dehiscence in anastomotic sites"

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DESCRIPTION

The present invention relates, in general, to surgical anastomosis techniques.

The primary treatment for most non-metastatic cases of colorectal cancer consists of surgical resection.

Anastomotic leaks are one of the most feared surgical complications, with significant morbidity, prolonged hospital stays, high costs, mortality and a high risk of recurrence in patients subjected to colorectal surgery.

The initial integrity of an intestinal anastomosis depends on a perfect surgical technique, but also on the ability of the submucosal layer to retain manual and mechanical sutures, and on the rapid formation of a fibrin mesh on the serous coat.

Various methods have been proposed and studied to achieve a rapid strengthening of the anastomosis, particularly in the initial days of postoperative surgery, during the highest level of weakness.

One method consists of wrapping the anastomosis with bioabsorbable, biological or synthetic materials. This method envisages the provision of a layer that facilitates rapid deposition of fibrin on the serous coat. One disadvantage is that, in some cases, wrapping of the anastomosis can produce stenosis of the body lumen. This method also prevents the further problem of intestinal anastomoses that is caused by the formation of adherence to other organs. To prevent this occurrence, it is common to wrap the anastomosis with various reabsorbable materials including carboxymethylcellulose and hyaluronic acid.

Another method is the use of stents as a support to withstand the internal pressure, thus providing a greater anastomotic resistance in the short-term. The resulting anastomosis is devoid of compressive stresses, and the damage to the submucosal vascular plexus and to the mesenteric vessels is thus minimized. Stents must be bioabsorbable, they can carry drugs, but alone they are not able to improve collagen scarring or the anastomotic resistance, while to some extent they prevent anastomotic leaks.

Another technique is the so-called "buttressing"; in this regard, it was proposed to place a support material at the site to be anastomized. Three main types of support materials are recognized: permanent (e.g. ePTFE sheaths), semi-absorbable (e.g. bovine pericardium patches, intestinal submucosal patches) and bioabsorbable (e.g. fibrin glue and polyglycolic acid) .

Another technique is the administration of pentoxifylline. One of the most important factors affecting the perfusion of organs and tissues is the erythrocyte deformability and the plasma viscosity. To remove metabolic waste products and maintain oxygenation, erythrocytes should be able to squeeze into confined areas. This capacity is called deformability . It is well known that many vasoactive drugs increase the blood flow to the tissues and the oxygenation. Pentoxifylline is one of these drugs, which is able to increase the flexibility, the deformation capacity and the viscosity of erythrocytes, while at the same time reducing the platelet aggregation capabilities, and has been successfully used in the experimental wound healing of anastomosis.

Another method is the administration of doxycycline. Doxycycline is an antimicrobial but also a metalloprotease inhibitor. Several studies have reported a greater activity of the matrix metalloproteases (MMP) in anastomoses, which causes local tissue degradation around the suture.

Some studies have shown that systemic administration of MMP inhibitors can cause side effects. More recently, local administration of doxycycline was reported to decrease the metalloprotease content in the colon wall using an intraluminal stent.

Another method involves the welding of tissues. This is an interesting method to accelerate the healing of the lesions, even in the intestines, and has been attempted with various thermal sources, by cauterization with bipolar laser pliers.

The use of lasers to seal accidental and surgical wounds is emerging as an effective and sustainable technique, and is perceived as a minimally invasive technique that can be an important perspective in biomedicine.

Two laser welding techniques are known.

The first, known as "laser soldering", essentially mimics the physiological process of coagulation, and uses an exogenous paste such as a polymer or protein that coagulates following heating. The exogenous fluid is mixed with an exogenous chromophore, and then positioned between the wound margins and irradiated with a near infrared laser (NIR) . Solid clots seal the wound, which then gradually heals.

The second technique, known as "laser welding", uses a chromophore directly on the open margin of the wound. Therefore, the heat produced by activation of the chromophore by means of an NIR laser is intended to activate and control the local thermal reorganization of the endogenous tissue by diffusion. Examples of direct laser welding using organic chromophores such as green indocyanine have been reported.

Techniques for soldering of the tissues and for drug-release based on the heating of nanoparticles have also been proposed.

Metal nanoparticles incorporated in a dielectric medium exhibit very strong localized plasmonic resonances. The excitation of these charge oscillations activates a variety of processes from tissue soldering to the release of remotely-activated drugs.

For tissue welding, gold nanoparticles have been recently used, organized in nanorods and conjugated with green indocyanine.

Superparamagnetic iron nanoparticles (SPIONs) can be heated by an external magnetic field gradient. This remote action, combined with the intrinsic penetration of magnetic fields into human tissues, paves the way for many applications. Recently, magnetic resonance imaging has been used to simultaneously capture imaging and heating of magnetic nanoparticles. These particles could be used for electromagnetic welding of tissues, which has the advantage over laser welding in that it is virtually free of any energy attenuation during the crossing of the tissues.

Laser welding is particularly applicable in regions where manual or mechanical suture application may not be feasible. However, this technique has shown some defects when used alone (insufficient resistance, peripheral tissue damage) ; with the introduction of an exogenous (protein-based) membrane, these defects have been overcome.

An object of the invention is therefore to provide a system for addressing at least some of the drawbacks of the prior art.

In view of this object, the invention aims to provide an anastomotic device implantable into the human or animal body, said device being ring-shaped with a T-shaped radial cross-section, and consisting of a radially outer annular part and a radially inner annular part, the radially inner annular part being axially less wide than the radially outer annular part, wherein the radially inner annular part is configured to be interposed as a buttress between two segments to be anastomized, and sutured thereto, and the radially outer annular part is configured to wrap around the anastomosis site.

The particular T-shape of the cross-section of the anastomotic ring allows the device to act as a reinforcement system for suture lines applied manually or with a circular mechanical suturing machine. This effect is given by the interposition of the "leg" of the T between the two segments to be anastomized. The "horizontal" part of the "T" is placed, once the device is applied, so as to surround the anastomosis, providing protection against dehiscence.

According to a particularly preferred embodiment of the invention, this horizontal part can be used to weld the tissues by heating and/or prevent the formation of adhesions at the anastomotic site.

All or part of the device can be used to carry drugs that can help heal tissues and/or carry anticancer drugs, and/or chemical species, such as nanoparticles , which release drugs according to a predetermined release method, particularly during periods other than that of the implant.

Although the device according to the invention has been conceived with particular reference to intestinal anastomoses, it can also be applied to vascular anastomoses or hollow organs in general, particularly anastomoses performed in an end-terminal or end-lateral manner .

Preferred embodiments of the invention are defined in the dependent claims, which are to be understood as an integral part of the present description.

Further characteristics and advantages of the device according to the invention will become clearer with the following detailed description of an embodiment of the invention, made with reference to the attached drawings, provided purely as illustrative and non-limiting, wherein

-Figures 1 and 2 are perspective views of an anastomotic device according to the invention;

-Figure 3 is a cross-sectional view of another embodiment of the anastomotic device;

-Figure 4 is a cross-sectional view of the device of Figure 1;

-Figure 5 is a schematic cross-sectional view of two segments of a hollow body subjected to anastomosis with the device according to the invention, immediately after implantation; and

-Figure 6 is a view similar to that of Figure 5, wherein the anastomosis site has been subjected to tissue welding, some time after implantation.

With reference to Figures 1, 2 and 4, an anastomotic device is schematically illustrated, implantable in the human or animal body, indicated overall by 10.

The device 10 has a ring shape with a T-shaped radial section, and consists of a radially outer annular part 12 and a radially inner annular part 14. The radially inner annular part 14 is axially less wide than the radially outer annular part 12.

For the purposes of the present invention, "T- shaped radial section" intends that, in the radial cross-section of the device, it is possible to identify a "stem" part 14 and a "head" part 12 attached to one end of the part of the stem part 12. The specific shape of the "T" can also be different from those shown in the figures. For example, the two wings of the head part can have different shapes and lengths from each other, and/or not necessarily be perpendicular to the stem part. Furthermore, the shape of the stem part and/or the head part can be non-rectangular, and exhibit inclined or curved parts or surfaces. By way of example, Figure 3 represents an embodiment in which the wings of the head part/radially outer annular part 12 have inclined respective radially outer surfaces 12a. The radially outer annular part 12 thus has a generally polygonal shape, having an increased thickness in the radial direction at its axially median part 12b. This arrangement serves to reinforce the device and prevent it from flexing at the axially median part 12b. Both the stem and the horizontal part can take several forms, e.g. convex or concave profiles, or with inclined sides to favor rigidity, shape retention, adaptability to the tissues or to different types of mechanical suturing machines.

The radially inner annular part 14 of the device 10, hereinafter also called "buttressing" or support part, is configured to be interposed as a buttress between two segments to be anastomized and sutured thereto .

The radially outer annular part 12 of the device 10, hereinafter also called welding part, is configured to be wrapped around the anastomosis site.

The radially inner annular part 14 of the device 10 can be of any known, absorbable or non-absorbable material. In particular, the radially inner annular portion 14 can consist of a polysaccharide, heteropolysaccharide or glycosaminoglycan hydrogel. For example, the radially inner annular part 14 can consist of a pectin hydrogel. Other possible examples can be hydrogels of alginate, chitosan, hyaluronic acid, carboxymethylcellulose, polyglycolic acid, alone or in combination with each other or with pectin. The polysaccharide, heteropolysaccharide or glycosaminoglycan hydrogel serves as a scaffold for tissue growth and as a support for any drugs and/or nanoparticles , as will be described below.

The radially outer annular part 12 of the device can be of any known, absorbable or non-absorbable material. In particular, the radially outer annular part 12 can consist of a polysaccharide-protein, heteropolysaccharide-protein or glycosaminoglycan- protein hybrid hydrogel. The polysaccharide, heteropolysaccharide or glycosaminoglycan can be, for example, of the above-mentioned type. The protein can be, for example, albumin or collagen, and serves as a sealing agent.

According to an alternative embodiment, the radially outer annular part 12 of the device can comprise a protein film, for example, of collagen or albumin .

In the case where it is made with hydrogel, the device can be produced, for example, by mold casting or other modeling techniques.

Prototypes have been made using a solution of pectin and water in the range of 1:10 to 1:1 v/v. Pectin powder is dissolved in water; the resulting mixture is then heated to about 70°C and then inserted into the mold. The complex is then placed into a dryer and dried at 40°C for 6-24 hours.

The water-carbohydrate mixture can be treated with microwaves or other known methods that produce cross- linking. It is also possible to add elasticizing components such as glycerol or the like.

A radiation-interacting chemical species 20 can be incorporated into, or applied to, the radially outer annular part 12 of the device 10 to cause the radially outer annular part 12 to be welded to the tissues following application of an electromagnetic field and/or electromagnetic radiation.

This chemical species is selected from the group consisting of chromophores , metallic nanoparticles (for example gold particles), magnetic nanoparticles, or a combination thereof. It can be embedded into the structure and/or placed to cover the surface and/or applied at a time other than during production of the device.

The application of an electromagnetic field and/or electromagnetic radiation can consist of the application of laser radiation, radiofrequency radiation, nuclear magnetic resonance, or a combination thereof (or other methods capable of inducing heating of the chemical species, whether it is a chromophore, nanoparticle or other) .

By heating the inserted chemical species, it is possible to cause the protein (collagen) to be welded to the tissues of the patient by remote heating of the protein part by means of the chromophore or metallic and/or magnetic nanoparticles. In fact, following stimulation with laser or radiofrequency or magnetic resonance, the nanoparticles heat up to temperatures that can cause welding of the protein of the radially outer annular part 12 of the device. The same applies for the chromophore.

A pharmaceutical active ingredient can be incorporated into, or applied to, the radially outer annular part 12 and/or the radially inner annular part 14 of the device 10. Drugs that can be used include, for example, drugs that improve healing of the anastomosis (e.g. pentoxifylline and doxycycline) , drugs that cause collagen welding, drugs that provide hemostasis, drugs that locally fight cancer cells, or others .

According to one particularly preferred embodiment, the pharmaceutical active ingredient is formulated in a controlled-release dosage form.

For example, the pharmaceutical active ingredient can be associated with nanoparticles , indicated by 30 in the figures. In particular, these nanoparticles can be gold nanoparticles, which can either be used for the controlled drug release or for the welding of tissues following application of an electromagnetic field and/or electromagnetic radiation.

With reference to Figures 5 and 6, a possible protocol of application of the device according to the invention in the case of colorectal anastomosis will now be illustrated.

The device 10 is placed at the anastomotic site during a surgical intervention. Figure 5 shows the device 10 immediately after implantation. A and B represent two anastomized segments of the same hollow organ or two different hollow organs. The layers that make up the wall of the hollow organ are also represented; in the order- from inside to outside- mucous membrane, submucous coat, muscular coat and serous coat.

As can be seen, the radially outer annular part 12 of the device is radially outside the serous coat, and extends for a certain distance in both directions of the axial direction, in order to wrap around or surround the anastomotic site (the ends of the segments A and B) . The radially inner annular part 14 of the device protrudes radially towards the lumen of the anastomotic site, and is interposed between the ends of the two segments A and B.

Initially, the device 10 provides physical support to the anastomosis (buttressing) and releases drugs (e.g. pentoxifylline) .

The moment in which the radiation is applied to heat the chemical species inserted into the device can vary from the very moment of the implant during surgery until several days after surgery. As an example, a possible application range can be between day 3 and day 5 after surgery. The patient is subjected to colonoscopy or magnetic resonance imaging and tissue welding by heating of the chromophore or nanoparticles 20 (Figure 6) . This allows induction of welding of the tissues and/or the release of definable and possibly ideal tissue healing drugs.