RU2756124C1 - Method for improving the functional properties of mesh implants for hernial plasty - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery, and discloses a method for improving mesh implants for hernial plasty. The method is characterised by the fact that an aluminium oxide substrate with a thickness of 10 nm and then a nanofilm of titanium/vanadium oxides with a thickness of 18 nm are applied to the implant.

EFFECT: nanofilm of titanium/vanadium oxides significantly improves the biocompatibility of a mesh endoprosthesis and the barrier and functional properties thereof, increases the durability of the implant; aluminium oxide substrates contribute to better adhesion of the nanofilm of titanium/vanadium oxides to the mesh, contribute to the strength of the film, prevent destruction of the mesh endoprosthesis caused by the impact of an oxidising environment and occurrence of long-term postoperative complications, such as wrinkling, migration of the mesh; invention can be used in hernial operations using mesh implants.

13 cl, 2 ex

Description

The invention relates to medicine, namely to surgery, can be used in hernia operations using mesh implants.

Analogs

More than 20 million hernia operations are performed annually in the world, which is 10-15% of all surgical interventions (Adamyan A.A., 2003; Zhebrovsky V.V. et al., 2004; Egiev V.N., 2006; Schumpelick V. et al., 1999) In Russia, abdominal wall plastic surgery for hernial defects is performed in about 180 thousand patients, in Germany - in 280 thousand, in the USA - in more than 500 thousand (Fedorov V.D. et al., 2000 ; Klinge U., 2002; Peiper S. et al., 2006) There are a large number of hernia surgery techniques, most of which are plastic with their own tissues. However, with these plastic techniques, the recurrence rate ranges from 10-15% to 40% (Cornell RB et al., 1994) (Anthony T. et al., 2000; Berger D. et al., 2002; Macintyre I.M., 2003)

In this regard, synthetic implants are increasingly used for the repair of postoperative hernial defects. Unlike traditional methods of plastics, this technique allows you to avoid tissue tension and significantly reduce the number of not only early, but also late postoperative complications and relapses (Belokonev V.I. et al. 2003; Soloviev N.A. et al. 2004; Surkov N.A., 2007; Burger JWA et al., 2004)

About 1 million mesh implantations are performed in the world annually.

Criticism of analogues

The use of Marlex polypropylene mesh implants was first proposed by F. Asher in 1958 (Usher FC, e.a., 1958). Although he revolutionized this field, the use of mesh implants led and still lead to various kinds of postoperative complications, such as chronic pain, wound erosion, migration and wrinkling of the mesh, the formation of coarse non-absorbable fibrous tissue compressing adjacent anatomical structures, mesh rejection, etc. (Poppas DP EA, 2016).

The main types of prostheses for hernioplasty made of PTFE and PP, as indicated by R.A. Mamedov (2013) and E.S. Mishina et al. (2015), have certain disadvantages: Teflon, in their opinion, is poorly fixed to tissues, which leads to displacement of the prosthesis and relapse of the disease. Polypropylene causes the formation of a rough connective tissue capsule, which shrinks the hernioprosthesis.

In addition, in recent years it has become clear that the use of synthetic materials for hernioplasty has led to the emergence of new types of complications that had not previously developed during these operations. These are complications such as the migration of a synthetic implant into the abdominal cavity, adhesive intestinal obstruction as a result of adhesion of the intestine and mesh, the formation of fistulas as a result of a pressure ulcer of the bowel wall and endoprosthesis, and the formation of seromas in the area of the implant (Borovskiy O.O., 2013; Mamedov R. A. 2013; Mishina et al., 2015). The presence of such a variety of types of endoprostheses is explained by the fact that none of the mesh implants proposed so far meets the requirements of an "ideal mesh".

Therefore, the problem of finding a plastic material that meets the requirements of an ideal hernioprosthesis, that is, having not only high strength, but also maximum histocompatibility, remains urgent (Borovskiy O.O., 2013; Mishina E.S., 2015).

Prototype

As a prototype of the proposed method, endoproez-mesh TiO ₂ Mesh (Biocer, Bayreuth, Germany) is given. TiO ₂ Mesh ™ is a surgical mesh implant specifically designed to repair abdominal soft tissue defects where non-absorbable support material is required (FIG. 1). Relevant areas of application include the treatment of inguinal and incisional hernias in all common surgical procedures and even in IPOM. Federal (USA) law restricts this device to sale by or on the order of a physician.

The endoprosthesis-mesh TiO ₂ Mesh ™ is made of monofilament polypropylene thread and has a large pore structure with blue orientation stripes. Individual fibers of mesh implants are completely covered with a surface coating of titanium oxide.

TiO ₂ Mesh mesh is a mesh implant where polypropylene threads are coated with several layers of titanium oxide using the so-called PACVD (Chemical Vapor Deposition) technology.

The PACVD (or CVD) technology is as follows: all precursors are fed into the reactor at the same time and the reaction proceeds over the substrate, and the resulting film is then deposited on the substrate. Therefore, it is almost impossible to control the thickness of the target film in the case of PACVD or CVD. Due to the uneven distribution of the mass of precursors over the entire volume of the chamber above the substrate, the distribution of the concentration of reaction products throughout the volume of the reactor is uneven; therefore, nanofilms obtained on the basis of PACVD or CVD are uneven and inhomogeneous, there is no conformity. Thus, in PACVD or CVD processes, precursor depletion limits uniform coverage over large areas of the substrate surface. Vapor-based film deposition (CVD) processes, including plasma exposure (PACVD) to surfaces at atmospheric pressure, often suffer from non-uniform surface modification due to limitations in the straightness of application and delivery of precursors.

In the plasma PACVD process (a process that is activated by a plasma, usually a microwave plasma), an electric discharge in a gas, at a pressure of <100 Pa, is used to accelerate the kinetics of the CVD reaction due to the additional activation energy of precursor molecules. This can reduce the reaction temperature by several hundred degrees (conventional CVD is carried out at temperatures above 600 ° C), but the rate of coating is dramatically reduced.

This PACVD or CVD, which is manufactured by the technology TiO ₂ Mesh Mesh (Biocer, Bayreuth, Germany) received the prototype, all precursors are fed simultaneously into the reactor, and the reaction proceeds over the net, and the formed film is then deposited on the hernia mesh. Therefore, it is practically impossible to control the thickness of the target film in the case of PACVD or CVD due to the uneven distribution of precursor concentrations throughout the chamber volume above the mesh; therefore, nanofilms obtained on the basis of PACVD or CVD from titanium oxide are uneven, inhomogeneous, there is no conformity and do not possess bactericidal properties. like a titanium / vanadium oxide nanofilm.

Criticism of the prototype:

1. The coating is not conformal (conformity is less than 70%, ie, a stepped coating with areas devoid of coating; aerosol particles appear on the surface of the film - the composition of the film is inhomogeneous).

2. The coating is uneven (uniformity can be achieved only in small areas, locally), due to which gaps appear between the particles and with the continuous part of the film, which greatly affects the characteristics of the coating and its properties (adhesion to the substrate and, accordingly, barrier properties of the mesh itself).

3. The process is uncontrolled, so the film thickness is uneven.

4. The temperature latitude is low, and the use of high temperatures damages the polypropylene yarns from which the mesh is knitted.

5. The process is carried out only by creating a high vacuum.

6. Titanium oxide adheres worse to a polypropylene mesh than to a pre-coated aluminum oxide (10 nm thick), as in our proposed method.

7. The titanium oxide nanofilm used in the prototype does not possess bactericidal properties.

The purpose of the proposed method

The purpose of the proposed method is to provide implants: resistance to infection and adhesions, fix well, be biocompatible, strong enough and without deep scarring and rough encapsulation.

This goal is realized as follows: preliminary application to the implant, which is a hernial endoprosthesis-mesh, substrates made of aluminum oxide 10 nm thick, and then nanofilms of titanium / vanadium oxides, using the ALD technology (atomic layer deposition). ALD (Atomic Layer Deposition) technology is that one of the precursors is exposed to the vapors of the previous precursor, which forms a monolayer on the substrate surface. After removing the excess of the preceding precursor from the vapor phase using a purge gas (for example, argon, Ar), the reagent gas reacts with the adsorbed layer of the preceding precursor, forming a layer of the target film-forming material, i.e., the precursors are fed sequentially and in turn, and the reaction flows directly on the surface of the substrate.

The essence of the proposed method The essence of the proposed method is illustrated in Fig. 1 showing TiO ₂ Mesh implants. FIG. 2 shows the standard mesh endoprosthesis "Esfil", which we used in the experiment, manufactured by LLC "Lintex", St. Petersburg.

FIG. 3 shows the growth of cultures after 48 hours on Endo medium. From left to right: solid growth - the mesh is not processed, the growth around the perimeter of the mesh is a mesh coated with titanium oxide, growth only in the corner of the mesh is a mesh coated with titanium / vanadium oxides.

FIG. 4 shows the adhesion on the left in the uncoated mesh projection 5 weeks after implantation.

FIG. 5, figs. 6, figs. 7 and FIG. 8 shows staining with hematoxylin and eosin. FIG. 5, figs. 6 and FIG. 8 shows the use of a x10 objective, FIG. 7 shows the use of a x40 lens.

FIG. 9, figs. 10, figs. 11 and FIG. 12 shows hematoxylin and eosin staining. FIG. 9, figs. 10 and FIG. 12 shows the use of a x10 lens. FIG. 11 shows the use of a x40 lens.

According to the proposed method, the target film is built up layer by layer on the substrate, which allows you to control the thickness of the resulting nanofilm of titanium / vanadium oxides on the polypropylene endoprosthesis-mesh "Esfil" standard, produced by St. Petersburg LLC "Lintex", Endoprosthesis-mesh "Esfil" standard, used by us in the experiment, produced by LLC "Lintex", St. Petersburg (Fig. 2).

A film with a thickness of 18 nm, applied layer-by-layer: one layer of titanium oxide, a layer of vanadium oxide is applied to it, and so, repeating layer after layer of 150 cycles - titanium oxide (75 cycles) and vanadium oxide (75 cycles). Only the number of repetitions of the cycles used in the process is tracked to create the desired film thickness.

The application of nanofilms on the surface of the endoprostheses used on the basis of the proposed ASO technology is carried out at significantly lower temperatures (85 ° C and even at a temperature of 80 ° C) than using the PACVD or CVD technology. This is a significant difference between the proposed method and the prototype, since it makes it possible to coat more heat-sensitive materials such as those often used in hernioplasty, including polypropylene or polytetrafluoroethylene nets.

Comparative analysis of the features of the prototype and the proposed method of the invention

- With our proposed ASO technology, no gas-phase reaction over the substrate, as in the case of PACVD or CVD, occurs.

- According to the proposed method, the ASO technology is used to apply nanofilms of controlled thickness (with an accuracy of 1 angstrom), to achieve uniformity and purity of the coating. ALD technology used according to the proposed method allows the application of a nanofilm at low temperatures and, if necessary, the use of high temperatures for applying a film to products made of refractory material, which allows the technology of coating such heat-sensitive materials as polypropylene and other mesh endoprostheses used in hernioplasty ...

- According to the prototype, PACVD is used, in which it is impossible to achieve purity and uniformity of the film (coating defects occur), as well as to control the thickness of the coating. According to the prototype (using PACVD or CVD technology), it is impossible to coat heat-sensitive materials, since the use of high temperatures is required, at which polypropylene and polytetrafluoroethylene nets are partially damaged.

- According to the prototype, the technology requires the creation of a high vacuum in the chamber of the installation for the reaction to proceed, and according to the proposed method, a medium vacuum is sufficient, which simplifies the technological process.

- According to the proposed method, the conformity of the coating is 100% and the composition of the coating is precisely controlled, and according to the prototype, the conformity of the film is less than 70% and the composition of the film is not controlled.

- According to the prototype, the coating is applied directly to the mesh, and according to the proposed method, a substrate of aluminum oxide (10 nm thick) is first created, which is applied to the mesh endoprosthesis, and then the main coating is applied to this substrate, which allows the nanofilm to be firmly fixed on the mesh endoprosthesis with a backing.

- According to the prototype, a titanium oxide film is applied to the hernial polypropylene mesh, which improves, according to the manufacturer's advertisement, the biocompatible properties and strength of the implant, but does not exhibit bactericidal properties.

- According to the proposed method, a nanofilm of titanium / vanadium oxides is applied to the hernial endoprosthesis mesh, which, in addition to bactericidal activity, exhibits sufficient strength and good biocompatibility.

Examples of specific implementation of the method

Extract from the laboratory journal of FGUZ "Dagestan antiplague station" of Rospotrebnadzor

An experiment was set up to establish the bactericidal properties of a titanium / vanadium oxide film using nutrient media (Endo medium, blood agar and yolk-salt agar) in the laboratory of the Dagestan Antiplague Station of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare.

Three strips of the Esfil mesh endoprosthesis with the same area, but different geometric shapes: without applying a film (square shape), with a titanium oxide film, as in the prototype (rectangular shape) and with our proposed nanofilm of titanium / vanadium oxides applied according to ASO technology (triangular shape), sterilized in 70 degree alcohol, rinsed in distilled water, then dipped in a daily culture of laboratory strains of Staphylococcus aureus and Proteus vulgaris (with a titer of 1000 microbial bodies / ml) were placed on the above nutrient media at 37 degrees C Celsius. Tracked the growth of cultures on nutrient media after 24 and 48 hours.

Continuous culture growth was observed around the uncoated mesh, the titanium oxide coated mesh showed culture growth around the mesh perimeter, and there was no growth around the titanium / vanadium oxide coated mesh except for one colony at the corner of the triangular mesh. Culture growth after 48 hours on Endo medium. From left to right: 1) solid growth - the mesh is not processed, 2) growth around the mesh perimeter - mesh coated with titanium oxide, 3) growth only in the corner of the mesh - mesh coated with titanium / vanadium oxides is shown in Fig. 3.

The experiment shows that the titanium / vanadium oxide nanofilm exhibits bactericidal (or bacteriostatic) properties, at least against Staphylococcus aureus and Proteus vulgaris.

Extract from the laboratory journal of the Department of Normal Physiology of the DSMU

For a comparative study of biocompatible, barrier and functional properties of polypropylene hernial implants with nanocoating of titanium / vanadium oxides, we conducted an experiment on 5 male rabbits of 4 months of age, weighing 2.5-3 kg. In the left part of the abdominal wall, we implanted the control endoprosthesis-meshes "Esfil" standard uncoated (control), and the right part - the same meshes, but with a coating of titanium / vanadium oxides on an alumina substrate, applied to the meshes using the ASO technology. Operations on mesh implantation were carried out in the experimental laboratory of the Department of Normal Physiology of the DSMU under anesthesia (0.5 ml of xylanite + 0.4 ml of zoletil i / m, during the experiment, 0.2 ml of zoletil was added twice i / m).

After sterilization of the skin, a 5 cm incision was made along the white line of the abdomen. On both sides of the incision line, beds for meshes with dimensions of 2.5 × 3 cm were created between the transverse and internal oblique muscles of the abdomen, having previously separated the posterior wall of the rectus sheath. The meshes were fixed with absorbable sutures in two diametrical corners. Then the separated fascia was fixed and the wound was sutured with 4 sutures. After 5 weeks, re-introducing the rabbits into a narcotic sleep, the tissues surrounding the mesh and the condition of the anterior abdominal wall were visually examined. In 3 out of five rabbits on the left, where the control mesh (mesh, uncoated with nanofilm) was installed, adhesion of the loop of the small intestine to the anterior abdominal wall in the mesh projection was noted, Spike on the left in the uncoated mesh projection 5 weeks after implantation of the implant in the rabbit. FIG. 4 shows the moment of the experiment: on the right, where the mesh with nanocoating of titanium / vanadium oxides was installed, no adhesions were formed in any case.

After examination, the implanted meshes were removed with the surrounding tissues, fixed in 10% neutral formalin, then, after passing an increasing concentration of alcohol through a battery, they were poured into paraffin blocks. In histological sections, 5-7 microns thick, made of paraffin blocks on a sled microtome, and then stained with hematoxylin and eosin, the reaction of the recipient tissues surrounding the implant to the implanted meshes was studied using the MEKOS-C1 software and hardware complex, which made it possible not to only to view and describe micropreparations using a light microscope, but also to display the image on a monitor for a more detailed structural study and photograph them in digital mode.

The comparative results obtained by us, describing the reaction of the tissues surrounding the mesh, are presented in Fig. 5, figs. 6, figs. 7 and FIG. 8, which shows an uncoated control grid. FIG. 5, figs. 6, figs. 7 and FIG. 8 shows staining with hematoxylin and eosin. FIG. 5, figs. 6, figs. 7 and FIG. 8 shows the use of a x10 objective, FIG. 7 shows the use of a x40 objective.

FIG. 9, figs. 10, figs. 11 and FIG. 12 shows a mesh coated with a nanofilm according to the proposed method. FIG. 9, figs. 10, figs. 11 and FIG. 12 shows hematoxylin and eosin staining. FIG. 9, figs. 10, figs. 12 shows the use of a x10 objective, FIG. 11 shows the use of a x40 objective.

During histological examination in control animals, a layer of connective tissue with bundles of thick collagen fibers was determined around the mesh threads (Fig. 5). In some areas, there was a moderate productive inflammatory reaction with focal lymphocytic infiltration of the mesh filaments and their degradation (Fig. 6). A large number of eosinophils were observed among the cellular infiltrate (Fig. 7). On the periphery of the mesh, there was an uneven formation of fields of cicatricial connective tissue (Fig. 8).

In animals that were implanted with a mesh prepared according to the proposed method, around the mesh fibers there was an earlier development of fibrous connective tissue with an insignificant productive inflammatory response (Fig. 9.) and the formation of a network of small thin-walled blood vessels (Fig. 10). Among the cells of the infiltrate, the number of eosinophils was significantly less than in the first group (Fig. 11). Around the mesh was determined the formation of fields of fibrous tissue with a large number of collagen fibers, without gross deformation of the surrounding tissues (Fig. 12).

All the above examples of the implementation of the proposed method confirm the achievement of the goal set in the invention.

Comparative analysis of the experimental results showed:

1. Polypropylene endoprosthesis mesh "Esfil" standard with a nanocoating of titanium / vanadium oxides 18 nm thick on an alumina substrate 10 nm thick exhibits bactericidal properties, in contrast to a polypropylene mesh endoprosthesis with a titanium oxide coating and without a coating (Fig. 3).

2. In the case of implantation of an uncoated polypropylene mesh, in 60% of cases (in three out of five rabbits) adhesions of the small intestine loop to the anterior abdominal wall in the mesh projection (left) were formed, which may be associated with an inflammatory reaction of the soft tissues surrounding the mesh to the implant (photo 4), and when using the same mesh with a coating of titanium / vanadium oxides on an alumina substrate applied by the ALD technology, the inflammatory reaction did not appear, and no adhesions were formed.

3. When nanocoating of titanium / vanadium oxides on an aluminum oxide substrate is applied to the Esfil polypropylene mesh endoprosthesis using the ALO technology, the biocompatible properties of the implant are significantly improved: there is an earlier development of fibrous connective tissue with the formation of a network of small thin-walled blood vessels and fibrous fields. tissues with a large number of collagen fibers, without deformation of the surrounding tissues and in the absence of giant cells of foreign bodies. There was practically no eosinophilic infiltration (reaction to the implant) around the mesh (in 3 cases out of 5) or it was quite insignificant only in 2 cases (Fig. 11).

4. When a polypropylene endoprosthesis-mesh "Esfil" was implanted in rabbits without coating after 5 weeks, a layer of fibrous connective tissue with bundles of thick collagen fibers was detected around the mesh threads in all 5 cases. In some areas, there was a pronounced productive inflammatory reaction with focal lymphocytic infiltration of the mesh filaments and their degradation. A large number of eosinophils were observed among the cellular infiltrate. On the periphery of the mesh, there was an uneven formation of fields of coarse cicatricial connective tissue (Fig. 5, Fig. 6, Fig. 7, Fig. 8).

The positive effect of using the proposed method

The usefulness of the developed method, proposed as an invention, is based on the following properties of a titanium / vanadium oxide nanofilm with an aluminum oxide substrate applied to the Esfil mesh endoprosthesis using the ASO technology: a titanium / vanadium oxide nanofilm significantly improves the biocompatibility (histocompatibility) of the endoprosthesis - mesh and its barrier and functional properties, enhances strength;

Improving biocompatibility helps to reduce the response of the tissues surrounding the mesh, prevents the cellular, primarily eosinophilic cellular response, the development of foreign body granulomas and rough scar tissue. A titanium / vanadium oxide nanofilm with an aluminum oxide substrate promotes the earlier development of fibrous connective tissue with the formation of a network of small thin-walled blood vessels and fields of fibrous tissue with a large number of collagen fibers, without deforming the surrounding tissues, and also exhibits bactericidal properties. Possessing anti-inflammatory properties, it helps to minimize the inflammatory response around the implant, which prevents the formation of adhesions.

The technology used by ASO allows carrying out the process of applying nanofilm to the mesh endoprosthesis without creating a high vacuum and at relatively low temperatures (80-85 degrees Celsius), which contributes to better preservation of the heat-sensitive polypropylene threads of the mesh itself, as well as to control the thickness of the target film. In addition, the technology used by ASO creates a 100% coating conformity, purity and uniformity of the film.

The creation of a preliminary alumina substrate promotes better adhesion of the titanium / vanadium oxide nanofilm to the mesh, promotes film strength, prevents the destruction of the endoprosthesis mesh from the oxidative environment and the appearance of distant postoperative complications such as wrinkling, mesh migration, etc.

The developed method for improving the biocompatible, barrier and functional properties of endoprosthesis meshes by applying a titanium / vanadium oxide nanocoating with an alumina substrate on the Esfil endoprosthesis mesh using ASO technology is technically simple to perform, in comparison with PACVD or CVD technology, and allows cover simultaneously relatively large areas, which, in turn, reduce material costs and increase economic efficiency.

We used the Esfil mesh endoprosthesis with a titanium / vanadium oxide nanocoating with an aluminum oxide substrate in an experiment on rats and rabbits. formation of rough scar tissue and adhesions, reduction of eosinophilic-cell and lymphocytic-cell reactions of the tissues surrounding the implant.

Information taken into account

Kazantsev A.A. Application of titanium-containing mesh and suture materials. Analytical review and collection of articles // A.A. Kazantsev, A.A. Kolpakov, V.V. Parshikov, K.A. Shemyatovsky, D.L. Titarov, I.I. Babichenko, N.M. Gevondyan, A.I. Alekhin, M. Yu. Glazunov / Central Design Bureau of the Russian Academy of Sciences - Moscow, 2015 .-- 95 p. (S. 20, 38-48. - prototype).

Claims (1)

A method for improving the biocompatibility and strength of mesh implants for hernia repair, which consists in using a surface coating of titanium oxide, characterized in that an aluminum oxide substrate 10 nm thick is applied to the implant and then a nanofilm of titanium and vanadium oxides 18 nm thick using the ASO technology (atomic layer deposition), and the temperature of nanofilm deposition is 80 ° C or 85 ° C.

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