Patent Application
20210330868
The present disclosure relates to a membrane for re-establishing the continuity of injured biological tissues. In particular, the present disclosure relates to a membrane for re-establishing the continuity of injured biological tissues, wherein said membrane comprises a non-woven fabric comprising fibers of a polyhydroxyalkanoate (PHA).
It is well known that in abdominal (veterinary and human) surgery there are basically two similar conditions, although very distant from each other in terms of anatomy and surgical technique, in which surgeons face a series of complications and factors that prevent a successful outcome of the surgical intervention.
These two conditions are represented by the anastomoses of the gastrointestinal tract and the incisional hernias. In fact, in both cases, the surgeon tries to re-establish the continuity of injured tissues by affixing foreign material to the organism represented by sutures or prosthetic meshes. This material favors the continuity of the tissues and therefore the healing. Healing is represented in both cases by the resistance of the final construct (tissue+surgical material) to tensile forces and is obtained by the apposition of collagen by fibroblasts. In both cases, in fact, the final success is determined by the correct apposition of collagen by fibroblasts and by its transformation into fibrous tissue.
Intestinal Anastomosis
With regard to intestinal anastomosis, intestine healing comprises a series of delicate passages in which the mucosal barrier is re-established, and the tissue subjected to surgical insult heals. The healing phases follow four steps: inflammatory phase, lag phase, proliferation phase and remodeling phase, during which different physiological phenomena involve molecular and cellular mechanisms.
Modern intestinal anastomosis techniques are aimed at reducing interference with these phases and promoting their progression. The dehiscence of anastomosis is a multifactorial mechanism and cannot be attributed to a single cause or a predisposing factor and the search for a method to prevent this catastrophic event remains a current problem. Several solutions have been evaluated for preventive purposes. Furthermore, a variety of surgical supports were applied with different success: intraluminal stents to support the anastomotic site and extraluminal wraps to protect it externally.
The primary integrity of the intestinal anastomosis depends on the surgical technique, on the ability of the tissues to support the suture or the staples, and on the healing process. Many methods have been studied to increase the initial strength of the anastomosis, especially in the first post-operative days. The most commonly used method is the buttressing or reinforcement of the suture line with interposition of different materials (bovine pericardium, synthetic materials) between the intestine stumps. The application of intraluminal stents or the bandage of the anastomosis (wrap) with biomaterials was also tested. These methods favor the deposition of fibrin on the serosa. However, they have the drawback that, in some cases, the excess of healing turns into stenosis.
More specifically:
Incisional Hernia
The incisional wound is that wound, made during surgery, on the wall of the abdomen (laparotomy) during surgical interventions in the intestine, the abdominal viscera, and in the female reproductive system. If the healing of this wound becomes complicated (infection, tension, tissue rupture), it can give rise to what is called incisional (or ventral) hernia. Incisional hernias occur in 20% of patients undergoing laparotomy. From the patient's point of view, a ventral hernia can cause pain, alteration of normal functions, and can increase in volume resulting in deformation of the abdomen and imprisonment or strangulation of the intestine or other abdominal organs. The only known cure is to repair the ventral hernia by further surgery.
A truly effective and univocally accepted treatment to reduce the complications of incisional wounds has not yet been found.
The only method of proven efficacy (even if not able to totally eliminate the problem) is the use of a perfect aseptic technique, possibly associated with suture threads that release antibiotics.
Incisional hernias derive from the lack of healing of the initially separated and then sutured tissues after laparotomy interventions. Following laparotomy, the surgical incision is closed by one or more suture planes, to which the construct resistance is initially and entirely entrusted. Following the initial inflammatory phase, fibroblasts begin to affix collagen which, giving rise then to fibrous tissue, shift the task of providing resistance to the construct from the suture thread to the tissues.
If during this phase adverse factors occur (infections, excessive tension, metabolic disorders), the construct may be broken down, causing the two margins of the initial incision to separate. This physical distance between the two margins causes the fibroblasts to no longer apply collagen effectively and the result is the formation of a hernia.
To remedy this possibility, the most effective method is the implantation of prosthetic material, typically in the form of membranes or meshes. These meshes act as a support and as a “bridge” for fibroblasts, which are able to re-establish the continuity of the collagen matrix from one side of the incision to the other and thus to remedy the initial lack of healing producing a solid fibrous tissue wall that incorporates the implanted material.
There are membranes or meshes of different materials, for example polypropylene, polyglycolic acid and dual-component membranes (polypropylene and Teflon). As can be seen, these materials are profoundly different from each other: from those that are slowly reabsorbable (polyglycolic acid) to non-resorbable (polypropylene) ones, from those that cause a strong inflammatory reaction and therefore a consistent affixing of fibrous tissue (polypropylene) with the risk of adhesions of intestinal tracts on the mesh itself, to those with a very reactive material (polypropylene) on one side combined with a non-adherent (Teflon) one on the other.
This derives from the fact that, as often happens, there is not yet a completely effective method or material of choice to solve problems related to the repair of incisional hernias.
The Applicant has therefore posed the problem of developing a membrane to re-establish the continuity of injured biological tissues, using a material that has the capacity of promoting the healing of injured biological tissues relatively quickly, without inducing inflammatory or rejection reactions.
The Applicant has now found that this problem, and others which will be better illustrated hereafter, may be solved by using a membrane comprising a non-woven fabric comprising polyhydroxyalkanoate (PHA) fibers as hereinafter defined.
In a first aspect thereof, the present disclosure therefore relates to a membrane for re-establishing the continuity of injured biological tissues, which comprises a non-woven fabric of fibres of a polyhydroxyalkanoate (PHA) containing 3-hydroxybutyrate monomer units, wherein said fibers have an average diameter comprised from 800 nm to 3500 nm. Preferably comprised from 1000 nm to 3000 nm.
Therefore, in the context of the present description and of the accompanying claims, the terms “to re-establish the continuity of injured biological tissues” means that healing process, known to the skilled person in the art, mediated by the affixing of collagen by fibroblasts, in the proximity of the margins of the injury, whose purpose is to induce closure and therefore the healing of the injury itself.
In the context of the present description and of the accompanying claims, the term “non-woven fabric” refers to a textile structure comprising fibers which are arranged in a substantially random manner, that is to say, without a predetermined order which is instead characteristic of the actual fabrics, which are obtained by weaving (crossing of weft and warp threads by loom) or knitwear.
Tests carried out by the Applicant (described in detail hereafter) have surprisingly shown that the membrane according to the present disclosure has the advantages of promoting the healing of injured biological tissues relatively quickly, without inducing excessive inflammatory or rejection reactions, thus demonstrating a high biocompatibility, thereby providing a valid support in the healing process of biological tissue injuries and preventing the formation of dehiscences and incisional hernias.
The membrane, in order to re-establish the continuity of an injured biological tissue, is preferably inserted into the injury and fixed, by means of one or more sutures, to the area adjacent to the tissue injury. Subsequently, the injury is closed by suture and the membrane, being near the injured area, promotes the healing process, thereby re-establishing the continuity of the injured biological tissue.
In the context of the present description and of the accompanying claims, the term “biological tissue” refers to a set of cells, structurally similar, associated by function. It constitutes a higher level of cellular organization, intended to play a decisive role in an animal organism. According to the present disclosure, preferred biological tissues are: epithelial tissue, muscle tissue, nerve tissue, connective tissue. Even more preferably, the biological tissue is epithelial tissue.
According to the purposes of the present disclosure, the PHA containing 3-hydroxybutyrate monomer units which forms the fibers of the non-woven fabric is preferably a poly-3-hydroxybutyrate homopolymer (P3HB) or a copolymer containing at least 20 mol % of 3-hydroxybutyrate monomer units, the remainder being hydroxyalkanoates monomer units other than 3-hydroxybutyrate.
In general, PHAs suitable for the present disclosure are homopolymers comprising 3-hydroxybutyrate monomer units:
—O—CH(CH3)—CH2—CO— (I)
or copolymers of 3-hydroxybutyrate monomer units with at least one hydroxyalkanoate monomer unit having the formula
—O—CHR1—(CH2)n—CO— (II)
wherein:
R1 is selected from: —H and C1-C12 alkyl;
n is zero or an integer comprised in the range from 1 to 6, and is preferably 1 or 2; with the proviso that, when R1 is methyl, n is different from 1. Preferably, R1 is methyl or ethyl. Preferably, n is 1 or 2.
In the case of a copolymer, it preferably contains at least 20 mol %, more preferably at least 30 mol %, of 3-hydroxybutyrate monomer units, the remainder being hydroxyalkanoate monomer units other than 3-hydroxybutyrate. In such copolymers, the quantity of 3-hydroxybutyrate monomer units is generally equal to or less than 99 mol %, preferably equal to or less than 90 mol %.
Particularly preferred hydroxyalkanoates monomer units other than 3-hydroxybutyrate are those deriving from: 4-hydroxybutyrate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyoctanoate, 3-hydroxyundec-10-enoate, 4-hydroxyvalerate.
In the case of copolymers of PHA, they are preferably selected from: poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (P3HBV), poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (P3HBH), poly(3-hydroxybutyrate-co-4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxyvalerate (P3HBVV), or mixtures thereof.
According to the purposes of the present disclosure, preferably the PHA is a poly-3-hydroxybutyrate homopolymer (P3HB).
PHAs suitable for the present disclosure preferably have a weight average molecular weight (Mw) comprised in the range from 5,000 to 1,500,000 Da, more preferably from 100,000 to 1,000,000 Da. The weight average molecular weight can be determined according to known techniques, in particular by means of GPC (Gel Permeation Chromatography) analysis.
The Applicant believes that the use of PHA fibers containing 3-hydroxybutyrate monomeric units, and in particular poly-3-hydroxybutyrate fibers (P3HB), ensures a substantially complete resorption of the fibers themselves by the organism in which the membrane has been implanted, without any toxic or harmful effect.
In fact, when the PHA containing 3-hydroxybutyrate monomer units is metabolized within the organism, the 3-hydroxybutyric acid monomer is released, which, due to the presence of an OH group on the carbon in beta position, undergoes a dehydration reaction catalysed by some enzymes, resulting in the formation of crotonic acid (an alpha-beta-unsaturated acid). Within the organism, the crotonic acid undergoes a reaction of addition of hydrogen with consequent formation of butyric acid (a “Short Chain Fatty Acid” SCFA that is easily assimilated by the organism). This metabolic pathway is impossible with other monomers derived from other PHAs, such as with 4-hydroxybutyric acid which is generated as a result of the metabolization of poly-4-hydroxybutyrate (P4HB): in fact, in 4-hydroxybutyric acid the OH group is positioned on the gamma carbon and not on the beta carbon, thus making it impossible the formation of crotonic acid by dehydration.
Preferably, the PHA fibers of the non-woven fabric according to the present disclosure are produced by electrospinning. In the context of the present description and of the accompanying claims, “electrospinning” means a spinning method, known in the art, which exploits the interaction that is created between a polymeric solution and an external electric field. Electrospinning makes it possible to produce very small diameter filaments, generally of the order of tens or hundreds of microns, with high speed and accurate process control, a result difficult to obtain with common fiber production techniques by extrusion spinning.
An electrospinning system mainly comprises a pump connected to a syringe containing the polymer solution, a spinneret connected to the syringe, a high voltage source and a manifold. Due to the action of the pump, the polymer solution is pushed outside the syringe, towards the manifold, passing through the spinneret with a constant and controllable flow. When a high potential difference (usually between 1 and 30 kV) is applied between the spinneret and the manifold, a drop of polymer is generated at the tip of the spinneret. As the difference in potential increases, the drop is subjected to increasing repulsive forces between its surface charges and the electrostatic forces exerted by the external electric field, up to the distortion of the drop itself with the formation of a cone commonly known as Taylor's cone. As soon as the electric field exceeds a critical value, specific for each polymeric solution, the electrostatic forces prevail over the surface tension leading to the formation of a polymeric fiber or thread.
Preferably, the non-woven fabric according to the disclosure may be made by electrospinning, with dimensions suitable for surgical needs, that is to say, depending on the length and the extent of the injury to be treated. Generally, the non-woven fabric may has dimensions comprised from 1 cm2 to 50 cm2 and have a rectangular, rhomboidal, square, oval, round or irregular shape. The non-woven fabric may have a thickness comprised from 10 μm to 700 μm, more preferably comprised from 50 μm to 500 μm.
According to another aspect thereof, the present disclosure relates to a method for producing a membrane comprising a non-woven fabric according to the present disclosure, which comprises:
The organic solvent that can be used for the preparation of the spinning solution may be selected from those in which the PHA is soluble and which also have features of adequate electrical conductivity, polarity, vapor pressure, etc., such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), chloroform, N,N-dimethylformamide (DMF), or mixtures thereof.
In the spinning solution, the PHA containing 3-hydroxybutyrate monomer units preferably has a concentration comprised from 1% to 20% w/v, more preferably comprised from 2% w/v to 10% w/v.
According to a preferred embodiment of the membrane according to the present disclosure, at least one active ingredient is associated with the fibers of the non-woven fabric of the membrane.
The at least one active ingredient which may be associated with the fibers of the non-woven fabric is preferably selected from: pentoxifylline, doxycycline, ibuprofen, cefazolin, rifampicin, paclitaxel, itraconazole, mefoxin, tetracycline hydrochloride or mixtures thereof.
Pentoxifylline is one of the most important xenobiotics, it has an effect on the perfusion of organs and tissues, on the deformability of erythrocytes and on the viscosity of the plasma. Many vasoactive substances are known to increase blood flow in tissues and, consequently, oxygenation. Pentoxifylline is one of these substances capable of increasing the flexibility, the ability to deform and the viscosity of the erythrocytes, decreasing the aggregation of the platelets.
Doxycycline is an antibiotic and a metalloprotease inhibitor. Several studies report an increase in matrix metalloproteases (MMP) activity in the anastomoses, with a consequent increase in the degradation of the local tissue present around the suture. Therefore, the administration of an active ingredient inhibiting of MMP leads to a decrease in the degradation of the tissue present around the suture.
Even cells and autologous products (Platelet Rich Plasma, PRP) can be associated with fibers of non-woven fabrics.
Preferably, the active ingredient, associated with fibers of the non-woven fabric, is doxycycline. Doxycycline is preferably present at a concentration comprised from 0.1% w/w to 4% w/w, more preferably comprised from 0.2% w/w to 2% w/w, with respect to the weight of the PHA.
In the case in which it is intended to produce a non-woven fabric comprising at least one active ingredient, preferably the spinning solution further comprises the at least one active ingredient. In particular, the at least one active ingredient may be associated with the fibers mainly in two ways:
The feature of providing a non-woven fabric comprising at least one active ingredient provides the advantage of giving the membrane according to the present disclosure a further therapeutic effect, specific according to the active ingredient used. For example, the use of doxycycline gives the therapeutic advantage of increasing the inhibition of MMPs. Said therapeutic effect is particularly advantageous in preventing the formation of dehiscences and incisional hernias, since, as described above, the administration of an active ingredient inhibiting of MMP, by inhibiting their action leads to a decrease in the degradation of the issue surrounding the suture. This decrease promotes the physiological healing process.
The following embodiment examples are provided purely for illustrative purposes of the present disclosure and should not be interpreted as limiting the scope of protection defined by the accompanying claims.
The purified P3HB was dissolved in chloroform so as to obtain a spinning solution with a concentration of 6% w/v. The solution was stirred on a heating plate at 800 rpm at a temperature of 80° C. for about 2 hours in order to facilitate the complete dissolution of the polymer.
After complete dissolution, N,N-dimethylformamide (DMF) was added to the solution until a chloroform/DMF ratio of 90:10 v/v was achieved.
The solution was stirred at 800 rpm at a temperature of 25° C. for about 2 hours.
Thereafter, the solution was cooled, poured into a 10 mL plastic syringe and placed inside the electrospinning system to be processed. The P3HB filament deposition was made by means of a spinneret and a rotating cylindrical support placed substantially perpendicular to the spinning direction, using a configuration called “horizontal arrangement”. Once the deposition on the rotating support had been carried out, the deposition was opened and laid in order to obtain the non-woven fabric in the form of a flat membrane.
The deposition of the P3HB filament on the rotating cylindrical support therefore allowed obtaining the non-woven fabric.
The following parameters were used for the electrospinning process
Spinning solution: purified P3HB dissolved in chloroform/DMF (90:10 v/v) at 6% w/v;
solution volume processed: 120 mL;
solution rate: 8 mL/hour;
translational speed of the spinneret: 8 mm/s;
distance between the tip of the spinneret and the cylindrical support (gap): 15 cm;
voltage applied to the electrodes: 20 kV;
rotation speed of the cylindrical support: 150 rpm;
diameter of the spinneret outlet hole: 2.15 mm;
The purified P3HB was dissolved in chloroform so as to obtain a spinning solution with a concentration of 6% w/v. The solution was stirred on a heating plate at 800 rpm at a temperature of 80° C. for about 2 hours in order to facilitate the complete dissolution of the polymer.
At the same time, a stock solution of doxycycline was prepared by dissolving the active ingredient in N,N-dimethylformamide (DMF). The resulting solution was stirred on a plate at 800 rpm at a temperature of 25° C. for about 1 hours.
The stock solution of doxycycline in DMF was diluted three times in order to obtain three solutions having different concentrations of doxycycline:
The three solutions were stirred at 800 rpm at a temperature of 25° C. for about 2 hours.
Thereafter, the three solutions were made to cool, were respectively poured into three 10 mL plastic syringes and one at a time placed inside the electrospinning system to be processed in succession. The P3HB+doxycycline filament deposition was made by means of a spinneret and a rotating cylindrical support placed substantially perpendicular to the spinning direction, using a configuration called “horizontal arrangement”. Once deposition on the rotating cylindrical support had been carried out, the deposition was opened and laid in order to obtain the non-woven fabric admixed with doxycycline in the form of a membrane. The deposition of the P3HB+doxycycline filament on the rotating cylindrical support therefore allowed obtaining the non-woven fabric added of the active ingredient.
The following parameters were used for the electrospinning process of solution 1:
spinning solution 1: purified P3HB (6% w/v) and doxycycline (0.1% w/v) dissolved in chloroform/DMF (90:10 v/v);
solution 1 volume processed: 50 mL;
solution 1 rate: 7 mL/hour;
translational speed of the spinneret: 6 mm/s;
distance between the tip of the spinneret and the cylindrical support (gap): 20 cm;
voltage applied to the electrodes: 20 kV;
movement speed of the flat support: 200 rpm;
diameter of the spinneret outlet hole: 2.15 mm;
The following parameters were used solution 2 for the electrospinning process of solution 2 spinning solution 2: purified P3HB (6% w/v) and doxycycline (0.25% w/v) dissolved in chloroform/DMF (90:10 v/v);
solution 2 volume processed: 50 mL;
solution 2 rate: 7 mL/hour;
translational speed of the spinneret: 6 mm/s;
distance between the tip of the spinneret and the cylindrical support (gap): 20 cm;
voltage applied to the electrodes: 20 kV;
rotation speed of the cylindrical support: 200 rpm;
diameter of the spinneret outlet hole: 2.15 mm;
The following parameters were used solution 3 for the electrospinning process of solution 3 spinning solution 3: purified P3HB (6% w/v) and doxycycline (0.5% w/v) dissolved in chloroform/DMF (90:10 v/v);
solution 3 volume processed: 50 mL;
solution 3 rate: 7 mL/hour;
translational speed of the spinneret: 6 mm/s;
distance between the tip of the spinneret and the cylindrical support (gap): 20 cm;
voltage applied to the electrodes: 20 kV;
movement speed of the cylindrical support: 200 rpm;
diameter of the spinneret outlet hole: 2.15 mm;
The concentration of doxycycline trapped within the three non-woven fabrics was then determined by the following method.
A rectangular portion of about 150 mg of weight was cut from each non-woven fabric. Each portion was in turn cut and reduced into small pieces, in order to promote the release of trapped doxycycline. The pieces of each non-woven fabric were immersed, within a 50 mL falcon, in 10 mL 0.1 M NaOH. The three suspensions obtained were stirred overnight on a rotating plate and subsequently put in centrifuge at 6000 rpm for 15 minutes. The supernatant solution of each falcon was diluted and analyzed by UV-Vis (results reported in Table 1).
25%
1%
a) Materials and Methods
The study was conducted according to the good practices described in the following documents:
“ISO 10993-2:2006 Biological evaluation of medical devices Part 2: Animal welfare requirements”;
“ISO 10993-6:2016 Biological evaluation of medical devices—Part 6: Tests for local effects after implantation”;
“F763-04 (2016) Standard Practice for Short-Term Screening of Implant Materials”;
“F1904-14 Standard Practice for Testing the Biological Responses to Particles in vivo”;
“F1983-14 Standard Practice for Assessment of Selected Tissue Effects of Absorbable Biomaterials for Implant Applications”.
Adult Sprague-Dawley male rats weighing 225-250 g each were used.
42 animals (of the total 120 used) were randomly allocated to the groups:
b) Biocompatibility
The animals were subjected to an intraperitoneal implant of a portion of 1 cm2 of membrane comprising non-woven fabric to be tested. After laparotomy on the midline, the membrane was implanted in the abdomen adhering to the parietal peritoneum about 1 cm to the left of the white line.
An incision of 2 cm was performed on the median plane comprising skin, subcutis and the white line.
The membrane was then implanted as described by “Azab AK, Doviner V, Orkin B, Kleinstern J, Srebnik M, Nissan A, Rubinstein A: Biocompatibility evaluation of crosslinked chitosan hydrogels after subcutaneous and intraperitoneal implantation in the rat; J Biomed Mater Res A 2007, November; 83(2):414-422”. Briefly, a single 1 cm2 portion was inserted through the surgical incision and fixated at about 1 cm from the white line to the left abdominal wall with a single simple suture point. The abdominal wound was then closed on two planes with a simple continuous suture with glycomer 631 USP 3-0 for the band and USP 3-0 nylon for the skin.
In the negative control group, the procedure was performed in the same way but without insertion of the membrane.
The surgical procedures lasted about 20 minutes each, while the anaesthesia time of each rat was about 1 hour.
During and after the procedures, the rats were kept on a heated plate and under an infrared lamp to avoid hypothermia and 5 ml of isotonic physiological solution (0.9%) were administered subcutaneously before putting them in their respective cages.
In the post-operative period, the administration of analgesics (Carprofen 5-10 mg/kg subcutaneously for 2-3 days), antibiotics (penicillin+dihydrostreptomycin 0.2-0.3 mg/kg subcutaneously every 2 days 2 times a day) was assured.
The subjects were kept in single cages and then subjected to euthanasia on day 14, and then for each rat the left abdominal wall, in the portion comprising the membrane, was removed and fixated in formalin. Thereafter, the tissue was dissected, stained with hematoxylin and eosin and examined by a pathologist not aware of the sample assignment group.
The following parameters were considered to histologically define the tissue response:
For each parameter, a score was assigned on a scale from 0 (absent) to 4 (very abundant).
Furthermore, the expression of COX-2 (cyclooxygenase 2) was evaluated to define the degree of inflammation of the tissue.
All the data obtained were analyzed to verify the normality thereof by the Shapiro-Wilk test.
Non-parametric tests (Kruskal-Wallis) were then used to determine their significance.
c) Results
Table 2 reports the results concerning neovascularization.
These results indicate that the two membranes comprising non-woven fabrics are comparable with respect to neovascularization.
Table 3 reports the results related to fibrosis.
These results indicate that P3HB+DOXY induces a more pronounced fibrosis compared to P3HB. This is attributable to the fact that doxycycline has an inhibiting effect on the metalloproteases responsible for the inhibition of collagen remodeling.
Table 4 shows the results concerning adipose infiltration.
ap = 0.0143
bp = 0.0156
These results indicate that P3HB+DOXY induces a lower adipose infiltration compared to P3HB. This result can also be explained by the inhibition of metalloproteases by doxycycline which, potentially, causes a substitution of adipose tissue with fibrous tissue.
COX-2 expression was not significantly different between the two groups (data not shown). This indicates that the degree of inflammation induced by the presence of the two membranes comprising the non-woven fabrics is comparable.
d) Conclusions
The membrane comprising the P3HB+DOXY non-woven fabric was found to induce a superior tissue response compared to the membrane comprising the P3HB non-woven fabric, causing greater fibrous tissue apposition.
Not having shown any signs of toxicity and not having caused reactions different from those expected for this type of implant, the two membranes comprising the tested non-woven fabrics have proven to be largely biocompatible, capable of promoting healing of the injured biological tissue relatively quickly, without inducing inflammatory or rejection reactions. The membranes comprising the tested non-woven fabrics have therefore proved to be a valid support in the healing process of biological tissue injuries, capable of preventing the formation of dehiscences and incisional hernias.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2018/056805 | 9/6/2018 | WO | 00 |
