] // ACS Pharmacol. Transl. Sci. – 2021 – No. 3-4 – P. 54. – URL: https://pubs.acs.org/doi/full/10.1021/acsptsci.0c00174 (access date: 11/08/2022).

4. Novel High Efficient Coatings for Anti-Microbial Surgical Sutures Using Chlorhexidine in Fatty Acid Slow-Release Carrier Systems / A. Obermeier, J. Schneide, S. Wehner // Plos One. – 2014 – V. 9. – No. 7. – URL: https://pubmed.ncbi.nlm.nih.gov/24983633/#affiliation-1 (access date: 11/08/2022).

Claims (1)

A method for producing surgical suture materials with antibacterial properties on the surface of a polypropylene surgical thread, which includes applying an antibacterial functional nanomaterial to them - titanium-vanadium oxide nanofilm (TiVO _x ) 12 nm thick, using titanium tetrachloride (TiCl ₄ ), vanadium oxytrichloride (VOCl ₃ ) and water (H ₂ O), based on the atomic layer deposition method at a temperature of 80 °C.