Biomaterial including animal corneal tissue

ES 2 249 459 T3

DESCRIPTION

Biomaterial that includes animal cornea tissue.

Technical field

The present invention is concerned with tissue material. In particular, such a biomaterial can be used for the production of heart valves.

The present invention relates to the field of repair or replacement of human or animal tissues affected by pathological processes, and particularly with the use of a tissue biomaterial derived from the animal cornea that has been made immunologically biocompatible and subjected to processing methods. suitable for obtaining simple or compound products for implantation. Background in the state of the art

It is well known, in implantology, the use of biomaterials of human or animal origin to be implanted in the body of a patient.

Despite the achievement of important objectives in the production of prosthetic substitutes derived from the technology of materials and the treatment of tissues of animal origin, all of the required characteristics of a permanent implant have not yet been completely fulfilled.

In particular, biological tissues taken from an animal and suitably devitalized are commonly used in the biomedical field as implants or for the production of prostheses. For example, some bovine pericardium or pig heart valve tissue have been used for the production of heart valves.

For example, the entire US patent US-4,692,164 describes a heart valve whose cusps are made of a biological material explanted from the aorta of an animal or a human being.

US-A-4,755,593 also describes the use of a treated biomaterial that includes some peritoneal tissue.

Major disadvantages are currently associated with advantages derived from implants made from animal tissues. Considered among these are a possible antigenicity, a certain loss of mechanical characteristics, and biological degeneration of the tissues.

Interdisciplinary research efforts are encouraged by the search for new biomaterials and the realization of biological tissue treatment methods capable of improving both mechanical and biological characteristics.

However, the use of this type of tissue involves a series of problems since they contain fats and other substances that must be removed by means of a complex treatment before the tissue can be implanted in the living organism. Disclosure of the invention

The main aim of the present invention is therefore to provide an easy-to-find tissue biomaterial having biological and mechanical characteristics such as making it compatible, for example, with the manufacture of heart valves.

Therefore, according to the present invention, a biomaterial is made for use in medical devices characterized by including stromal tissue from an animal cornea, particularly a fish cornea.

Furthermore, a further purpose of the present invention is to produce an innovative heart valve using the aforementioned biomaterial.

Therefore, the present invention has the purpose of facing and solving fundamental aspects related to the use of a biomaterial as a permanent implant in the human or animal organism. In this context, its biophysical stability plays an important role, and the possibility of further processing, such as making it usable for the construction of simple or composite implants.

The research has been conducted with the aim of identifying a possible source of biological material with the desired potential characteristics. Such research has led to the finding of the material considered to be the most suitable and, within the scope of such, for the identification of a particular component constituting the selected tissue.

In addition, a simple and safe method of removing animal carcasses has been developed that does not alter the desired characteristics of the material.

A method of preserving tissue that was inactivated, with unchanged mechanical characteristics, has also been carried out to make it sterile and available for implantation.

The availability of the biological tissue has also been evaluated and has proven to be fully capable of solving the problems correlated with the industrial production of prostheses or implants.

Furthermore, the removal and processing of biological tissue under cool conditions, that is, before the development of the autolytic phenomenon and bacterial degradation, typical of cadaver tissues, is a feature that is fully implemented by the invention.

In more detail, according to the present invention, the tissue biomaterial is produced according to the following steps:

1. The discovery and explantation of the organ from which the biomaterial is taken.

two. Mechanical preparation

3. Chemical treatment

Four. Construction of the final product (simple or compound)

5. Sterilization and packaging

In particular:

1. The discovery and explantation, of the organ from which the biomaterial is taken

Ocular globules from animal carcasses, preferably fish (and within the specific field, tuna), free from macroscopic lesions by means of a detailed objective examination, are completely removed, under optimal storage conditions (freshness).

The cornea of ​​fish, particularly tuna, is physiologically capable of withstanding considerable stress, as it can withstand up to 40-50 atmospheres of pressure when the fish is underwater.

Ocular globules, for example from tuna, can be removed by trained personnel and preserved immediately, preferably in phosphate buffered saline at pH 7.4 and 4 ° C. However, alternative preservation solutions can be used.

Removal of the organ under conditions of fres2

ES 2 249 459 T3 cure and the initiation of subsequent processing steps in very fast times are of particular importance, in order to prevent the phenomenon of enzymatic and / or bacterial degradation of biological tissue.

two. Mechanical preparation

Having transferred each explanted organ into a medium preferably free of environmental microbiological contamination, the trained personnel proceed with the removal in the laboratory of the component of the organ destined for the production of the biomaterial. A thorough investigation has identified, in the constituent component of the corneal stroma, the biological material with the most appropriate characteristics for the production of a suitable material for the proposed objective of the present invention.

The stroma is explanted by incision of the limbus of the cornea with a special ophthalmic scalpel and closed dissection of the stromal layer from the underlying layers using blunt scissors. Alternatively, for the removal of the stromal component, it is possible to use an injection of fluid (for example, an injection of a physiologically sterile solution, or, alternatively, a solution of phosphate buffered saline at pH 7.4) between the different layers of the cornea, or another method commonly used in ophthalmic surgery.

The execution of the tissue removal procedure requires the utmost care and the technical stratagem necessary to obtain a uniform sample that has the appropriate dimensions for the production of the biomaterial. It is possible, therefore, to obtain tissue samples of a generally round shape (ovoid in some animal species) with a diameter of 4 cm or more (larger or smaller depending on the size of the animal), in any case, sufficient for the subsequent production of the biomaterial.

Repeated washing, preferably with a physiologically sterile solution, or, alternatively, with a phosphate buffered saline solution at pH 7.4, of the biological tissue during explantation, helps to obtain a material free of impurities.

Particular care is also taken not to subject the material under discussion to traction or distortion, in order to preserve its biological and mechanical characteristics.

After the explantation is complete, additional washing of the tissue, preferably with sterile physiological solution, completes the fresh tissue preparation step.

The explanted tissue is then preferably mounted on a support in order to keep its dimensional characteristics unaltered.

Then we proceed with the accommodation of the tissue, preferably mounted on the support, in a special container containing the appropriate fixative for subsequent treatment, for the construction of the biomaterial.

Particular care is taken so that all tissue surfaces come into equal contact with the fixative.

3. Chemical treatment

The fabric, preferably mounted on a suitable support, is then housed in special containers with chemical solutions.

Tissue fixation preferably takes place with a glutaraldehyde solution in varying concentrations from 0.1% to 5% (preferably 0.4%) in phosphate buffered saline solution at pH 7.4 for variable periods (preferably 3 months) . However, shorter or longer periods may be employed for tissue fixation.

The purpose of fixing the tissue by means of this procedure is to cause an increase in the cruciform bonds of tissue collagen, a conclusive factor to give the tissue a greater resistance to biodegradation and to reduce or cancel its antigenicity.

Alternative chemical solutions, at different pressures, are used for the purpose of imparting biological and mechanical characteristics that are particularly welcome in a biomaterial.

In the case of use by contact, with the hematic flow of the biomaterial, object of the invention, the treatment of the same with so-called bioactive materials (for example, heparin, antibiotics, anticalcification agents and drugs in general) was also contemplated, with the purpose of giving it additional potentially favorable characteristics (prevention of the phenomenon of calcification, increased antithrombogenicity, etc.)

Four. Construction of the final product (simple or compound)

The biomaterial obtained from the processing steps described above is subsequently taken from the containers, in which it has been subjected to chemical fixation methods, in order to be subjected to additional processing procedures, preferably manual, by qualified personnel. , to obtain products that can be used in the biomedical field, particularly in the field of human or animal organ or tissue replacement or reconstructive surgery.

The biomaterial is subjected to macroscopic or microscopic inspection before being sent to the production line of the final products.

Possible anomalies are identified in the previous processing steps, to proceed with the selection of suitable materials for further processing according to standardized parameters.

The examination under polarized light with high magnification allows the verification of the preservation of the structural integrity of the collagen component of the fixed material, the identification of damage or perforations of the biological tissue, and the preservation of the dimensional characteristics. Additional examinations may be carried out to ensure the dispatch of biomaterial samples that possess the optimal characteristics desired for the final processing stage.

For the production of particular products (for example, heart valve prostheses), the parameters are also evaluated, mainly the symmetry of the flaps obtained from the biomaterial, the homogeneity of the thickness, etc.

Biocompatible materials (eg, polyethylene terephthalate, polytetrafluoroethylene) can be used, in conjunction with the biomaterial, for the production of composite prostheses.

Processing procedures, such as punching or modeling the biomaterial, can be used for the production of biomaterial plates for different uses in the biomedical field, particu3

ES 2 249 459 T3 particularly in reconstructive or organ or tissue replacement surgery.

5. Sterilization and packaging

The simple or compound final products, obtained from the biomaterial processing stages, are then submitted for approval through standardized validation stages with the purpose of excluding products that fail to conform to the characteristics and use, from the next stages.

The sterilization of the biomaterial preferably occurs by immersion in a 0.6% glutaraldehyde solution and 20% ethanol in phosphate buffered saline solution at pH 7.4.

The sterilization of the biomaterial, like all medical products intended for implantation in the human or animal body, turns out to be essential. The purpose is to nullify the bacterial load that may be present in the implants, thus preventing the beginning of infections in the host organism.

Alternative methods of sterilizing the biomaterial may include chemical agents (eg, formaldehyde, etc.), gas (eg, ethylene oxide), radiation (eg, beta or gamma rays).

Furthermore, the cryopreservation of the biomaterial at extremely low temperatures can represent an additional method of preservation and sterilization.

The packaging of the biomaterial takes place in containers specially elaborated with the purpose of preserving the biological, mechanical and general conservation characteristics of the material unaltered for prolonged periods of time.

Biomaterial washing, through repeated passage through a sterile physiological solution for standard times, is essential before implantation in the body to remove any residue of chemical substances. This procedure is accepted practice in the course of all chemically pretreated biological material implants.

Applications

The biomaterial, object of the present invention, has been conveniently used for the construction of cardiac valve prostheses (the so-called "biological valves") with innovative characteristics not only due to the use of the biomaterial under discussion but due to structural peculiarities and structures expressly studied with the purpose of improving the hemodynamic performance of implants.

The valves produced have been investigated in vitro and in vivo for the examination of hemodynamic performance, duration and biological behavior.

The construction of the valves makes use of a manual processing (punching, folding, suturing, etc.) of biomaterial segments according to the invention, and a possible combination of the same with synthetic materials (for example, polyethylene terephthalate, polytetrafluoroethylene , etc.).

The prototypes of the cardiac valve prostheses have been elaborated with a monocuspid configuration, or with two, three or four flaps produced with the main objective biomaterial of the present invention.

The valves have been made of biological tissue using either simply the biomaterial, object of the invention, or a combination of the present biomaterial with other biomaterials, especially bovine or animal pericardium in general.

Heart valve prostheses have been made by combining biomaterial with synthetic tissues.

The biomaterial under discussion, in the form of a plate or in tubular form, has undergone in vitro and in vivo tests to verify its applicability in areas of the body such as blood vessels, cavity organs, viscera, and as plates for correction. of congenital heart abnormalities (interarterial or interventricular defects). Furthermore, the use of the biomaterial object of the present invention is possible as a component of an artificial cardiocirculatory assistance system, such as, for example, a membrane for an artificial heart, or a valve for an artificial heart.

Brief description of the drawings

A non-limiting embodiment of the present invention will now be described with reference to the accompanying designs, in which:

figure 1 shows an axonometric view of a heart valve that includes the biomaterial, the main object of the present invention;

figure 2 shows an axonometric view of a support structure used in the heart valve of figure 1; Y

- Figure 3 represents an axonometric view of the roof of the structure of Figure 2.

The best way to carry out the invention

In Figure 1, 10 denotes a complete heart valve.

This heart valve 10 includes a support structure 11 (figure 2) that represents, as if it were, the metallic "soul" that supports the entire structure that makes up the heart valve 10 itself.

The metallic structure 11 is conveniently, but not necessarily, made of polypropylene, or an alloy based on titanium, aluminum and vanadium, and is basically toroidal in shape.

On this toroidal structure 11 there is attached, in a manner known per se, an external part of the cover 12, for example made of Terylene or PTFE (polytetrafluoroethylene), and an internal part of the cover 13 made of a pore fluoroplastic material. fine. The outer part 12 also a suture ring 14 (Figures 2, 3), which allows the securing of the heart valve 10 by means of a suture to the heart of the patient. The securing system of the external part 12 and of the internal part 13 to the structure 11 is known per se and will not be described in detail.

More particularly, with reference to Figure 2, the structure 11 includes an upper molding 11a ', a lower molding 11b whose course is identical to that of the molding 11a, and a series of slightly arched supports 11c, each of the which are integrated with both the molding 10a and the molding 11b. The slightly arched supports 11c are responsible for the aforementioned toroidal shape of the structure

11.

The particular toroidal shape of the heart valve 10 and the characteristics of the materials with which it is constructed are responsible for its elasticity during the systole and diastole stages of the heart in which the valve 10 is implanted.

As shown in Figure 1, the heart valve 10 is completed with a multitude of cusps 15,

ES 2 249 459 T3 which in the form of the embodiment shown in the figure are three and in the form of a sector of a circle.

It is incidentally said that, even if there are three cusps 15 in the modality shown, it is possible to consider alternatives that present only one or two cusps.

The curved side 15a of each of the cusps 15 is sutured onto the upper molding 11a itself, while each of the straight sides 15b of the two straight sides 15b of each cusp 15 rests lightly on a straight side 15b of a adjacent cusp 15.

During the systole stage, the blood is pushed in the F1 direction and, due to the driving energy it possesses, as it passes through the valve 10, to deform the cusps 15 and to pass between the interstices 16 that it leaves free between the two straight sides 15b of the adjacent god cusps 15.

Therefore, it is extremely important that the cusps 15 are made of a material that has very good mechanical characteristics, greater resistance to use and to attack of biological and chemical origin.

As we have said, in-depth research has identified in the first constituent component of the corneal stroma, the most suitable characteristics for the production of a suitable biomaterial for the production of the cusps 15.