EP1596893A1

EP1596893A1 - Surgical implant

Info

Publication number: EP1596893A1
Application number: EP04710832A
Authority: EP
Inventors: Christoph Walther
Original assignee: Ethicon GmbH
Current assignee: Johnson and Johnson Medical GmbH
Priority date: 2003-02-25
Filing date: 2004-02-13
Publication date: 2005-11-23
Also published as: WO2004075936A1; DE10307946B4; DE10307946A1

Abstract

A surgical implant has a flexible basic structure which comprises a first component of resorbable material and a second component of non-resorbable material and/or of slowly resorbable material which is resorbed more slowly than the material of the first component. Before implantation, the elongation at tear of the first component is at least 1.25 times the elongation at tear of the second component. The first component and the second component are designed such that, after implantation, the elongation at tear of the first component and that of the second component are equal at a time which lies in the range of from 2 days to 90 days after implantation.

Description

Surgical implant

The invention relates to a surgical implant, in particular an implant with a flexible basic structure configured as an implant mesh.

After they have been implanted, the implants available on the market cause a moderate to severe inflammatory reaction and substantial connective tissue induction which, in the case of areal implants, leads to the formation of scar plates. In recent developments (areal implants with low material mass) , it is true that the inflammatory reaction and connective _>r,tissue induction are reduced, but the resorbable part of these implants, for example consisting of copolymers of glycolide and lactides, ' often initially causes moderate induction of connective tissue.

The object of the invention is to provide a surgical implant, in particular an implant with a flexible basic structure configured as an implant mesh, which, after implantation, shows a reduced inflammatory reaction and reduced connective tissue induction.

This object is achieved by a surgical implant with the features of Claim 1. Advantageous embodiments of the invention are set out in the dependent claims.

The surgical implant according to the invention has a flexible basic structure which comprises a first component of resorbable material and a second component of non-resorbable material and/or of slowly resorbable material. The slowly resorbable material of the second component, if present, _ is resorbed more slowly than the material of the first component. The slowly resorbable material preferably has a resorption time of at least 60 days or still has a tear strength, 30 days after implantation, which is at least 10% of the initial tear strength. Before implantation, the elongation at tear of the first component is at least 1.25 times the elongation at tear of the second component. The first component and the second component are designed such that, after implantation, the elongation at tear of the first component and that of the second component are identical at a time which lies in the range of from 2 days to 90 days after implantation.

In a particularly preferred embodiment of the invention, the basic structure is configured as an implant mesh, the first component having filaments of a copolymer of glycolide and caprolactone and the second component having filaments of polypropylene. The filaments of the first component are preferably monofilaments with a thickness in the range of from

0.04 mm to 0.5 mm, and the filaments of the second component are preferably monofilaments with a thickness in the range of from 0.08 mm to 0.15 mm. The pores of the basic structure configured as an implant mesh preferably have, across at least 90% of the total pore surface, a respective area in the range of from 2 mm² to 25 mm², i.e. the pores are relatively large.

In the first phase after implantation, the implant according to the invention has a relatively high degree of strength in order to mechanically stabilize the area in which the initial wound healing takes place. This high initial strength is a result of the relatively high elongation at tear of the first component, correlating with a high tear strength. After implantation, however, the tear strength of the first component rapidly declines so that the subsequent phase of wound healing can run its course without mechanical irritation by the implant. This leads to a marked reduction in the inflammatory reaction, and there is no initial increase in connective tissue induction. The second component ensures the mechanical stability in the later phase of healing. On account of the materials chosen, the particularly preferred embodiment is already relatively soft to start with (i.e. before implantation and immediately thereafter) and has a low rigidity, particularly if large pores are provided and relatively thin monofilaments are used, as is indicated above. The initial ratio of the elongation at tear of the first component and that of the second component results in a favourable elongation behaviour, and the marked reduction of the inflammatory reaction and the absence of an initial increase in connective tissue induction have already been mentioned. After just 2 to 20 days, the resorbable first component already has a lower elongation at tear than the in this case non-resorbable second component, and it will thereafter decline still further.

The favourable behaviour in the initial phase after implantation of an implant according to the invention is demonstrated in tolerance tests (see below) . Thus, in the particularly preferred embodiment in which the elongation at tear of the first component is initially about 1.6 times that of the second component, the tissue reaction is much less pronounced than in commercially available comparison samples, namely non- resorbable implant meshes made of polypropylene and resorbable implant meshes made of glycolide/lactide copolymers ("Vicryl", Ethicon, glycolide to lactide ratio 90:10). This is very surprising since the tissue reaction is not only less than in the case of a "Vicryl" mesh, but also less than in the case of a polypropylene mesh, although an initial reaction to the products of degradation of the first component is to be expected. The initial elongation at tear of Vicryl" and of polypropylene is about 20%, in other words roughly equal, in contrast to the initial elongation at tear of the first component and of the second component of the implant according to the invention. In the particularly preferred embodiment, the material of the first component comprises copolymers of glycolide and caprolactone ("Monocryl", Ethicon) . For the first component, however, other materials are also possible, for example poly-p-dioxanone ("PDS", Ethicon) .

In addition to polypropylene (PP) ("Prolene", Ethicon), possible materials of the second component are in particular fluorine-containing polyolefins and mixtures of polyvinylidene fluoride and copolymers of vinylidene fluoride and hexafluoropropylene (e.g. the material "Pronova" from Ethicon), and other materials too.

While the tear strength of a filament in the materials customarily used for implants depends predominantly on the thread thickness and less so on the material itself, the elongation at tear is more dependent on the material, if the drawing conditions during monofilament extrusion of the filaments to be compared are similar.

Typical ranges of the elongation at tear for the first component (resorbable part) are:

- "Monocryl" monofilaments : ca. 25% to 40% esp. 30% to 35% ^λPDS" monofilaments: ca. 25% to 40%

Typical ranges of the elongation at tear for the second component (non-resorbable or slowly resorbable part) are:

"Prolene" monofilaments : ca. 15% to 25% "Pronova" monofilaments : ca. 18% to 28%

The first component can be present in the implant in many different forms, for example as yarn, monofilament, multifilament, twine, twisted structure or tape, and also in several of these forms or in other forms. The same applies to the second component. In addition, mixed forms are conceivable, for example twines consisting of filaments of the first component and filaments of the second component. In forms such as yarns, monofilaments, multifilaments or twines, the thickness is preferably in the range of from 0.01 mm to 0.5 mm, while the width of a tape is preferably in the range of from 0.05 mm to 1 mm.

In the particularly preferred embodiment of the implant, the basic structure is areal and configured as an implant mesh (in particular for hernia repair or for use at the pelvic floor), e.g. as a _^knitted structure. A great many configurations are in general conceivable for the basic structure, for example areal structures, mesh-like structures, knitted mesh-like structures, supports for tissue cultures, supports for cell cultures, supports for active substances, textile configurations, three-dimensional structures.

If the implant according to the invention is provided with colour markings (for example in the form of stripes) , for example with the aid of filaments of different colour worked into the basic structure or with marking stripes imprinted onto the basic structure, the handling of the implant can be made easier, depending on the application.

The invention is described in more detail below on the basis of examples and with reference to the figures, in which:

Fig. 1 shows a histogram illustrating in graph form the results from Example 3 (Table 3) ,

Fig. 2 shows a further histogram illustrating in graph form the results from Example 3 (Table 4),

Fig. 3 shows an illustration of the fibrous reaction of conventional implant meshes in the course of resorption,

Fig. 4 shows an illustration of the inflammatory reaction of conventional implant meshes in the course of resorption.

Example 1

To illustrate the force-elongation behaviour of preferred materials for the basic structure of the surgical implant, monofilaments made of a copolymer of glycolide and caprolactone ("Monocryl", Ethicon; thread thickness #6-0, i.e. diameter 0.07 mm; resorbable) and of polypropylene ("Prolene", Ethicon; 3.5 mils diameter, i.e. diameter 0.089 mm; non-resorbable) were tested.

For this purpose, a twine was first produced on a "Lezzini" two-stage twining machine, one "Monocryl" monofilament and one "Prolene" monofilament being highly twisted at 170 S T/m and the two components then being twined at 120 Z T/m.

The tear strength (in N) and the elongation at tear (in %, with respect to the length of the unloaded sample) of the two components were determine^'d by measurements of the twine ^' using a ^,ΛStatima"t" testing machine, specifically for different degrees of resorption of the "Monocryl" component. To set a degree of resorption, the respective twine was artificially aged for a predetermined time in a climatic cabinet at 25 °C and 85% relative humidity, for up to 2 weeks to obtain the highest degree of resorption. A measure of the degree of degradation of the resorbable part is the inherent viscosity.

The measurements for each degree of resorption were carried out on five samples of the twine. Table 1 below shows the tear strength and elongation at tear for the two monofilaments (components), and the inherent viscosity as a measure of the degree of resorption of the " onocryl" component, specifically as the mean value for the five samples.

It will be seen that the two monofilaments initially differ in tear strength and elongation at tear. During the resorption or partial resorption, which of course is predominantly a hydrolytic degradation, the tear strength and the elongation at tear of the resorbable component continuously decline until they practically match the tear strength and the elongation at tear of the non-resorbable part at inherent viscosities of 0.83 dl/g.

Table 1: Tear strength and elongation at tear of the monofilaments

Example 2

The production of five basic structures of surgical implants configured as an implant mesh is described below, designated "Mesh 1" to "Mesh 5". In the examples, the surgical implants have no constituent parts additional to the basic structures; implants with additional constituent parts are, however, also conceivable in principle.

Mesh 1

This mesh was produced as a crochet galloon knit of PP monofilaments ("Prolene", Ethicon) of thread thickness 3.5 mils (0.089 mm) and a resorbable monofilament ("Monocryl", Ethicon, copolymer of glycolide and caprolactone) of thread thickness #5-0 (according to USP; i.e. 0.1 mm) .

Pattern: warp as dense fringe (PP monofilament)

Warp: PP monofilament, 3.5 mils

Guide bars :

Bar 6: 2-4/2-4/0-4/2-4/2-6//

PP monofilament/"Monocryl" monofilament # 5-0

Bar 7: 4-2/4-2/6-2/4-2/4-0// -

PP monofilament/"Monocryl"^' monofilament # 5-0

Mesh density: ca. 1.5 meshes/cm

The PP monofilament/"Monocryl" monofilament mixture can be doubled, but preferably also twined.

The crochet galloon knit was washed with an organic solvent in order to wash off residues of processing aids, then tensioned on frames and annealed at high temperatures for several hours under a dry inert gas. In this concrete example, the knit was annealed at 113 °C for 9 hours in a dry nitrogen atmosphere (dew point <-20°C) .

The knit (crochet galloon knit) was then cut to size, packaged, and sterilized with ethylene oxide.

The "Monocryl" part of the mesh had an inherent viscosity (measured in hexafluoroisopropanol as solvent) of 1.19 dl/g.

Mesh 2 :

Before sterilization, the crochet galloon knit produced as in the description of Mesh 1 was degraded for 5 days in an aqueous phosphate buffer (pH 7.25) at relatively high temperatures, washed with distilled water, dried, packaged, and then sterilized.

The "Monocryl" part had an inherent viscosity of 0.59 dl/g.

Mesh 3 :

Mesh 3 was produced analogously to Mesh 1, but instead of "Monocryl" of thread size # 5-0, the thinner thread size # 6-0 (according to 'USP; i.e. 0.07 mm) was used. Part of the "Monocryl" was coloured with "D+C violet" so that areas of the implant had coloured stripes.

The inherent viscosity of the "Monocryl" part of the sterile finished knit was 0.97 dl/g.

Mesh 4 :

This mesh was produced analogously to Mesh 3. After incubation in a phosphate buffer, the inherent viscosity of the "Monocryl" part was 0.48 dl/g. Mesh 5 :

As comparison sample, a mesh made of pure polypropylene was produced (Prolene 3.5 mils, i.e. 0.089 mm), analogously to Mesh 1, but without "Monocryl" in the fringe.

Variants :

Polypropylene (PP) can for example^' be replaced by "Pronova" (Ethicon; mixture of fluorinated polyolefins, specifically of polyvinylidene fluoride and copolymers of vinylidene fluoride and hexafluoropropylene) , "Monocryl" for example by "PDS" (Ethicon; homopolymer of poly-p-dioxanone) .

Twines .can be produced in the manner indicated in Example 1. From such a twine, it is possible for example to produce an areal basic structure as crochet galloon knit.

Example 3

Tests of the tissue reaction and of the local effects of the surgical implant after implantation are described below.

First, five implant meshes of the same construction were produced on a crochet galloon machine, specifically the implant meshes designated as Mesh 1 to

Mesh 5 in Example 2. They all include a "Prolene" monofilament with a thread diameter of 3.5 mils (0.089 mm), and meshes 1 to 4 additionally include a

"Monocryl" monofilament, its thread size and degree of polymerization differing between the meshes. Mesh 5 serving as a control sample consists only of "Prolene".

The properties of these implant meshes are . summarized in Table 2. Table 2: Properties of the implant meshes

An implantation study on rats according to ISO 10993 Part 6 (Test of local effects after implantation) was carried out with these meshes. The meshes were implanted in 25 mm x 35 mm format in the subcutaneous tissue of the rats^ backs. The animals, divided into groups of 3 rats each, were sacrificed after 28, 56, 84 or 140 days and the implants were histologically examined.

The test was carried out with the aid , of paraffin sections and EvG-, HE- and PS-stained slides. Microscopic and morphometric evaluations were performed by means of conventional light microscopy (HE stain, EvG stain, Sirius RED stain) .

For each preparation, the inflammatory infiltrate (IF) was measured at 10 representative sites as distance in μm; this is the width of the inner granuloma part (macrophage wall) . Great care was taken to ensure that the measurements were made only at the outer contact surfaces in the area of the "Prolene" and "Monocryl" filaments and not in the spaces between these.

The connective tissue capsule (CT) was measured in eacn preparation at 10 representative sites as distance in μm; this is the width of the outer granuloma part (fibrocyte wall) . Great care was taken to ensure that the measurements were made only at the outer contact faces in the area of the "Prolene" and "Monocryl" filaments and not in the spaces between these.

The immunohistochemistry results on cell response (Ki 67, Tunel) were measured in 10 grid squares with an edge length of 250 μm per section. To determine the percentage cell proportion, the total cell number appearing in the grid square was determined on the one hand, and the specifically Ki 67-positive and Tunel- positive cells were counted on the other.

The results for the inflammatory infiltrate and the connective tissue capsule are summarized in Tables 3 and 4, respectively, and as histograms in Figures 1 and 2, respectively.

Table 3: Inflammatory infiltrate [μm]

Table 4 : Connective tissue capsule [μm]

Quantitative morphometry reveals that the two implant meshes Mesh 1 and Mesh 3 have a significantly lower inflammatory reaction compared to the control mesh (Mesh 5, without "Monocryl") , specifically over the entire observation period. The two other "Monocryl"- containing meshes with a lower degree of polymerization in the "Monocryl" part (Mesh 2, Mesh 4) show a markedly weaker inflammatory reaction after an implantation period of 84 days. The "Monocryl" part is resorbed after 84 days to 140 days.

For the two implant meshes Mesh 1 and Mesh 3, there is significantly less connective tissue induction after just 28 days.

A further striking difference between the mesh variants is seen in the cell proliferation (Ki 67) . Here, the "Monocryl"-containing implant meshes have slightly increased values, which already reach significance level because of the large number of measurements. The differences in the Tunel test (terminal desoxyribosyl transferase- ediated dUTP nick end labeling) are clearer. (The Tunel test reveals the DNA strand breaks occurring during apoptosis and permits identification of apoptotic cells) . Here, the "Monocryl"-containing implant meshes have .. highly significantly lower values. The results are summarized in Tables 5 and 6. Table 5: Cell proliferation (Ki 67 [%] )

Table 6: Tunel test [-'

Interpreting the available measured values, it is evident that, in contrast to "Vicryl"-containing mesh variants, the "Monocryl"-containing implant meshes cause no initial increase in connective tissue induction.

Figures 3 and 4 illustrate, for comparison, typical results of fibrous reaction and inflammatory reaction for heavy implant meshes made of polypropylene monofilaments (with a surface weight of ca. 100 g/m²) , for a "Vicryl"-containing composite mesh ("vypro", Ethicon, made of polypropylene multifilament yarn and "Vicryl" yarn) , for a pure "Vicryl" mesh, and for controls without implant.

Claims

1. Surgical implant with a flexible basic structure - which comprises a first component of resorbable material and which comprises a second component of non- resorbable material and/or of slowly resorbable material which is resorbed more slowly than the material of the first component, where, before implantation, the elongation at tear of the first component is at least 1.25 times the elongation at tear of the second component, and - where the first component and the second component are designed such that, after implantation, the elongation at tear of the first component and that of the second component are equal at a time which lies in the range of from 2 days to 90 days after implantation .

2. Implant according to Claim 1, characterized in that the material of the first component comprises at least one of the substances selected from the following group: poly-p-dioxanone, copolymers of glycolide and caprolactone .

3. Implant according to Claim 1 or 2, characterized in that the material of the second component comprises at least one of the substances selected from the following group: polypropylene, fluorine- containing polyolefins, mixtures of polyvinylidene fluoride and copolymers of vinylidene fluoride and hexafluoropropylene.

4. Implant according to one of Claims 1 to 3, characterized in that the first component has at least one of the forms selected from the following group: yarns, monofilaments, multifilaments, twines, twisted structures, tapes.

5. Implant according to one of Claims 1 to 4, characterized in that the second component has at least one of the forms selected from the following group: yarns, monofilaments, multifilaments, twines, twisted structures, tapes.

6. Implant according to Claim 4 or 5, characterized in that the thickness of at least one yarn, monofilament, multifilament or twine lies in the range of from 0.01 mm to 0.5 mm and the width of at least one tape lies in the range of from 0.05 mm to 1 mm.

7. Implant according to one of Claims 1 to 6, characterized in that the basic structure has one of the configurations selected from the following group: areal structures, mesh-like structures, knitted mesh-like structures, supports for tissue cultures, supports for cell cultures, supports for active substances, textile configurations, three- dimensional structures.

8. Implant according to Claim 1, characterized in that the basic structure is configured as an implant mesh, the first component has filaments, preferably monofilaments with a thickness in the range of from 0.04 mm to 0.5 mm, of a copolymer of glycolide and caprolactone, and the second component has filaments, preferably monofilaments with a thickness in the range of from 0.08 mm to 0.15 mm, of polypropylene.

Implant according to Claim 8, characterized in that the pores of the basic structure configured as an implant mesh have, across at least 90% of the total pore surface, a respective area in the range of from 2 mm² to 25 mm².

10. Implant according to one of Claims 1 to 9, characterized by colour markings.