阅读说明：本技术 植入性材料、制备方法、植入性医疗器械及组织工程支架 (Implantable material, preparation method, implantable medical device and tissue engineering scaffold ) 是由 杜学敏 崔欢庆 于 2019-12-12 设计创作，主要内容包括：本发明提供一种植入性材料,用于制备植入性医疗器械或者组织工程支架,其包括基底及形成于所述基底的至少一个表面的水凝胶层,所述水凝胶层与所述基底通过氢键作用结合。本发明的植入性材料具有良好的生物兼容性,基底和水凝胶层之间具有强的粘附力,能够弯折千次以上而不产生分层。本发明还提供一种植入性材料的制备方法、植入性医疗器械及组织工程支架。(The invention provides an implantable material for preparing an implantable medical device or a tissue engineering scaffold, which comprises a substrate and a hydrogel layer formed on at least one surface of the substrate, wherein the hydrogel layer is combined with the substrate through hydrogen bonding. The implantable material of the invention has good biocompatibility, strong adhesion between the substrate and the hydrogel layer, and can be bent more than a thousand times without layering. The invention also provides a preparation method of the implantable material, an implantable medical device and a tissue engineering scaffold.)

1. An implantable material for use in the preparation of an implantable medical device or tissue engineering scaffold, comprising a substrate and a hydrogel layer formed on at least one surface of the substrate, the hydrogel layer being hydrogen bonded to the substrate.

2. The implantable material of claim 1 wherein the substrate is made of a material selected from the group consisting of: polydimethylsiloxane, parylene, polyimide, silica gel, stainless steel, titanium alloy, cobalt alloy, nickel titanium alloy, magnesium alloy, alumina, zinc oxide, silicon carbide, bioglass, hydroxyapatite, coral hydroxyapatite, calcium phosphate cement, tricalcium phosphate, bioactive ceramic, collagen, chitosan, alginic acid, silk fiber membrane, spider silk film, polytetrafluoroethylene, polyurethane, carbon fiber, polyester fiber, polyglycolic acid, polylactic acid, polyglycolic acid, polyglycolide, polylactide, polycaprolactone, polyethylene glycol, bioabsorbable fiber, or a copolymer or derivative containing the above units.

3. The implantable material of claim 1 wherein the hydrogel layer comprises one or more of the group consisting of: collagen, chitin, chitosan, gelatin, elastin-like polypeptides, agarose, cellulose, polyvinyl alcohol, dextran, hyaluronic acid, sodium hyaluronate, fibrin, polypeptides, proteins, DNA, starch, polyhydroxyethyl methacrylate, polyethylene glycol, alginic acid, sodium alginate, poly-L-lysine, poly-L-glutamic acid, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, poly-L-glutamic acid, polyhistidine, polyaspartic acid or copolymers or derivatives comprising the above units.

4. The implantable material of claim 1 wherein the substrate has a thickness of 1 μ ι η -5 cm; the thickness of the hydrogel layer is 1 μm-5 cm; the hydrogel layer has a water content of 1-99%.

5. A method of preparing an implantable material according to any one of claims 1 to 4, comprising:

carrying out plasma activation on a substrate to hydroxylate the surface of the substrate;

forming a hydrogel layer on at least one surface of a substrate, the hydrogel layer being hydrogen bonded to the substrate.

6. The method for preparing an implantable material according to claim 5, wherein the time for the plasma activation is 0.5min to 10 min.

7. An implantable medical device made from the implantable material of any one of claims 1-4.

8. A scaffold for tissue engineering, made of the implantable material according to any one of claims 1 to 4.

9. An implantable medical device is characterized by comprising a device body and a hydrogel layer formed on the surface of the device body.

10. A tissue engineering bracket is characterized by comprising a bracket body and a hydrogel layer formed on the surface of the bracket body.

Technical Field

The invention relates to the field of medical instruments, in particular to an implantable material, a preparation method, an implantable medical instrument and a tissue engineering scaffold.

Background

Implantable medical devices are used in a wide range of clinical applications, for example: the artificial retina treats age-related macular degeneration and helps the blind restore vision; the artificial cochlea helps hearing loss patients to recover hearing, and the cardiovascular implanted stent treats thrombus and the like. The implantable medical device or the tissue engineering scaffold is required to have good biocompatibility, and meanwhile, the hardness of the implantable medical device or the tissue engineering scaffold is required to be equivalent to that of human tissues, the implantable medical device or the tissue engineering scaffold stays in a human body for a long time and is harmless to the human body, and the material is stable and does not generate adverse reactions such as layering and the like.

The existing material for preparing implantable medical devices or tissue engineering scaffolds has good biocompatibility, is hard in most cases, and is easy to damage tissues in the implantation process to cause inflammatory reaction; the hardness degree or Young modulus of the material is equivalent to that of human tissues, and the material is not poor in biocompatibility or has certain harm to human bodies due to chemical reagents adopted in the preparation process; or the material has insufficient adhesive strength and weak bending resistance, and is easily layered in human body.

Disclosure of Invention

In view of the above, embodiments of the present invention provide an implantable material that has good biocompatibility, strong adhesion between the substrate and the hydrogel layer, and is capable of being bent more than a thousand times without delamination.

The invention provides an implantable material for preparing an implantable medical device or a tissue engineering scaffold, which comprises a substrate and a hydrogel layer formed on at least one surface of the substrate, wherein the hydrogel layer is combined with the substrate through hydrogen bonding.

Further, the material of the substrate comprises one or more of the following group: polydimethylsiloxane, parylene, polyimide, silica gel, stainless steel, titanium alloy, cobalt alloy, nickel titanium alloy, magnesium alloy, alumina, zinc oxide, silicon carbide, bioglass, hydroxyapatite, coral hydroxyapatite, calcium phosphate cement, tricalcium phosphate, bioactive ceramic, collagen, chitosan, alginic acid, silk fiber membrane, spider silk film, polytetrafluoroethylene, polyurethane, carbon fiber, polyester fiber, polyglycolic acid, polylactic acid, polyglycolic acid, polyglycolide, polylactide, polycaprolactone, polyethylene glycol, bioabsorbable fiber, or a copolymer or derivative containing the above units.

Further, the material of the hydrogel layer comprises one or more of the following groups: collagen, chitin, chitosan, gelatin, elastin-like polypeptides, agarose, cellulose, polyvinyl alcohol, dextran, hyaluronic acid, sodium hyaluronate, fibrin, polypeptides, proteins, DNA, starch, polyhydroxyethyl methacrylate, polyethylene glycol, alginic acid, sodium alginate, poly-L-lysine, poly-L-glutamic acid, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, poly-L-glutamic acid, polyhistidine, polyaspartic acid or copolymers or derivatives comprising the above units.

Further, the thickness of the substrate is 1 μm-5 cm; the thickness of the hydrogel layer is 1 μm-5 cm.

Further, the water content of the hydrogel layer is 1% -99%.

The invention also provides a preparation method of the implant material, which comprises the following steps:

carrying out plasma activation on a substrate to hydroxylate the surface of the substrate;

forming a hydrogel layer on at least one surface of a substrate, the hydrogel layer being hydrogen bonded to the substrate.

Further, the activation time of the plasma is 0.5min-10 min.

The invention also provides an implantable medical device which is made of the implantable material.

The invention also provides a tissue engineering scaffold which is made of the implantable material.

The invention also provides an implantable medical device which comprises a device body and the hydrogel layer formed on the surface of the device body.

The invention also provides a tissue engineering bracket which comprises a bracket body and a hydrogel layer formed on the surface of the bracket body.

The implantable material comprises a substrate and a hydrogel layer formed on at least one surface of the substrate, wherein the hydrogel layer is combined with the substrate through hydrogen bond action, has strong adhesive force and can be bent for more than thousands of times without layering; the implanted material has good biocompatibility, the hardness degree or the Young modulus of the implanted material is equivalent to that of human tissues, no harmful reagent is introduced, and the implanted material can be used for preparing implanted medical instruments or tissue engineering scaffolds, so that the reliability can be improved, and the tissue damage can be reduced.

Drawings

To more clearly illustrate the structural features and effects of the present invention, a detailed description is given below with reference to the accompanying drawings and specific embodiments.

Fig. 1 is a schematic structural diagram of an implantable material according to an embodiment of the present invention.

Fig. 2 is a schematic structural view of an implantable material according to yet another embodiment of the present invention.

Fig. 3 is a flow chart of the preparation of an implantable material according to an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, shall fall within the scope of protection of the present invention.

Referring to fig. 1 or 2, the implantable material 100 of the present invention for preparing an implantable medical device or a tissue engineering scaffold includes a substrate 10 and a hydrogel layer 30 formed on at least one surface of the substrate 10; the substrate 10 is bonded to the hydrogel layer 30 by hydrogen bonding. The strong hydrogen bond interaction forces may simplify the product manufacturing process, cost, and in addition, the strong hydrogen bond interaction forces may make the substrate 10 and the hydrogel layer 30 more tightly bonded and less likely to separate.

In some embodiments, the substrate 10 has a thickness of 1 μm to 5 cm. When the thickness of the substrate 10 is in this range, the substrate 10 has good bendability while being easily processed. When the thickness of the substrate 10 is less than 1 μm, the processing is difficult and it is difficult to secure the flatness of the substrate 10. When the thickness of the substrate 10 is greater than 5cm, the bending modulus of the substrate 10 is too large and is not easy to bend, so that the application of the implantable material 100 is limited.

In some embodiments, the hydrogel layer 30 has a thickness of 1 μm to 5 cm. When the hydrogel layer 30 thickness is within this range, the hydrogel layer 30 has good flexibility while being easily prepared. When the thickness of the base hydrogel layer 30 is less than 1 μm, it is difficult to control the coating or spraying process and to ensure the flatness of the hydrogel layer 30. When the thickness of the hydrogel layer 30 is greater than 5cm, the hydrogel layer 30 has an excessively high flexural modulus and is not easily bent, limiting the application of the implantable material 100.

Hydrogels (hydrogels) are a class of very hydrophilic three-dimensional network-structured gels that swell rapidly in water and in this swollen state can hold a large volume of water without dissolving. Due to the presence of the crosslinked network, the hydrogel can swell and retain a large amount of water, the amount of water absorbed being closely related to the degree of crosslinking. The higher the degree of crosslinking, the lower the water absorption. This property is very much like a soft tissue. The water content in the hydrogel can be as low as a few percent, and can also be as high as 99 percent. The gel is neither a completely solid nor a completely liquid in its aggregate state. The behavior of a solid is that it can maintain a certain shape and volume under certain conditions, and the behavior of a liquid is that a solute can diffuse or permeate from the hydrogel.

In some embodiments, the substrate 10 and hydrogel layer 30 are both made of biocompatible materials. The implantable material 10 requires a material that is biocompatible and does not damage human tissue.

In some embodiments, the material of the substrate 10 includes one or more of the following group:

polydimethylsiloxane, parylene, polyimide, silica gel, stainless steel, titanium alloy, cobalt alloy, nickel titanium alloy, magnesium alloy, alumina, zinc oxide, silicon carbide, bioglass, hydroxyapatite, coral hydroxyapatite, calcium phosphate cement, tricalcium phosphate, bioactive ceramic, collagen, chitosan, alginic acid, silk fiber membrane, spider silk film, polytetrafluoroethylene, polyurethane, carbon fiber, polyester fiber, polyglycolic acid, polylactic acid, polyglycolic acid, polyglycolide, polylactide, polycaprolactone, polyethylene glycol, bioabsorbable fiber, or a copolymer or derivative containing the above units.

The materials have good biocompatibility, and meanwhile, the Young modulus is equivalent to that of tissues of a human body, so that the materials can be well applied to implantable medical devices or tissue engineering scaffolds.

More specifically, polydimethylsiloxane, parylene, polyimide, silica gel, stainless steel, titanium alloy, cobalt alloy, nickel titanium alloy, magnesium alloy, alumina, zinc oxide, silicon carbide, bioglass, hydroxyapatite, coral hydroxyapatite, calcium phosphate cement, tricalcium phosphate, bioactive ceramic, or a copolymer or derivative containing the above units may be used to prepare the substrate 10 of the tissue engineering scaffold.

Collagen, chitosan, alginic acid, silk fiber membranes, spider silk membranes, polytetrafluoroethylene, polyurethane, carbon fibers, dacron, polyglycolic acid, polylactic acid, polyglycolic acid, polyglycolide, polylactide, polycaprolactone, polyethylene glycol, bioabsorbable fibers, or copolymers or derivatives containing the above units may be used to prepare the substrate 10 of the implantable medical device.

In some embodiments, the material of the hydrogel layer 30 includes one or more from the following group: collagen, chitin, chitosan, gelatin, elastin-like polypeptides, agarose, cellulose, polyvinyl alcohol, dextran, hyaluronic acid, sodium hyaluronate, fibrin, polypeptides, proteins, DNA, starch, polyhydroxyethyl methacrylate, polyethylene glycol, alginic acid, sodium alginate, poly-L-lysine, poly-L-glutamic acid, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, poly-L-glutamic acid, polyhistidine, polyaspartic acid or copolymers or derivatives comprising the above units. In one embodiment, the hydrogel layer 30 has a moisture content of 1% to 99%.

Specifically, the hydrogel layer 30 is prepared by dissolving the above-mentioned substances in water to prepare a hydrogel solution, and then applying the hydrogel solution to the substrate 10. Further, the hydrogel solution may also include a chemical crosslinking agent or the like that causes the hydrogel solution to form a stable crosslinked hydrogel layer.

The implantable material 100 of the present invention has a young's modulus similar to that of human tissue, and while ensuring biocompatibility, the implantable material 100 of the present invention has a strong adhesion between the substrate and the hydrogel layer, and can be bent more than a thousand times without delamination. The implantable material of the invention has no harmful reagent, and can improve the reliability and reduce the tissue damage when being used for preparing implantable medical devices or tissue engineering scaffolds.

Referring to fig. 3, the present invention further provides a method for preparing the above-mentioned implantable material, including:

1) activating the substrate by plasma to hydroxylate the surface of the substrate 10;

wherein the plasma activation time is specifically 0.5min-10min, more specifically 1min-5 min. When the plasma activation time is too short, the surface of the substrate cannot be well activated, the amount of hydroxyl generated on the surface of the substrate 10 is small, and strong hydrogen bond action cannot be generated between the substrate 10 and the hydrogel layer 30, so that the hydrogen bond acting force between the substrate 10 and the hydrogel layer 30 is insufficient, and the material cannot be guaranteed to be difficult to separate under the bending condition. When the plasma activation time is too long, the surface topography of the substrate 10 is destroyed and cannot meet the requirements for use as an implantable material.

Specifically, the substrate 10 is placed in a plasma cleaning agent for activation for 0.5min to 10min, so that a large number of hydroxyl groups are formed on the surface of the substrate 10.

A plasma cleaner (plasma cleaner) is also called a plasma cleaner or a plasma surface treatment instrument, and plasma is a state of a substance, is also called a fourth state of the substance, and is not common solid, liquid and gas states. Sufficient energy is applied to the gas to ionize it into a plasma state. The "active" components of the plasma include: ions, electrons, atoms, reactive groups, excited state species (metastable state), photons, and the like. The plasma cleaning machine is used for treating the surface of a sample by utilizing the properties of active components, so as to achieve the purposes of cleaning, coating and the like.

2) A hydrogel layer is formed on at least one surface of the substrate, and the hydrogel layer 30 is bonded to the substrate 10 by hydrogen bonding.

Wherein the water content of the hydrogel layer is 1-99%.

Specifically, a hydrogel solution is applied to one or both surfaces of the substrate and allowed to stand to gel.

In some embodiments, the hydrogel solution is made of a material comprising one or more of the following group: collagen, chitin, chitosan, gelatin, elastin-like polypeptides, agarose, cellulose, polyvinyl alcohol, dextran, hyaluronic acid, sodium hyaluronate, fibrin, polypeptides, proteins, DNA, starch, polyhydroxyethyl methacrylate, polyethylene glycol, alginic acid, sodium alginate, poly-L-lysine, poly-L-glutamic acid, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, poly-L-glutamic acid, polyhistidine, polyaspartic acid or copolymers or derivatives comprising the above units.

Specifically, the hydrogel solution is prepared by dissolving the above-mentioned substances in a solvent. The solvent may be water, an aqueous acetic acid solution, a PBS buffer solution, or the like, which has biocompatibility and is capable of dissolving the above substances to prepare a hydrogel solution. The water content of the hydrogel solution is 1-99%.

In some embodiments, the chemical cross-linking agent is Genipin, calcium chloride or silver nitrate, Genipin (Genipin) is a product of geniposide hydrolyzed by β -glucosidase, is an excellent natural biological cross-linking agent, can be cross-linked with protein, collagen, gelatin, chitosan and the like to manufacture biological materials, such as artificial bones, wound packing materials and the like, and has far lower toxicity than glutaraldehyde and other common chemical cross-linking agents.

In some embodiments, before step 2), further comprising: a hydrogel solution was prepared.

Specifically, the above-mentioned substance or the above-mentioned substance and a chemical crosslinking agent are dissolved in a solvent to prepare a hydrogel solution.

In some embodiments, before step 2), further comprising: a spacer is provided on one surface of the substrate for controlling the shape of the implantable material. The pad is removed after the hydrogel layer is formed. In one embodiment, the gasket is polytetrafluoroethylene.

The implantable material of the present invention has been measured to be resistant to separation after being bent more than a thousand times. The Young's modulus of the hydrogel layer 30 is 1KPa to 100MPa, and the Young's modulus of the substrate is 10KPa to 100 GPa.

The following is a further description of the embodiments.