SUTURE-FREE COAGULATION-ASSISTED FIXED CARDIAC PATCH AND PREPARATION METHOD THEREOF

Abstract

A suture-free coagulation-assisted fixed cardiac patch and fabrication method thereof are provided. The cardiac patch includes a polymeric procoagulant base and a barbed microneedle fixed on the polymeric procoagulant base, and a side surface of the polymeric procoagulant base with the microneedle has a microporous structure which does not penetrate the solid base of the polymer; an included angle ? between the microneedle and the plane where the polymeric procoagulant base located is 60-90?, and the microneedles are evenly distributed on the polymeric procoagulant base at a density of 5-50 threads/cm2; the barbs are located on the curved surface of the microneedle and are inclined toward the polymeric procoagulant base. The fabrication method includes using a mold pore-forming, a porogen pore-forming, or a thermally induced phase separation pore-forming, and combining the barbed microneedle while forming the microporous structure to obtain a suture-free coagulation-assisted fixed cardiac patch.

Claims

1. A method of fabricating a suture-free coagulation-assisted fixed cardiac patch, comprising the following steps: (1) printing a first model by 3D printing, wherein the first model comprises a base, with several columns and spherical concave structures formed on a side surface of the base, and the several columns are perpendicular to the side surface; (2) fixing the first model horizontally in a container with the several columns facing upwards, and pouring a polydimethylsiloxane solution into the container to completely cover the first model, removing bubbles, then heating and curing to obtain a second mold; wherein the second mold has column hole structures and spherical protrusion structures, the column hole structures being formed by the several columns on the first model, and the spherical protrusion structures being formed by the spherical concave structures on the first model; (3) first, inserting a barbed microneedle dipped in a high-temperature paraffin into a column hole of the second mold, wherein a barb direction is opposite to an insertion direction, and the barbed microneedle corresponds to the column hole one by one; then casting a first solution on the second mold arranged with a microneedle array and located on a side pointed by the barb direction; finally, after a solvent in the first solution is completely volatilized, removing the second mold, a paraffin, and excess barbed microneedles; wherein a solid structure is formed during a volatilization; wherein the first solution is obtained by dissolving a polymer used to form a polymeric procoagulant base in a hexafluoroisopropanol solution or a dioxane solution; wherein the suture-free coagulation-assisted fixed cardiac patch comprises the polymeric procoagulant base and the barbed microneedle fixed on the polymeric procoagulant base, and a side surface of the polymeric procoagulant base with the barbed microneedle has a microporous structure not penetrating a solid base of the polymer; wherein the barbed microneedle is a microneedle with barbs and biocompatibility, an included angle ? between the microneedle and a plane where the polymeric procoagulant base located is 60-90?, and microneedles are evenly distributed on the polymeric procoagulant base with a density of 5-50 threads/cm.sup.2; wherein the barbs are located on a curved surface of the microneedle and inclined toward the polymeric procoagulant base; wherein a material of the polymeric procoagulant base is more than one selected from polyurethane, silicone rubber, polyurethane-polyurea, and polylactic acid-polycaprolactone.

2. A method of fabricating a suture-free coagulation-assisted fixed cardiac patch, comprising the following steps: (1) printing a third model by 3D printing, the third model comprises a base, with several columns formed on a side surface of the base, and the several columns are perpendicular to the side surface; a number of the several columns is equal to a number of several barbed microneedles; (2) fixing the third model horizontally in a container with the several columns facing upwards, and pouring a polydimethylsiloxane solution into the container to completely cover the third model, removing bubbles, then heating and curing to obtain a fourth mold; wherein the fourth mold has column hole structures, and the column hole structures are formed by the several columns on the third model; (3) first, inserting a barbed microneedle into a column hole of the fourth mold, a barb direction being identical to an insertion direction, and the barbed microneedle corresponding to the column hole one by one; then casting a second solution several times on the fourth mold arranged with a microneedle array and located on a side opposite to the barb direction, and after a last casting, evenly distributing a porogen in the second solution not completely volatilizing a solvent, finally, after the solvent is completely volatilized, removing the fourth mold, the porogen, and excess barbed microneedles; wherein a solid structure is formed during a volatilization; wherein the porogen is NaCl particles or gelatin microspheres; wherein the second solution is obtained by dissolving a polymer used to form a polymeric procoagulant base in a hexafluoroisopropanol solution or a dioxane solution; wherein the suture-free coagulation-assisted fixed cardiac patch comprises the polymeric procoagulant base and the barbed microneedle fixed on the polymeric procoagulant base, and a side surface of the polymeric procoagulant base with the barbed microneedle has a microporous structure not penetrating a solid base of the polymer; wherein the barbed microneedle is a microneedle with barbs and biocompatibility, an included angle ? between the microneedle and a plane where the polymeric procoagulant base located is 60-90?, and microneedles are evenly distributed on the polymeric procoagulant base with a density of 5-50 threads/cm.sup.2; wherein the barbs are located on a curved surface of the microneedle and inclined toward the polymeric procoagulant base; wherein a material of the polymeric procoagulant base is more than one selected from polyurethane, silicone rubber, polyurethane-polyurea, and polylactic acid-polycaprolactone.

3. A method of fabricating a suture-free coagulation-assisted fixed cardiac patch, comprising the following steps: (1) printing a fifth model by 3D printing, wherein the fifth model comprises a base, with several columns formed on a side surface of the base, and the several columns are perpendicular to the side surface; a number of the several columns is equal to a number of several barbed microneedles; (2) fixing the fifth model horizontally in a container with the several columns facing upwards, and pouring a polydimethylsiloxane solution into the container to completely cover the fifth model, removing bubbles, then heating and curing to obtain a sixth mold; wherein the sixth mold has column hole structures, and the column hole structures are formed by the several columns on the fifth model; (3) first, inserting a barbed microneedle into a column hole of the sixth mold, a barbed direction is identical to an insertion direction, and the barbed microneedle corresponding to the column hole one by one; (4) casting a third solution over the column hole of the sixth mold arranged with a microneedle array, and forming a solid structure after a solvent in the third solution is completely volatilized; wherein the third solution is obtained by dissolving a polymer used to form a polymeric procoagulant base in a hexafluoroisopropanol solution or a dioxane solution; (5) casting a fourth solution over the polymer in the sixth mold obtained in step (4), and using a thermally induced phase separation method to completely remove a solvent in the fourth solution to obtain a microporous structure, finally removing the sixth mold and excess barbed microneedles; wherein the fourth solution is obtained by dissolving the polymer in the dioxane solution; wherein the suture-free coagulation-assisted fixed cardiac patch comprises the polymeric procoagulant base and the barbed microneedle fixed on the polymeric procoagulant base, and a side surface of the polymeric procoagulant base with the barbed microneedle has the microporous structure not penetrating a solid base of the polymer; wherein the barbed microneedle is a microneedle with barbs and biocompatibility, an included angle ? between the microneedle and a plane where the polymeric procoagulant base located is 60-90?, and microneedles are evenly distributed on the polymeric procoagulant base with a density of 5-50 threads/cm.sup.2; wherein the barbs are located on a curved surface of the microneedle and inclined toward the polymeric procoagulant base; wherein a material of the polymeric procoagulant base is more than one selected from polyurethane, silicone rubber, polyurethane-polyurea, and polylactic acid-polycaprolactone.

4. A method of fabricating a suture-free coagulation-assisted fixed cardiac patch, comprising the following steps: (1) printing a seventh model by 3D printing, wherein the seventh model comprises a base, with several columns formed on a side surface of the base, and the several columns are perpendicular to the side surface; a number of the several columns is equal to a number of several barbed microneedles; (2) fixing the seventh model horizontally in a first container with the several columns facing upwards, and pouring a polydimethylsiloxane solution into the first container to completely cover the seventh model, removing bubbles, then heating and curing to obtain an eighth mold; wherein the eighth mold has column hole structures, and the column hole structures are formed by the several columns on the seventh model; wherein an inner diameter of a column hole is 80-110% of a diameter of a microneedle; (3) first, inserting a barbed microneedle into the column hole of the eighth mold, a barb direction being opposite to an insertion direction, the barbed microneedle corresponding to the column hole one by one, and one end of the barbed microneedle being exposed outside the column hole; mixing a mixture of a prepolymer of dimethylsiloxane and an initiator, then pouring it into a second container; and then evenly distributing NaCl particles or gelatin microspheres on a surface of the mixture, inverting the eighth mold to insert the barbed microneedle exposed outside the column hole into the mixture, finally, the eighth mold and a porogen are removed after a solution is cured by heating to form a silicone rubber; wherein the suture-free coagulation-assisted fixed cardiac patch comprises a polymeric procoagulant base and the barbed microneedle fixed on the polymeric procoagulant base, and a side surface of the polymeric procoagulant base with the barbed microneedle has a microporous structure not penetrating a solid base of a polymer; wherein the barbed microneedle is the microneedle with barbs and biocompatibility, an included angle ? between the microneedle and a plane where the polymeric procoagulant base located is 60-90?, and microneedles are evenly distributed on the polymeric procoagulant base with a density of 5-50 threads/cm.sup.2; wherein the barbs are located on a curved surface of the microneedle and inclined toward the polymeric procoagulant base; wherein a material of the polymeric procoagulant base is the silicone rubber.

5. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 1, wherein a cross-sectional shape of each of the barbs is triangular or square.

6. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 1, wherein 3-6 groups of the barbs are distributed along a longitudinal direction of the microneedle, each group consisting of 2-4 barbs, and from a cross-section of the barbed microneedle, each barb in the each group of the barbs is equidistantly located on a circumference of the cross-section; wherein an included angle between the barb and the microneedle is greater than 0? and less than or equal to 90?.

7. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 1, wherein a first end of the microneedle is a beveled needle tip, a second end of the microneedle is a flat surface, and an end of the flat surface is fixedly bonded to the polymeric procoagulant base; wherein an included angle between a bevel of the beveled needle tip and an axial direction of the microneedle is 5-45?.

8. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 1, wherein a length of the microneedle is 1-5 mm; wherein a material of the barbed microneedle is more than one selected from polylactic acid, polycaprolactone, PDO, polyethylene, and polypropylene.

9. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 1, wherein an average pore diameter of the microporous structure is 50-200 ?m, an average depth of micropores is 20-120 mm, and a density of the micropores is 25-400/mm.sup.2.

10. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 2, wherein a cross-sectional shape of each of the barbs is triangular or square.

11. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 3, wherein a cross-sectional shape of each of the barbs is triangular or square.

12. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 4, wherein a cross-sectional shape of each of the barbs is triangular or square.

13. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 2, wherein 3-6 groups of the barbs are distributed along a longitudinal direction of the microneedle, each group consisting of 2-4 barbs, and from a cross-section of the barbed microneedle, each barb in the each group of the barbs is equidistantly located on a circumference of the cross-section; wherein an included angle between the barb and the microneedle is greater than 0? and less than or equal to 90?.

14. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 3, wherein 3-6 groups of the barbs are distributed along a longitudinal direction of the microneedle, each group consisting of 2-4 barbs, and from a cross-section of the barbed microneedle, each barb in the each group of the barbs is equidistantly located on a circumference of the cross-section; wherein an included angle between the barb and the microneedle is greater than 0? and less than or equal to 90?.

15. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 4, wherein 3-6 groups of the barbs are distributed along a longitudinal direction of the microneedle, each group consisting of 2-4 barbs, and from a cross-section of the barbed microneedle, each barb in the each group of the barbs is equidistantly located on a circumference of the cross-section; wherein an included angle between the barb and the microneedle is greater than 0? and less than or equal to 90?.

16. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 2, wherein a first end of the microneedle is a beveled needle tip, a second end of the microneedle is a flat surface, and an end of the flat surface is fixedly bonded to the polymeric procoagulant base; wherein an included angle between a bevel of the beveled needle tip and an axial direction of the microneedle is 5-45?.

17. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 3, wherein a first end of the microneedle is a beveled needle tip, a second end of the microneedle is a flat surface, and an end of the flat surface is fixedly bonded to the polymeric procoagulant base; wherein an included angle between a bevel of the beveled needle tip and an axial direction of the microneedle is 5-45?.

18. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 4, wherein a first end of the microneedle is a beveled needle tip, a second end of the microneedle is a flat surface, and an end of the flat surface is fixedly bonded to the polymeric procoagulant base; wherein an included angle between a bevel of the beveled needle tip and an axial direction of the microneedle is 5-45?.

19. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 2, wherein a length of the microneedle is 1-5 mm; wherein a material of the barbed microneedle is more than one selected from polylactic acid, polycaprolactone, PDO, polyethylene, and polypropylene.

20. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 3, wherein a length of the microneedle is 1-5 mm; wherein a material of the barbed microneedle is more than one selected from polylactic acid, polycaprolactone, PDO, polyethylene, and polypropylene.

21. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 4, wherein a length of the microneedle is 1-5 mm; wherein a material of the barbed microneedle is more than one selected from polylactic acid, polycaprolactone, PDO, polyethylene, and polypropylene.

22. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 2, wherein an average pore diameter of the microporous structure is 50-200 ?m, an average depth of micropores is 20-120 mm, and a density of the micropores is 25-400/mm.sup.2.

23. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 3, wherein an average pore diameter of the microporous structure is 50-200 ?m, an average depth of micropores is 20-120 mm, and a density of the micropores is 25-400/mm.sup.2.

24. The method of fabricating the suture-free coagulation-assisted fixed cardiac patch according to claim 4, wherein an average pore diameter of the microporous structure is 50-200 ?m, an average depth of micropores is 20-120 mm, and a density of the micropores is 25-400/mm.sup.2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG. 1A is an SEM diagram of the microporous structure on the polymeric procoagulant base;

[0063] FIG. 1B is an SEM diagram of a cross-section of a solid part on the polymeric procoagulant base;

[0064] FIG. 2 is a partial schematic diagram of the mold B; wherein the numbers in the figure refer to: 2.1mold B, 2.2spherical protrusion structure, 2.3column hole structure on the mold B;

[0065] FIG. 3 is a schematic diagram of the positional relationship of the barbed microneedle inserted into the column hole of the mold D; wherein the numbers in the figure refer to: 3.1barbed microneedle in the mold D, 3.2mold D, 3.3column hole on mold D;

[0066] FIG. 4 is a schematic diagram of the positional relationship of the barbed microneedles located in the mold H inserted into the mixture, wherein the numbers in the figure refer to: 4.1mold H, 4.2barbed microneedles in the mold H, 4.3mixture.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0067] Based on above mentioned method, the following embodiments are carried out for further demonstration of the present invention. It is to be understood that these embodiments are only intended to illustrate the invention and are not intended to limit the scope of the invention. In addition, it should be understood that after reading the contents described in the present invention, those technical personnel in this field can make various changes or modifications to the invention, and these equivalent forms also fall within the scope of the claims attached to the application.

[0068] The structure of the barbed microneedle in the invention is as follows: [0069] the barbed microneedle is a microneedle with barbs, one end of the microneedle (diameter 0.3-0.5 mm) is a beveled needle tip, and the barb faces away from the tip; the cross-sectional shape of the barb is more than one selected from round, triangular, square, wedge, oval, octagonal, rectangular or flat; the barb is located on the curved surface of the microneedle. The included angle between the bevel of the beveled needle tip and the axial direction of the microneedle is 5-45?. [0070] 3-6 groups of barbs are distributed along the longitudinal direction of the microneedle, each group consisting of 2-4 barbs, and from the cross-section of the barbed microneedle, each barb in each group of barbs is equidistantly located on the circumference of the cross-section; [0071] wherein an included angle between the barb and the microneedle is greater than 0? and less than or equal to 90?.

[0072] The material of the barbed microneedle is more than one selected from polylactic acid, polycaprolactone, PDO, polyethylene and polypropylene.

[0073] Since the basic function of the barbed microneedle is to fix the base, the structure of the barbed microneedle in the invention ensures a good fixing effect and can cooperate with the polymeric procoagulant base to achieve the optimal therapeutic effect.

[0074] When the barbed microneedle is designed, the performance of the barbed microneedle is evaluated by using a universal mechanical testing machine (Instron 5543A), specifically, the force when the microneedle is pulled out of the chicken breast after being inserted into the chicken breast is measured, and the operation process is as follows: [0075] turn on the switch of the universal mechanical testing machine, cut the chicken breast by using a scalpel into rectangular blocks with a thickness of about 5 mm, a length of 3-4 cm, and a width of 1-2 cm, and place them on the smooth base of the testing machine; replace the instrument for compressing on the upper part of the testing machine with a stretching clamp, use tweezers to clamp the barbed microneedle to about 5-10 mm from the needle tip, and insert the needle tip vertically into the chicken breast surface until the 3.5 mm mark is just inserted into the chicken breast; clamp the upperend label of the suture by the clamp, and move the position of the chicken breast to make the suture in a vertical state. Open the Bluehill software, fix the chicken chest by tweezers and set the experiment to stop after a displacement of 5 mm. Start the tensile experiment to measure the maximum force required to pull out the suture completely. Remove the suture, change the position of the suture tied into the chicken breast, and repeat the above operation 4 times. If the tip of the suture becomes worn and bent during the experiment, the worn and bent part of the tip needs to be cut off to keep the tip sharp and re-marked, then continue the experiment. Record the experimental data.

[0076] After calculating the average value, the force of the barbed microneedle required to be pulled out from the tissue ranges from 0.1-0.35 N, while the force of the smooth microneedle (i.e, the microneedle without barbs) required to be pulled out of the tissue is much less than 0.1 N, or even negligible.

Example 1

[0077] A method of fabricating the suture-free coagulation-assisted fixed cardiac patch, comprising the following steps:

The Preparation of Raw Materials:

[0078] Barbed microneedle: the diameter of the microneedle is 0.4 mm, and the included angle between the bevel of the beveled needle tip and the axial direction of the microneedle is 30?; the cross-sectional shape of the barb is triangular; 3 groups of barbs are distributed along the longitudinal direction of the microneedle, each group consists of 3 barbs, and the included angle between the barb and the microneedle is 30?; the material of the barbed microneedle is polylactic acid.

[0079] The universal mechanical testing machine (Instron 5543A) is used to measure the force when the barbed microneedle is pulled out of the chicken breast after being inserted into the chicken breast, which is 0.122 N. [0080] (1) Printing the model A by 3D printing, the model A consists of the base, with several columns and spherical concave structures are formed on the side surface of the base, and several columns are perpendicular to the side surface; [0081] (2) fixing the model A horizontally in a container with the columns facing upwards, and pouring the polydimethylsiloxane solution into the container to completely cover the model A, removing bubbles, then heating and curing to obtain a circular mold B with a diameter of 8 mm; [0082] wherein the mold B 2.1 has column hole structures 2.3 (evenly distributed on the edge of the circular mold and the number is 4) and a spherical protrusion structure 2.2 (evenly distributed on the upper surface of the mold), the column hole structure being formed by columns on the model A, and the spherical protrusion structure being formed by the spherical concave structure on the model A; the partial schematic diagram is shown in FIG. 2; [0083] (3) first inserting the barbed microneedle (4 pieces, and the length of the microneedle is 3 mm) dipped in high-temperature paraffin into the column hole of the mold B, the barbed direction is opposite to the insertion direction, and the barbed microneedle corresponds to the column hole one by one; then casting the solution a (obtained by dissolving polyurethane in the hexafluoroisopropanol solution, and the concentration is 0.1 g/mL) on the mold B arranged with the microneedle array and located on the side pointed by the barb direction; finally after the solvent in the solution a is completely volatilized, removing the mold B, paraffin and excess barbed microneedles, forming the solid structure during the volatilization and obtaining the suture-free coagulation-assisted fixed cardiac patch;

[0084] The prepared suture-free coagulation-assisted fixed cardiac patch, comprises the polymer procoagulant base and the barbed microneedle fixed on the polymer procoagulant base (the material is polyurethane and the thickness is 0.4 mm), and the side surface of the polymer procoagulant base with the microneedle has a microporous structure that does not penetrate the solid base of the polymer (as shown in FIGS. 1A-1B); the average pore diameter of the microporous structure is 100 ?m, the average depth of the micropores is 80 mm, and the density of the micropores is 100/mm.sup.2. The included angle ? between the microneedle of the barbed microneedle and the plane where the polymer procoagulant base located is 90?; the barbs are inclined toward the polymeric procoagulant base; the end of the flat surface of the microneedle is fixedly connected to the polymer procoagulant base.

Example 2

[0085] A method of fabricating the suture-free coagulation-assisted fixed cardiac patch, comprising the following steps:

The Preparation of Raw Materials:

[0086] Barbed microneedle: the diameter of the microneedle is 0.5 mm, and the included angle between the bevel of the beveled needle tip and the axial direction of the microneedle is 30?; the cross-sectional shape of the barb is triangular; 4 groups of barbs are distributed along the longitudinal direction of the microneedle, each group consists of 3 barbs, and the included angle between the barb and the microneedle is 30?; the material of the barbed microneedle is polycaprolactone.

[0087] The universal mechanical testing machine (Instron 5543A) is used to measure the force when the barbed microneedle is pulled out of the chicken breast after being inserted into the chicken breast, which is 0.200 N.

[0088] Porogen: use a sieve to screen out gelatin microspheres with a diameter of 100 ?m. [0089] (1) Printing a model C by 3D printing, the model C comprises the base, with several columns formed on the side surface of the base, and several columns are perpendicular to the side surface; the number of several columns is the same as the number of several barbed microneedles; [0090] (2) fixing the model C horizontally in the container with the columns facing upwards, and pouring the polydimethylsiloxane solution into the container to completely cover the model C, removing bubbles, then heating and curing to obtain a circular mold D with a diameter of 8 mm; [0091] wherein the mold D has the column hole structure (evenly distributed at the edge of the circular mold and the number is 4), and the column hole structure is formed by columns on the model C; [0092] (3) first inserting the barbed microneedle 3.1 (4 pieces, and the length of the microneedle is 4 mm) into the column hole 3.3 of the mold D 3.2, the barbed direction is the same as the insertion direction, and the barbed microneedle corresponds to the column hole one by one, the schematic diagram of the position is shown in FIG. 3; then casting the solution b (obtained by dissolving polyurethane in the hexafluoroisopropanol solution, and the concentration is 0.1 g/mL) 4 times (0.25 mL each) on the mold D arranged with the microneedle array and located on the side opposite to the barb direction, and after the last casting, evenly distributing a porogen in the solution b which does not completely volatilize the solvent, finally after the solvent is completely volatilized, removing the mold D, the porogen and excess barbed microneedles, forming the solid structure during the volatilization and obtaining the suture-free coagulation-assisted fixed cardiac patch;

[0093] The prepared suture-free coagulation-assisted fixed cardiac patch, comprises the polymeric procoagulant base and the barbed microneedle fixed on the polymer procoagulant base (the material is polyurethane and the thickness is 0.4 mm), and the side surface of the polymeric procoagulant base with the microneedle has a microporous structure that does not penetrate the solid base of the polymer; the average pore diameter of the microporous structure is 100 ?m, the average depth of the micropores is 80 mm, and the density of the micropores is 100/mm.sup.2. The included angle ? between the microneedle of the barbed microneedle and the plane where the polymer procoagulant base located is 90?; the barbs are inclined toward the polymeric procoagulant base; the end of the flat surface of the microneedle is fixedly connected to the polymer procoagulant base.

Example 3

[0094] A method of fabricating the suture-free coagulation-assisted fixed cardiac patch, comprising the following steps:

The Preparation of Raw Materials:

[0095] Barbed microneedle: the diameter of the microneedle is 0.4 mm, and the included angle between the bevel of the beveled needle tip and the axial direction of the microneedle is 30?; the cross-sectional shape of the barb is square; 5 groups of barbs are distributed along the longitudinal direction of the microneedle, each group consists of 3 barbs, and the included angle between the barb and the microneedle is 30?; the material of the barbed microneedle is polypropylene.

[0096] The universal mechanical testing machine (Instron 5543A) is used to measure the force when the barbed microneedle is pulled out of the chicken breast after being inserted into the chicken breast, which is 0.220 N. [0097] (1) Printing a model E by 3D printing, the model E consists of the base, with several columns formed on the side surface of the base, and several columns are perpendicular to the side surface; the number of several columns is the same as the number of several barbed microneedles; [0098] (2) fixing the model E horizontally in the container with the columns facing upwards, and pouring the polydimethylsiloxane solution into the container to completely cover the model E, removing bubbles, then heating and curing to obtain a circular mold F with a diameter of 8 mm; [0099] wherein the mold F has the column hole structure (evenly distributed at the edge of the circular mold and the number is 4), and the column hole structure is formed by columns on the model E; [0100] (3) first inserting the barbed microneedle (4 pieces, and the length of the microneedle is 4 mm) into the column hole of the mold F, the barbed direction is the same as the insertion direction, and the barbed microneedle corresponds to the column hole one by one; [0101] (4) along the insertion direction, casting (3 times in total, 0.25 mL each) the solution c (obtained by dissolving polyurethane in the hexafluoroisopropanol solution, and the concentration is 0.1 g/mL) over the column holes of the mold F arranged with the microneedle array, and forming the solid structure after the solvent in the solution c is completely volatilized; [0102] (5) along the insertion direction, casting (0.25 mL) the solution d (using a dioxane solution as a solvent to prepare a 6% w/v polyurethane solution) over the polymer in the mold F obtained in step (4), and using a thermally induced phase separation method to completely remove the solvent in the solution d to obtain the microporous structure, finally removing the mold F and excess barbed microneedles, and obtaining the suture-free coagulation-assisted fixed cardiac patch; wherein the specific process of completely removing the solvent from the solution d to obtain the microporous structure by using the thermally induced phase separation method is as follows: preheating at 37? C. for 1 hour, then transferring to ?20? C. and leaving overnight to completely crystallize the dioxane; then freeze-drying the cured solution d under vacuum at ?20? C.

[0103] The prepared suture-free coagulation-assisted fixed cardiac patch, comprises the polymer procoagulant base and the barbed microneedle fixed on the polymer procoagulant base (the material is polyurethane and the thickness is 0.4 mm), and the side surface of the polymer procoagulant base with the microneedle has a microporous structure that does not penetrate the solid base of the polymer; the average pore diameter of the microporous structure is 100 ?m, the average depth of the micropores is 80 mm, and the density of the micropores is 100/mm.sup.2. The included angle ? between the microneedle of the barbed microneedle and the plane where the polymer procoagulant base located is 90?; the barbs are inclined toward the polymeric procoagulant base; the end of the flat surface of the microneedle is fixedly connected to the polymer procoagulant base.

Example 4

[0104] A method of fabricating the suture-free coagulation-assisted fixed cardiac patch, comprising the following steps:

The Preparation of Raw Materials:

[0105] Barbed microneedle: the diameter of the microneedle is 0.4 mm, and the included angle between the bevel of the beveled needle tip and the axial direction of the microneedle is 30?; the cross-sectional shape of the barb is triangular; 4 groups of barbs are distributed along the longitudinal direction of the microneedle, each group consists of 4 barbs, and the included angle between the barb and the microneedle is 30?; the material of the barbed microneedle is polylactic acid.

[0106] The universal mechanical testing machine (Instron 5543A) is used to measure the force when the barbed microneedle is pulled out of the chicken breast after being inserted into the chicken breast, which is 0.210 N.

[0107] Porogen: use a sieve to screen out NaCl particles with a diameter of 100 ?m. [0108] (1) printing a model G by 3D printing, wherein the model G comprises the base, with several columns formed on the side surface of the base, and several columns are perpendicular to the side surface; the number of several columns is the same as the number of several barbed microneedles; [0109] (2) fixing the model G horizontally in a container x with the columns facing upwards, and pouring the polydimethylsiloxane solution into the container to completely cover the model G, removing bubbles, then heating and curing to obtain a circular mold H with a diameter of 8 mm; [0110] wherein the mold H has the column hole structure (evenly distributed on the edge of the circular mold and the number is 4), and the column hole structure is formed by columns on the model G; wherein an inner diameter of the column hole is 90% of a diameter of the microneedle; [0111] (3) first inserting the barbed microneedle (4 pieces, and the length of the microneedle is 4 mm) into the column hole of the mold H, the barb direction is opposite to the insertion direction, the barbed microneedle corresponds to the column hole one by one, and one end of the barbed microneedle is exposed outside the column hole; mixing a mixture of the prepolymer of dimethylsiloxane and the initiator (the mass ratio of the prepolymer and the initiator is 10:1, stirring evenly and removing bubbles), then pouring into a container y; and then evenly distributing the porogen on the surface of the mixture, inverting the mold H 4.1 to make the barbed microneedle 4.2 exposed outside the column hole into the mixture 4.3, the schematic diagram of the position is shown in FIG. 4 (after the mixture is poured into container y, the amount is less than the volume of container y and immerse 1-2 mm of the lower portion of the microneedle), finally removing the mold H and the porogen after the solution is cured by heat to form a silicone rubber, and obtaining the suture-free coagulation-assisted fixed cardiac patch.

[0112] The prepared suture-free coagulation-assisted fixed cardiac patch, comprises the polymer procoagulant base and the barbed microneedle fixed on the polymer procoagulant base (the material is silicone rubber), and the side surface of the polymer procoagulant base with the microneedle has a microporous structure that does not penetrate the solid base of the polymer; the average pore diameter of the microporous structure is 100 ?m, the average depth of the micropores is 80 mm, and the density of the micropores is 100/mm.sup.2. The included angle ? between the microneedle of the barbed microneedle and the plane where the polymer procoagulant base located is 90?; the end of the flat surface of the microneedle is fixedly connected to the polymer procoagulant base.

[0113] The fixation and treatment effects of the cardiac patch and myocardial tissue in Examples 1-4 are explored, including the following processes:

(I) Evaluation of Stress, Strain, and Load on the Myocardial Infarction Portion:

[0114] The experiment selected male rats with about 9 weeks old and about 230 g, divided into a sham group, an MI group and a patch group, with 5 rats in each group. Sham: sham operation group; MI: using a shaver to shave off the chest hair of healthy rats, injecting 1% pentobarbital anesthetic for anesthesia, fixing the four limbs of the rat on the wooden board, and connecting the ventilator to the rat's mouth, then cutting the chest skin of the rat, using a 6-0 band suture needle to ligate the coronary artery of the rat, which made the heart ischemic and hypoxic and caused myocardial infarction; Patch: to make the infarction the same as the MI group, after myocardial infarction immediately suturing the polyurethane film with a diameter of 8 mm (the thickness is 0.4 mm). The rats in three groups were sutured after surgery and then cultured for 7 days to observe the effects.

[0115] The 15 rats were taken after 7 days, turn on the universal mechanical testing machine and replace to a stretching clamp, then open the Bluehill software and clamp the hook on the fixture, so that the upper hook and the lower hook are vertical and aligned in the vertical plane. Use a shaver to shave off the chest hair of rats, inject 1% pentobarbital anesthetic for anesthesia, fix the four limbs of the rat to the wooden board, then cut the chest skin of the rat, cut off the artery connected to the heart, take it out and clean it in the Ringer's solution. Cut from the left ventricle of the heart by using scissors, spread into a rectangular plane, flatten and clamp the heart to the upper and lower hooks; adjust the position of the clamps so that the heart is just stretched, measure the length (the distance between the two hooks and the contact point of the heart), the width, and the thickness of the heart at this time by using a vernier caliper, and input into the test method of Bluehill software, set the strain produced by stretching to 30% and the strain will be completed within 1 second, then start the tensile experiment, save and export the experiment results.

[0116] The calculation results show that the stress, strain, and load of healthy myocardium are 4.890 kPa, 8.73%, and 0.00734 kgf respectively, those of the myocardial infarction part are 18.400 kPa, 10.51%, and 0.0223 kgf respectively, those of the myocardial infarction part after suturing the patch are 9.707 kPa, 5.55%, and 0.0125 kgf respectively.

[0117] Comparing the stress and strain of healthy myocardium and the myocardium of rats with myocardial infarction before and after stretching, it can be found that the strain of the myocardial infarction increases significantly after myocardial infarction, and bears a greater load, which is due to the hardening of the ventricular wall caused by myocardial fibrosis after myocardial infarction. Compared with myocardium after myocardial infarction without a patch, the stress, the strain, and the load of the myocardial infarction part after suturing the patch are significantly reduced, proving that the suture patch can provide certain mechanical support, slow down the strain increase of myocardial infarction, and make myocardial infarction part load with less burden.

[0118] Compared to myocardium after myocardial infarction without a patch, the stress, strain, and load of the myocardial infarction part with a patch are significantly reduced.

[0119] Similarly, applying the cardiac patch prepared in Examples 1-4 to the said myocardial infarction part of the heart, the experimental results showed that compared with myocardium after myocardial infarction without a patch, the stress, strain, and load of the myocardial infarction part attached by the suture-free coagulation-assisted fixed cardiac patch are significantly reduced, proving that the cardiac patch can provide certain mechanical support, slow down the strain increase of myocardial infarction, and make myocardial infarction part less loaded.

(II) Testing Process of Fixed Performance:

[0120] The experiment selected male rats with about 9 weeks old and weighing about 230 g, used a shaver to shave off the chest hair of healthy rats, injected 1% pentobarbital anesthetic for anesthesia, fixed the four limbs of the rat on the wooden board, and connected the ventilator to the rat's mouth, then cut the chest skin of the rat, used a 6-0 band suture needle to ligate the coronary artery of the rat, which made the heart ischemic and hypoxic and caused myocardial infarction; attach the cardiac patch prepared in Examples 1-4 to the myocardial infarction part of the beating heart of rats with tweezers, insert one by one and try to pull out; suture the chest skin of the rat after confirming that it was firm, culture for 7 days then check the fixation of the cardiac patch. The experimental results show that the cardiac patch can be inserted into the myocardium of living rats with myocardial infarction, and all microneedles can be inserted, the coagulation effect of the micropores is obvious; the self-locking effect is good when pulling out, which requires at least 1 N force; after the patch is implanted into the rats for 7 days, the results show that the patch can be very firmly combined with the myocardium.

(III) Testing Process of Cardiac Function:

[0121] Set three groups of rats as MI group, MI+ microneedle patch group without micropores, MI+ microneedle patch group with micropores, with 6 rats in each group, three groups of rats performed ultrasonic examination on 28 days after myocardial infarction, and dynamically observed the cardiac function change of the rats. Among them, the microneedle patch with micropores is the cardiac patch prepared in Example 2, and the difference between the microneedle patch without micropores and the cardiac patch prepared in Example 2 is only that there is no microporous structure on its surface;

[0122] The isoflurane is used for inhalation anesthesia, the precordial skin was prepared, a small animal ultrasound system was used to perform a cardiac ultrasound detection (VAVO2100, VisualSonics, Canada) on the left ventricular function of rats, with a probe frequency is 21 MHz. The probe was adjusted to obtain a clear M-type echocardiogram and a left long-axis 2D image. The average value of the left ventricular ejection fraction (LVEF) of the three groups of rats was calculated to be 49.33%, 54.70%, and 61.20%.

[0123] Comparing the data of the three groups, the MI group has no therapeutic effect; compared with the MI group, the left ventricular ejection fraction (LVEF) after the microneedle patch implantation is significantly increased, and the left ventricular systolic function is significantly improved. The left ventricular ejection fraction (LVEF) after implantation of the microneedle patch with micropores is the highest, the left ventricular systolic function is the most improved, and the therapeutic effect is the best.