CARDIAC VALVE PROSTHESIS

Abstract

It is provided a cardiac valve prosthesis, obtainable by a method comprising the following steps: a) providing human or animal body tissue, b) shaping the body tissue in a shaping process to give the body tissue a shape and size of a cardiac valve, c) fixation and stabilization of the body tissue by a cross-linking agent, thereby preserving the shape given to the body tissue by the shaping process and thus obtaining a cardiac valve prosthesis. In this context, the cross-linking agent comprises at least one compound having a structure according to general formula (I).

Claims

1. A cardiac valve prosthesis, obtainable by a method comprising the following steps: a) providing human or animal body tissue, b) shaping the body tissue in a shaping process to give the body tissue a shape and size of a cardiac valve, c) fixation and stabilization of the body tissue by a cross-linking agent, thereby preserving the shape given to the body tissue by the shaping process and thus obtaining a cardiac valve prosthesis, wherein the cross-linking agent comprises at least one compound having a structure according to general formula (I) or a salt or derivative thereof: ##STR00017## wherein R.sup.1 and R.sup.3 denote independently of each other and independently of other residues in the compound H or CH.sub.3, R.sup.4 denotes independently of other residues in the compound H or a residue having a structure according to general formula (II): ##STR00018## wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 denote independently of each other and independently of other residues in the compound H or OH, R.sup.2 denotes independently of other residues in the compound H, OH or a residue having a structure according to general formula (III): ##STR00019## wherein R.sup.10, R.sup.11, R.sup.12, R.sup.13 denote independently of each other and independently of other residues in the compound H or OH.

2. The cardiac valve prosthesis according to claim 1, wherein the residues of the structure according to formula (I) have a conformation according to formula (IV): ##STR00020##

3. The cardiac valve prosthesis according to claim 1, wherein the residue R.sup.2 has a structure according to general formula (III) and has a conformation according to formula (V): ##STR00021##

4. The cardiac valve prosthesis according to claim 1, wherein at least two of residues R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 denote OH.

5. The cardiac valve prosthesis according to claim 1, wherein residues R.sup.5, R.sup.6, and R.sup.9 denote H and in that residues R.sup.7 and R.sup.8 denote OH.

6. The cardiac valve prosthesis according to claim 1, wherein residues R.sup.1 and R.sup.3 denote CH.sub.3.

7. The cardiac valve prosthesis according to claim 1, wherein residue R.sup.2 denotes OH.

8. The cardiac valve prosthesis according to claim 1, wherein each of residues R.sup.10, R.sup.11, R.sup.12, R.sup.13 denotes OH.

9. The cardiac valve prosthesis according to claim 1, wherein residues R.sup.5, R.sup.6, and R.sup.9 denote H, in that residues R.sup.7 and R.sup.8 denote OH, in that residues R.sup.1 and R.sup.3 denote CH.sub.3, in that residue R.sup.2 corresponds to formula (III), and in that residues R.sup.10, R.sup.11, R.sup.12, R.sup.13 denote OH.

10. The cardiac valve prosthesis according to claim 2, wherein the residue R.sup.2 has a structure according to general formula (III) and has a conformation according to formula (V): ##STR00022## wherein residues R.sup.5, R.sup.6, and R.sup.9 denote H, wherein residues R.sup.7 and R.sup.8 denote OH, wherein residues R.sup.1 and R.sup.3 denote CH.sub.3, wherein residue R.sup.2 corresponds to formula (V), wherein residues R.sup.10, R.sup.11, R.sup.12, R.sup.13 denote OH, and wherein the residues of the structure according to formula (I) have a conformation according to formula (IV).

11. The cardiac valve prosthesis according to claim 1, wherein the body tissue is connective tissue, fascial tissue, peritoneal tissue or cardiac tissue.

12. The cardiac valve prosthesis according to claim 11, wherein the body tissue is pericardial tissue.

13. A medical method of treating a cardiac disease resulting from an impaired cardiac valve by replacing an impaired or diseased cardiac valve of a human or animal in need thereof by a cardiac valve prosthesis according to claim 1.

14. The method according to claim 13, wherein the cardiac valve prosthesis is implanted in the same human or animal body from whom the body tissue was obtained that is used to manufacture the cardiac valve prosthesis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Further details of aspects of the solution will be explained with respect to an exemplary embodiment and an accompanying Figure.

[0064] FIG. 1 shows a comparison between two possible cross-linking agents used for cross linking shaped body tissue.

DETAILED DESCRIPTION

[0065] To identify whether different cross-linking agents might have a different effect on the cross-linking of body tissue, in vitro tests were performed. For this purpose, human and animal body tissue was used and shaped in a deep-drawing process to give the body tissue the shape and size of a cardiac valve, namely of a pulmonary artery valve.

[0066] Afterwards, the shaped body tissue was fixated and stabilized by the addition of two different cross-linking agents. On the one hand, glutaraldehyde (GA) was used, on the other hand a compound having the structure of formula (X) was used. The latter compound will be referred to as compound X in the following. The final concentration of GA was chosen to be in a range of 0.2 to 0.625% in the treatment solution. The final concentration of compound X was chosen to be 0.05% in the treatment solution. The incubation was carried out over time period of 20 minutes (GA) or 24 hours (compound X) at a temperature lying in a range of 20 C. to 40 C. The treatment solution containing the cross-linking agent was buffered by a citrate buffer in a pH range of pH 4.8 to pH 5.0. Within the first 30 minutes of the cross-linking process, the shaped body tissue and the treatment solution were agitated by a rocking shaker at 100 rpm.

[0067] Afterwards, a tensile test was carried out. While both GA and compound X were generally able to cross-link the shaped body tissue, it turned out that compound X was even more appropriate for the cross-linking process since it resulted in a more stable structure of the shaped body tissue.

[0068] As can be seen from FIG. 1, the body tissue treated with compound X (curve 1) showed a 1.5-fold higher stress resistance than the body tissue cross-linked with GA (curve 2) (9.5 MPa vs. 6.7 MPa). At the same time, the maximum achieved strain was 10% higher in case of the cross-linking with GA than in case of compound X (57% vs. 51%). For the functioning of a cardiac valve, however, a higher stress resistance and a sufficiently high strain resistance is believed to be more important than a high strain resistance alone. Therefore, it was decided to carry out subsequent characterization tests only with respect to the shaped body tissue cross-linked with compound X.

[0069] An investigation of the shrinking temperature by differential scanning calorimetry (DSC) showed that the body tissue was sufficiently cross-linked. Subsequent cytotoxicity and biocompatibility tests showed no relevant cytotoxicity and sufficiently high biocompatibility. When placing the cross-linked body tissue into a fibroblast culture, no necroses could be observed.

[0070] Afterwards, in vivo tests were performed to evaluate the stability of the cross-linked body tissue over an extended period of time under real conditions.

[0071] In a first preclinical study, the general feasibility and safety of the heart valve replacement method was successfully shown.

[0072] In a second preclinical study, the long-term stability of the manufactured cardiac valve prosthesis was examined. A sufficiently high stabilization of the cross-linked tissue over a time period of 1.5 years was shown in an animal model (sheep). No cardiac insufficiency with more than 20% regurgitation fraction was observed. Furthermore, no cardiac valve stenosis could be observed.

[0073] The manufactured cardiac valve prosthesis was also subjected to different histologic examinations. The thickness, length, and structure of the manufactured valve prosthesis corresponded to the thickness, length and structure of the replaced natural heart valve. No thrombi could be observed in general and in the hinge region of the cusps. A full and correctly localized re-endothelialization was observed for the heart valve prosthesis. A correctly localized formation of neointima to a full extent could be observed.

[0074] Upon analyzing a foreign body response as well as other inflammation responses with a focus on M1 (CD80), M2 (CD163) macrophages, T cells (CD3), B cells (CD79a), an increased amount of M2 macrophages was observed. This can be taken as an indication of an immune response with desired subsequent differentiation to myofibroblasts.

[0075] No relevant neovascularization could be observed. The cardiac valve prosthesis showed full apposition onto the pulmonary arterial wall. No calcification could be observed. Furthermore, no indicators of necroses of the native pulmonary arterial wall could be seen.

[0076] Summarizing, the cardiac valve prosthesis manufactured by shaping body tissue and cross-linking it with cross-linking compound X resulted in a fully functional cardiac prosthesis that was properly integrated into the native surrounding body tissue and that remained stable over an extended period of time.