WO2011114218A2 - Endograft with cultured stem cells - Google Patents

Abstract

An implant with capacity of reparation of tissues and a method to obtain the same, the implant being employed in the reparation or replacement of a body part and wherein the implant is subject to a cell culture with capacity of reparation of tissues, to be coated by said repairing cell cultured.

Description

E DOGRAFT WITH CULTURED STEM CELLS

BACKGROUND OF THE INVENTION

1. Field of the Invention .

The present invention relates to the field of the devices and assemblies employed in the field of medicine, more particularly it refers to an implant for replacing or repairing a part of the body of a patient and, more particularly, the invention refers to an intraluminal implant, or an endoprosthesis, for mounting into a blood vessel, for example, in an aneurysm, and it has the property of repairing and integrating into the vessel thanks to the incorporation of a cover obtained by a cell culture over its components.

It is important to clarify that when the present description puts emphasis in the application of the invention in intraluminal implants, the teachings of the invention are applicable to any other type of implants or corporeal prosthesis.

2. Description of the Prior Art .

There are a lot of situations in patients with different physical disorders where it is necessary to implant in a cavity or body part of the patient a prosthesis designed to replace a damaged part of the body or repair that part by covering that part with a prosthesis that can isolate the affected part of the particular functional system. A familiar situation is one in which a blood vessel, for example an artery, presents a dilatation of the diseased wall with the risk of breaking and threatening the life of the patient. In this cases it is necessary to implant an endoprosthesis that must be affixed or anchored and remain firmly withheld against the healthy wall of the vessel to isolate the damaged portion of the blood flow circuit.

Among the more dangerous arterial disorders because of it consequences of life losing for the patient is the Abdominal Aortic Aneurysm (AAA) that causes the death of about 15.000 people by year in the United States and in its incidence is in amount in parallel with the amount of the atherosclerotic risk factors, having big predominance in males and compromising more frequently the infrarenal aorta .

The indications for surgery of AAA are, in the 87% of cases, for asymptomatic patients; in the 7% of cases, for patients with symptoms, and in the 5% of cases, for patients with ruptured aneurysm. The mortality for each one of these groups is 1.75%, 10%, 23% and 75% respectively. This mortality is greater for the patients with equal or grater age of 80.

The most common surgical techniques used are the Aorto-Aortic graft bridge and the Aorto-bifemoral bridge (by-pass) . Although these techniques include the open chest, abdominal cavity, surgical techniques, from the year 1991 the intraluminal treatment of the AAA has been imposed and which has ₍ generated a research and use of aortic endoprosthesis that are increasing. Among the advantages of this technique the absence of the paralysis symptoms, that can be observed in the conventional surgery, should be remarked, therefore the patients can be fed early and discharged.

Other advantages of the intraluminal treatment is that no general anaesthesia is needed; there is no post laparotomy symptoms; there is no hemodynamic changes associated to the aortic clamping and declamping; the absence of prolonged distal ischemia is remarkable; there is a reduction in the necessity of blood transfusions, and an early ambulation with reduction of hospitalization is achieved.

The indications for the conventional surgical reparation, or open abdominal cavity chest, of the AAA are, short proximal neck or lack of neck (neck is the segment of aorta without dilatation) , severe dilatation of the neck, cone-shaped neck, severe tortuosity of the neck of the aneurysm or the iliac arteries, small iliac arteries, with circumferential calcification or occluded. On the other hand, the indications for the intraluminal treatment are: high-risk surgical patients, chest aneurysm, pseudo aneurysm, and a fistula between the aorta and the vena cava. The ragged aneurysm or symptomatic and the aortonteric fistula also could be indications for this type of treatment.

An endoprosthesis is composed basically of a support which aims to anchor in the artery wall, in the academic field known as "STENT", usually metallic, and a cover fixed to the stent, sutured either inside or outside the stent, and which provides total or partial waterproofing. The cover can be of any proper tissue well known in the art, such as Polyester, preferably "Dacron". This metal support is, in the most of the commercial devices currently, of a shape memory material, like the "NITINOL". The Nitinol is an alloy of Nickel and Titanium that, "due to their characteristics of conformation, may be deformed at a temperature below a threshold temperature, for example the body temperature of 37°, and when released at a temperature above that threshold temperature it recovers the original shape. In the case of a stent, the Nitinol can be collapsed or folded at a temperature below the body temperature sand it can keep this collapsed form if it is not heated to a temperature above said threshold temperature. This allows to insert the stent inside a body cavity of restricted space like an artery. Once inserted in the body of the patient the Nitinol expands itself to let the stent take an expanded cylindrical shape. This type of stent is known as self-expanding one and the prosthesis that includes this stent it is known as a self-expanding prosthesis or implant. In this way the stent and the prosthesis is anchored with a radial expanding force against the aortic walls.

The basic premise for this device to act like an internal duct inside the aorta, is that it have to be affixed, that is to say, it has to be anchored, in a healthy sector of the aorta, at the level of the renal arteries as well as of the iliac arteries. This segment of the aorta, that must be healthy to attain an appropriate anchoring, is the aortic neck and its minimum recommended length for a successful implant is of 15 mm. However, and as it is described in many international literature works, the failure of a self-expanding endoprosthesis is the not integration or incorporation of the same to the aorta walls, with the addition that the self-expanding stent exerts a constant radial force against the aortic wall, finishing distending the aortic neck. This absence of healing and biologic incorporation makes that the endoprosthesis migrate distally causing, in a lot of cases, the occurrence of leakages, known as "endoleaks", and the pressurization of the aneurysmal sac.

Even though of the disadvantages mentioned in the previous paragraph, and since the intraluminal technique represents a method minimally invasive, the use of these devices has been promoted to a large extent, so now there are many prosthesis commercially available. The major limitations of this type of treatment, however, are the long term results; they can produce morphological changes in the diameter of the aneurysm and this can cause the migration of the prosthesis, the appearance of leaks or angulations and thrombosis. Little is known about the durability of the endoprosthesis device but failures due to fatigue of material as well as failures due to the interaction between the metal and the tissue of the prosthesis may be expected. The EUROSTAR registry included 1930 patients treated with these devices, where the success rate was of 97.7%, the mortality was of 2.1% and the incidence of early "endoleak" was of 16.7% and late "endoleak" was of 18%, with an incidence of conversion to surgical treatment of 5%.

Then it may be concluded that: 1) The intraluminal treatment of the AAA has been improved considerably since its appearance.

2) These improvements have dramatically increased the number of patients that can be treated successfully with this type of technique.

3) The long-term results show that the migration of the endoprosthesis and the development of "endoleaks" are the main complications.

In a field very different to the field of the endoprosthesis, the inventor of the present application has studied and investigated the field of the cell cultures that can apply to the techniques described above with successful results to solve the mentioned problems. Since some years ago it has been known about the capacity of mesenchymal cells to differentiate into connectives cells, fibroblasts, having great plastic and restoration capacity. In the same way, the capacity of the messenchymatic cells is closely related to the formation of neo blood vessels and vascular endothelium. Moreover, it has also been determined that the cell culture techniques of the messenchymatic cells, although their uses and therapeutic variants are still in study, evolved till its generalization .

Under the current state of the technique available to perform intraluminal procedures in the reparation of body parts, like the arteries, it may be convenient to count with a new technology that allows to take advantage of the endoprosthesis avoiding the most notable disadvantages that have been referenced above and that have to do with the defective anchoring and posterior subsequent migration of the stent-graft.

SUMMARY OF THE INVENTION

Ii is an object of the present invention to provide a new technology to allow to install a body implant in a part of a patient's body, wherein the implant is incorporated and integrated into the tissue of the patient such that to prevent subsequent movements and migrations of the implant after implantation.

Ii is another object of the present invention to provide an endograft device to be anchored into a blood vessel under the expansive charge of a self-expandable stent, said endograft being capable of incorporating and integrating into the arterial tissue in the way to stay firmly retained in the tissue of the artery.

It is still another object of the present invention to provide an implant with capacity of reparation of tissues, of the type used in the reparation or replacement of a body part, wherein the implant is subjected to a cell culture with capacity of reparation of tissues, in a manner that the implant is coated with said repairing cell culture .

It is a further object of the present invention to provide an implant with capacity to repair tissues, of the type used in the reparation or replacement of a body part, wherein at least one part of the implant is coated by a repairing cell culture.

Is is still another object of the present invention to provide an implant with capacity of reparation of tissues, of the type used in the reparation or replacement of a body part, wherein the implant is an intraluminal implant comprising an anchoring support for affixing to the blood vessel's wall where the implant have to be anchored, and a cover affixed to said support, designed to cover that wall, with at least one of the components, namely the anchoring support and the cover, is coated by said repairing cell culture.

It is another object of the present invention to provide a method for obtaining an implant with capacity of reparation of tissues, of the type used in the reparation or replacement of a body part, with the method comprising the steps of taking at least one of the implant components, namely the support and the cover, and subjecting it to a repairing cell culture. BRIEF DESCRIPTION OF THE DRAWINGS

For better clarity and comprehension of the object of the invention, the same has been illustrated in several figures, in which figures the invention has been presented in one of the preferred embodiments by way of example, wherein :

Figure 1 shows a perspective and partial cross- section view of an endoprosthesis made of two end stents and a cover, corresponding to the prior art;

Figure 2 show a perspective view of another endoprosthesis made of a complete stent and a cover, also taken from the prior art;

Figure 3 shows a perspective view of a tray of a cell culture with the endoprosthesis of figure 2 submerged into the culture, in an initial step of the culture, according to the teachings of the present invention;

Figure 4 shows a perspective view of the tray with the cell culture and with the endoprosthesis of Figure 3, in a later sequence of the culture, corresponding to the present invention;

Figure 5 shows a perspective view of the endoprosthesis of Figures 2 to 4 covered by the cell culture and ready for implantation in a cavity of a human being or an animal;

Figure 6 shows a cross-section of a laminar material of the cover of an endoprosthesis, of a waterproof type, that is colonized by a cell culture corresponding to the invention, and

Figure 7 shows a cross-section of a laminar material of the cover of the endoprosthesis, made of a permeable textile, colonized by a cell culture of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Making reference to the figures and having knowledge of a diversity of implants designed for usually implantation inside a body cavity, it is known that there are, among these implants, well-know endoluminal endoprosthesis or implants for anchoring inside the blood vessels. Two of these implants of the prior art, as examples, are illustrated in Figures 1 y 2. In fact, the Figure 1 shows a intraluminal prosthesis 1 comprised of two end retention or anchoring supports 2, 3, well-known in the art like "stents" so this term will be used because it is well known to any expert in this area. A cover 4, usually of a laminar material, that can be flexible and elastic, collapsible and complacent, like natural or synthetic materials, permeable or not, fabric, knitted textiles, etc. is affixed to the stents. Generally, cover 4 is of a textile material affixed to the stents. Generally, cover 4 is of a textile material of polyester fibres, for example terephthalate of polyethylene well-known as Dacron, and it is properly affixed to stents 2, 3 by any known means, preferably by suture means. Stent 2, 3 is usually a piece of metal that is in a folded or collapsible state in order to be introduced, for example, inside an artery. Once in the artery, it expands either through a balloon, when it comes with a balloon-expandable stent, or it expands due to its own constitution, when it is released inside the artery and when it is affixed to a self-expanding stent. The self- expanding stents are metallic and with elastic memory to be compressed, during the insertion in the artery, and to retrieve their expanding shape inside the artery. There are stents of this type that are composed of a material with elastic memory named Nitinol, and other polymeric ones that can be used in the present invention.

Figure 2 shows another example of intraluminal prosthesis, in this case an aortic prosthesis for the reparation of Abdominal Aortic Aneurysm (AAA) , made of an integral or complete stent 5, extending beyond the upper and lower edges of a cover or liner 6 having a pants-shape. Portion 7 of stent 5, appearing out of the upper edge, is designated to be anchored in the aortic neck, while portions 8, 9, appearing below the lower edges of cover 6, are designated to be anchored inside the iliac arteries. Both, in the case of Figure 1 and Figure 2, the prosthesis are anchored and retained against the arterial wall by the expansive force exerted by the stents.

As explained above in this description, the anchorage provided only by the stent is usually insufficient along the time because, at least according to one of the causes, the endoprosthesis do not integrate or incorporate to the wall of the aorta in the desired manner. In the case of endoprosthesis comprising self-expanding stents, this is worst because the self-expanding stent exerts a constant radial expansion against the aortic wall, it expands the aortic neck and therefore it does not heal nor biologically incorporates to the arterial wall. Finally, this promotes the distal migration of the endoprosthesis causing, in many cases, the appearance of leakage or endoleaks and the pressurization of the aneurismal sac.

The inventor of the present invention has improved the conditions of implant to solve this problem by causing the cover and/or the stent participate predominantly in the anchoring of the prosthesis to the lumen wall by providing an integration or biological incorporation of the assembly to the living tissue of the cavity, for example the artery, where it is anchored.

According to the invention, a new endoprosthesis and a new method to obtain the same are provided both designed to solve the two most important problems that are observed in long-term evolution, namely the migrations of the endoprosthesis and the leakage or endoleaks.

Particularly, according to the present invention, an implant with capacity of reparation of tissues is provided, with the implant being of the type used in the reparation or replacement of a body part, wherein at least one part of the implant is coated by a tissue repairing cell culture.

More particularly, the endoprosthesis is an intraluminal implant that comprises an anchoring support for anchoring in the blood vessel wall where the implant is to be anchored. The stent or stents can be of the type illustrated in Figure 1, such as a pair of stents 2, 3, or of the type shown in Figure 2, such as a complete stent 5, a balloon-expanding or a self-expanding one, for example of nitinol, or another type of know support, employed in the art. The implant also comprises a cover or liner or graft anchored to said support, designated to cover said wall, like cover 4 of Figure 1, or cover 6 of Figure 2, or another type of cover or liner know in the art, provided that the stent and/or the cover incorporate the teachings of the invention as described below.

The intraluminal implant or endoprosthesis is subject to a method or procedure whereby it is coated, covered or impregnated of a cell culture that is capable of incorporating and/or integrating the implant to the tissue or the wall of the body cavity where it has been implanted. The method for obtaining the new implant comprises the step of taking at least one of the components of the implant, namely the support and the cover, or the complete implant, and submitting or subjecting this component or the implant to a cell culture, preferably cells with capacity to repair tissues. More preferably, said cell culture is from autologous or alogenic mesenchymal stem cells of bone marrow, adipose tissue, dental tissue, muscle, blood, amniotic tissue, endometrium, umbilical cord mesenchymal stem cells; of genetic treated cells to transform them into mesenchymal and the like; of cloned and embrionary cells. Thus, the chosen part or component of the implant, or the implant in its complete conformation, is inserted or submerged into a cell culture, in autologous or autogenic whey or solution from the same patient, or in artificial substances or liquids. As it is shown in Figure 3, for example, cover 10 according to the present invention is submerged in a volume of solution or whey 11, contained in a tray 12 of any convenient type or in any plate or tray well known in the art, of a cell culture. In the solution the mesenchymal stem cells are seeded, preferably differentiated in connective cells, and the culture thrives under appropriate conditions, for example in temperature conditions, lower concentration of oxygen and appropriate glucose, with appropriate cellular nutrients, to achieve the cellular viability. Few colonies 13 may be seen in Figure 3 while Figure 4 shows the solution with colonies that practically occupy the entire tray. The cover is left and remains in the culture until a period of time when it can be determined that the culture has covered completely cover or graft 10, i.e. cover 10 or the endoprosthesis has been colonized, for example, during approximately two weeks. If only cover 10 has been subjected to cell colonization, once colonized it is removed from the tray and affixed to the stent or stents to assemble the colonized endoprosthesis that is is indicated by reference number 14 in Figure 5. Of course, it is also provided that the stent can be colonized separately, or the stent and the cover can be colonized together, for example already assembled.

Thus, endoprosthesis 14 is made of a stent 15 and cover 10 colonized, indicated with reference number 16 in Figure 5, ready to be implanted in a cavity where the application thereof is necessary. In this manner, the colonized cover 16 will be covered with a coat 17 of a mesenchymal cell culture, preferably of autologous mesenchymal stem cells and of marrow thank to the fact that cover 10 operates as a substrate forming the matrix for the cell culture, with substrate being a laminate material, as described above, for example a textile like Dacron. Also, as already indicated, the cell culture may be formed on the support or stent and/or the cover laminar material. For example, upper part 18 and lower parts 19, 20 of stent 15, extending beyond the edges of colonized cover 16, provide initial fixation of the endoprosthesis while the cell culture will provide further tissue integration.

Finally, Figures 6 and 7 show two examplary different laminate colonized cover materials. In the case of Figure 6, it shows a cross section of a cover sheet material or graft of the endoprosthesis, of the waterproof type, indicated by reference number 21, wherein the colonized cell culture 22 is covering the sheet material at least partially and, preferably totally, after material 21 has been subject to the culture according to the invention. Alternatively, Figure 7 shows a cross section of a cover sheet material or graft of the endoprosthesis conformed with a permeable textile 23, that is colonized by a cell culture 24 that, as shown, is impregnating textile 23 all across the threads or fibres of weft and warp 25, 26 after being maintained into the cell culture according to the invention .

The new endoprosthesis is thus coated with mesenchymal cells that create fibrotic tissue that secures the endoprosthesis to the aortic wall and also generates endothelial tissue overlying the prosthesis. Thus, the endoluminal device is integrated to the arterial wall and it works with the wall as a unity because it is incorporated or integrated into the wall. Therefore, in the case of an abdominal aortic aneurysm repair, changes in the volume and tone of the aortic wall does not generate or gauge pressure differences with the neck of the prosthesis, with the prosthesis being attached to the aortic wall by this fibrotic tissue and endothelial neo, and it can not migrate, thus there is no free room for blood to circulate and feed the aneurysm sac.

Also according to the invention, in adddition to the cells, other adhesives may be added to the endoprosthesis to enhance and promote adhesivity of the cells in order to prevent the appearance of sheer stress. These adhesives may by any of those well known in tha art which are biocompatible, non toxic, bioomedic, such as the cianoacrilates for surgical applications, polimeric adhesives, antural and artificial substances, colagen, animal and human cells to promote adhesxvity, lamininas, and the like.

Claims

CLAIMS:

1. An implant with capacity to repair tissues, of the type used in the reparation or replacement of a body part, characterized in that at least one part of the implant is coated by a repairing cell culture.

2. The implant of claim 1, characterized in that it is an intraluminal implant comprising an anchoring support for anchoring in a blood vessel's wall where the implant have to be anchored, and a cover affixed to said support, for covering said wall, at least one of the components, namely the anchoring support and the cover, being coated by said repairing cell culture.

3. The implant of claim 1 or 2, characterized in that the repairing cell culture is a mesenchymal cell culture .

4. The implant of claim 2 or 3, characterized in that said cover is a tissue that forms a matrix for said cell culture.

5. The implant of claim 2 or 3, characterized in that the cell culture is formed in said support and cover.

6. An implant according to any of the preceding claims, characterized in that the cell culture is of mesenchymal stem cells.

7. An implant according to any of the preceding claims, characterized in that the mesenchymal stem cell culture is autologous and from marrow.

8. The implant of claim 6, characterized in that the mesenchymal stem cells are selected from the group consisting of autologous, allergenic, of bone marrow, of adipose tissue, dental tissue, muscle, blood, amniotic tissue, endometrium, umbilical cord mesenchymal stem cell; of genetic treated cells to transform them into mesenchymal and similar; of cloned and embrionary cells.

9. An implant according to any of the preceding claims, characterized in that the cover is made of Dacron.

10. An implant according to any of the preceding claims, characterized in that the anchoring support is a self-expanding stent.

11. The implant of claim 10, characterized in that the self-expanding stent is made of nitinol.

12. A method for obtaining an implant according to any of the preceding claims, characterized by the steps of:

taking at least one of the implant components, namely the support and the cover, and subjecting it to a repairing cell culture.

13. The method of claim 12, characterized in that the cell culture is of autologous bone marrow mesenchymal stem cells.

14. The method of claims 12 or 13, characterized in that the cell culture is carried out in an autologous solution for about two weeks.

15. The method of claim 12, characterized in that said cover is inserted into the cell culture and when is determined that it is colonized it is affixed to the anchoring support.

16. The method of claim 12 to 15, characterized in that the anchoring support is a self-expandable stent.

17. The method of claim 12 to 16, characterized by the step of adding a biocompatible adhesive.

18. The method of claim 17, characterized in that the biocompatible adhesive is selected from the group consisting of cianoacrilates , polimeric adhesives, antural and artificial adhesives, colagen, animal and human cells to promote adhesivity and lamininas.