CN108744065B - Tissue repair stent and preparation method and application thereof - Google Patents
Tissue repair stent and preparation method and application thereof Download PDFInfo
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- CN108744065B CN108744065B CN201810879252.4A CN201810879252A CN108744065B CN 108744065 B CN108744065 B CN 108744065B CN 201810879252 A CN201810879252 A CN 201810879252A CN 108744065 B CN108744065 B CN 108744065B
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- tissue repair
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- cartilage
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Abstract
The invention provides a tissue repair scaffold and a preparation method and application thereof. The tissue repair scaffold comprises: the fiber bundle comprises one or more than two fiber yarns, and functional powder is arranged on the surface and/or inside of at least one fiber yarn; the material of the fiber yarn also comprises biodegradable synthetic high molecular compound. The active ingredients in the functional powder of the tissue repair scaffold can be separated out in a living body, so that the defect local part is stimulated in a targeted manner, and the tissue regeneration is promoted; further, the tissue repair scaffold has a suitable compressive modulus and a low probability of brittle fracture. The preparation method of the tissue repair scaffold can correspondingly adjust the average diameter of the single fiber filament of the tissue repair scaffold, the aperture, the porosity and the like of the tissue repair scaffold according to the requirement of the defect part, thereby being beneficial to meeting the requirement of different defect parts on the mechanical property of the tissue repair scaffold and keeping the biological activity of each component in the tissue repair scaffold in the printing process.
Description
Technical Field
The invention relates to a tissue repair scaffold and a preparation method and application thereof, belonging to the field of medical implant materials.
Background
Bone defects are a common condition in orthopedics clinics. In clinical operation, bone repair materials are usually adopted to fill the defect part, so as to promote the regeneration of autologous bone tissues and further achieve the aim of bone repair. However, the existing bone repair materials have the problems of poor biocompatibility, insufficient bone cell induction performance, inconsistent actual bone defect shapes in clinic and the like, and cannot realize bone repair well.
Although the bone grafting can fill a bone cavity and accelerate the healing of bone defect, the autologous bone grafting is widely accepted by clinicians as the 'gold standard' of the bone filling technology, but has the defects of damaged bone taking part, damaged supply area, insufficient bone grafting amount, incapability of being prepared into a special shape and the like, for example, when the shape of the bone defect is special, the taken bone is required to be cut and shaped, and the waste of the taken bone is caused.
Currently, joint cartilage degeneration or disease caused by trauma, disease, or external load that is often borne by long-term joint movement is a common clinical condition. The inside of the articular cartilage has no blood supply, no nerve and no immune response, and almost has no self-healing capability, so once suffering from diseases or injuries, the articular cartilage gradually deteriorates, finally leads to movement dysfunction and joint diseases, greatly influences the life quality, and even needs to replace artificial joints for patients with the later-stage articular cartilage injury.
Cartilage repair has made great progress, but still has a great distance from functional repair. Cartilage repair techniques aim to reduce pain and try to repair the original function of the tissue, making it not only morphologically similar to natural transparent tissue, but also keeping its composition and mechanical properties close to those of natural tissue in a long-term repair effect.
At present, the traditional technology is adopted for treating, the repaired tissue does not have the long-term biological performance of the natural cartilage-like tissue, and joint degeneration can occur within a period of time. The traditional treatment techniques can only meet the needs of patients in a short term, but not only are the traditional treatment techniques expensive, but also inflammation, rejection reaction and the like occur, and the long-term treatment effect is still controversial. For defects exceeding 3cm3The size can be repaired by adopting autologous bone/cartilage transplantation, the defect part can be filled with fresh and healthy autologous tissues, and the tissue repair is facilitated, but the method is not always sufficient in donor and weak in interface combination to generate rejection reaction.
Disclosure of Invention
Problems to be solved by the invention
In view of the technical problems in the tissue repair process in the prior art, for hard tissue repair, for example: poor biocompatibility, insufficient bone cell induction performance, mismatched stent and defect appearance and the like; for cartilage repair, for example: the appearance of the bracket can not meet the defect requirement, the mechanical property of the bracket is not matched with that of autologous cartilage, the mobility can not be recovered as soon as possible, and similar transparent cartilage tissues can not be formed after long-term use; the technical problem of fibrosis is easy to occur; the biological performance of the natural cartilage-like tissue is not long-lasting, and joint degeneration can occur within a period of time; donor deficiency; the interface bonding is not firm, thus generating rejection reaction and the like. The invention firstly provides a tissue repair scaffold which has excellent biocompatibility and excellent induction performance of hard tissue cells. When cartilage is repaired, the method is not only beneficial to tissue repair, but also can not generate rejection reaction, and can not cause the problems of fibrosis and the like.
Means for solving the problems
The present invention provides a tissue repair scaffold comprising:
the fiber bundle comprises one or more than two fiber yarns, wherein the surface and/or the interior of at least one fiber yarn is provided with functional powder, and the granularity of the functional powder is preferably 1 nm-500 mu m;
the material of the fiber yarn also comprises biodegradable synthetic high molecular compound.
The tissue repair scaffold at least partially has a plurality of pore structures, the average pore diameter of the tissue repair scaffold is between 50 and 1000 microns, and the porosity of the tissue repair scaffold is between 20 and 95 percent; preferably, at least part of the pore structure is formed by overlapping the fiber bundles and penetrates through the tissue repair scaffold; and/or, at least part of the pore structure is formed inside the fiber filament.
The tissue repair scaffold comprises a biodegradable synthetic polymer compound, wherein the biodegradable synthetic polymer compound comprises one or a combination of more than two of polycaprolactone, polylactic acid, polyglycolic acid and polylactic acid-glycolic acid copolymer.
The tissue repair scaffold according to the present invention, wherein the surface of at least one of the filaments has a concave structure; preferably, the average diameter of the individual filaments is between 50 μm and 1000 μm.
The tissue repair scaffold according to the present invention, wherein the functional powder comprises a powder component having osteogenic activity and/or a powder component having chondrogenic activity;
preferably, the powder component with osteogenesis activity comprises one or a combination of more than two of an inorganic component with osteogenesis activity, polymer microspheres with osteogenesis activity and an animal-derived bone matrix; the powder component with chondrogenic activity comprises animal cartilage matrix and/or high molecular microspheres with chondrogenic activity.
The tissue repair scaffold comprises a polymer microsphere with osteogenic activity, wherein the polymer microsphere with osteogenic activity contains growth factors promoting osteoblast proliferation; preferably, the content of the growth factor for promoting osteoblast proliferation is 0.1 ng/g-50 ng/g based on the mass of the polymer microsphere with osteogenic activity;
the polymer microspheres with chondrogenic activity comprise growth factors which promote the proliferation of chondrocytes; preferably, the content of the growth factor for promoting the proliferation of chondrocytes is 0.1 ng/g-50 ng/g based on the mass of the polymer microsphere having chondrogenic activity.
The tissue repair scaffold according to the present invention has a compressive modulus of 0.1 to 15 MPa.
The invention also provides a preparation method of the tissue repair scaffold, which comprises the following steps:
dissolving a biodegradable synthetic high molecular compound in a first solvent, and adding functional powder to obtain slurry; then, printing and extruding the slurry into a second solvent by using a 3D printing technology for precipitation molding, wherein
The second solvent is a poor solvent for the biodegradable synthetic polymer compound;
the tissue repair scaffold comprises a fiber bundle, wherein the fiber bundle comprises one or more than two fiber filaments, and functional powder is arranged on the surface and/or inside of at least one fiber filament, preferably, the particle size of the functional powder is 1 nm-500 mu m.
The preparation method comprises the following steps of adding 0.05-1 g/mL of biodegradable synthetic macromolecular compound in a first solvent;
preferably, the adding amount of the functional powder in the slurry is 0.01 g/mL-1 g/mL.
The method for preparing a tissue repair scaffold according to the present invention, wherein the second solvent includes water and/or ethanol.
The method for preparing a tissue repair scaffold according to the present invention, wherein the first solvent comprises one or a combination of two or more of dioxane, acetic acid, chloroform, hexafluoroisopropanol and dimethyl sulfoxide.
The invention also provides an application of the tissue repair scaffold or the tissue repair scaffold prepared by the preparation method of the tissue repair scaffold in preparation of at least one of craniomaxillofacial bone repair products, alveolar bone repair products, degradable bone connecting sheets, alar cartilage repair products, auricular cartilage repair copies, bone tissue defect repair products in bone surgery, articular cartilage defect repair products, rib repair products in thoracic surgery and thoracic deformity correction repair products.
ADVANTAGEOUS EFFECTS OF INVENTION
The active ingredients in the functional powder of the tissue repair scaffold can be separated out in a living body, and can pointedly stimulate defect local and promote tissue regeneration; further, the tissue repair scaffold has a suitable compressive modulus and a low probability of brittle fracture.
Furthermore, the preparation method of the tissue repair scaffold can correspondingly adjust the dosage proportion between the biodegradable synthetic polymer compound and the functional powder, the average diameter of a single fiber filament, the aperture and the porosity of the tissue repair scaffold and other parameters according to the requirements of the defect part, thereby being beneficial to meeting the requirements of different defect parts on the mechanical property of the tissue repair scaffold and keeping the bioactivity of each component in the tissue repair scaffold in the printing process.
On the other hand, the preparation method of the invention also has higher safety, lower cost and easy molding, and is suitable for industrial large-scale production.
Drawings
Fig. 1 is a perspective view illustrating a bone-cartilage integrated repair scaffold prepared according to a third embodiment of the present invention.
Fig. 2 shows an electron microscope image of the integrated bone-cartilage repair scaffold prepared according to the third embodiment of the present invention.
Fig. 3 is a partially enlarged view of an electron microscope of a scaffold for integrated bone-cartilage repair according to a third embodiment of the present invention.
FIG. 4 is a graph showing immunohistochemical staining of cartilage extracellular matrix type II collagen at cartilage sites 1 month after the integrated bone-cartilage repair scaffold of example 1 was implanted subcutaneously in nude mice.
Fig. 5 is a graph showing aliskiren blue staining of acidic glycosaminoglycan at a cartilage site 1 month after the implantation of the integrated bone-cartilage repair scaffold of example 1 subcutaneously in nude mice.
Description of the reference numerals
1: a bone repair layer; 2: a cartilage repair layer; 3: a fiber bundle.
Detailed Description
Various exemplary embodiments, features and aspects of the invention will be described in detail below. The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the present invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In other instances, methods, means, devices and steps which are well known to those skilled in the art have not been described in detail so as not to obscure the invention.
First embodiment
A first embodiment of the present invention provides a tissue repair stent. In the present invention, the tissue repair scaffold may include a hard tissue repair scaffold such as a bone repair scaffold, or may be a cartilage tissue repair scaffold, a bone-cartilage integrated repair scaffold, or the like. Wherein, the bone-cartilage integrated repair bracket can simultaneously realize cartilage repair and subchondral bone repair in the cartilage full-layer defect.
The tissue repair scaffold comprises a fiber bundle, wherein the fiber bundle comprises one or more than two fiber filaments; functional powder is arranged on the surface and/or inside of at least one fiber filament. In the present invention, the compressive modulus of the tissue repair scaffold may be adjusted according to the defective portion of the tissue repair scaffold. Preferably, the compressive modulus of the tissue repair scaffold is in the range of 0.1 to 15MPa, may be in the range of 0.5 to 10MPa, and may be in the range of 1 to 5MPa, and the like.
The invention relates to a method for testing compression modulus, which adopts a universal mechanical testing machine. Placing a tissue repair bracket or a bone repair layer or a cartilage repair layer with a certain shape, such as the upper surface and the lower surface which are approximately parallel, between two pressing plates of a universal mechanical testing machine, setting the compression rate of the pressing plates to be 0.5mm/min, and finishing compression after the tissue repair bracket is cracked to obtain a stress-strain curve. And selecting a linear region at the front section of the curve, and calculating to obtain the compression modulus of the stent.
< filament >
In the present invention, the material of the fiber yarn includes a biodegradable synthetic polymer compound. The biodegradable synthetic high molecular compound has good biocompatibility, and the mechanical property and the degradation speed of the material can be adjusted and controlled by adjusting the molecular weight and selecting different polymerization modes and forming means. Preferably, the biodegradable synthetic polymer compound may include one or a combination of two or more of polycaprolactone, polylactic acid, polyglycolic acid, and polylactic acid-glycolic acid copolymer, and the like.
In the present invention, the average diameter of the individual filaments is between 50 μm and 1000 μm, for example: may be 100 to 800 μm, may be 200 to 600 μm, may be 300 to 500 μm, may be 350 to 450 μm, may be 200 to 400 μm, may be 150 to 250 μm, or the like. The fiber yarn has good biocompatibility, can better promote the repair of human tissues, and does not produce adverse effects. In addition, preferably, the surface of at least one fiber filament of the tissue repair scaffold of the present invention has a concave structure to facilitate tissue growth. The recessed structures are formed during the fabrication process by drying the tissue repair scaffold to remove solvent.
< functional powder >
The tissue repair scaffold is added with functional powder. Specifically, at least one of the fiber filaments has a functional powder on the surface and/or inside thereof, and the particle size of the functional powder is preferably 1nm to 500 μm, may be 10nm to 400 μm, may be 100nm to 100 μm, and the like, and is preferably 50nm to 200 μm. Preferably, the functional powder is uniformly distributed on the surface and/or inside the fiber filaments of the tissue repair scaffold.
In the invention, the functional powder comprises a powder component with osteogenic activity and/or a powder component with chondrogenic activity; preferably, the powder component with osteogenesis activity comprises one or more of inorganic matter component with osteogenesis activity, polymer microsphere with osteogenesis activity, animal-derived bone matrix and the like; the powder component with chondrogenic activity comprises animal cartilage matrix and/or high molecular microspheres with chondrogenic activity and the like.
The inorganic substance component having osteogenic activity of the present invention may be various inorganic substances having osteogenic activity commonly used in the art. For example, it may be one or a combination of two or more of hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium oxide, calcium silicate, calcium sulfate, calcium carbonate, strontium phosphate, sodium phosphate, magnesium oxide, silicon oxide, zinc phosphate, zinc oxide, bioglass, and metal magnesium powder.
The polymer microsphere with osteogenic activity is biodegradable polymer microsphere containing growth factor for promoting bone cell proliferation. Among them, the growth factor that promotes the proliferation of the osteocyte can be various growth factors that promote the proliferation and differentiation of the osteocyte commonly used in the art. In the polymer microsphere with osteogenic activity, the adding amount of the growth factor for promoting the proliferation of the osteocyte is 0.1 ng/g-50 ng/g based on the mass of the polymer microsphere with osteogenic activity, for example: 0.5ng/g, 1ng/g, 10ng/g, 20ng/g, 30ng/g, 40ng/g, etc. In the present invention, the proliferation and differentiation of osteocytes can be rapidly promoted despite the use of such a low content of growth factors that promote the proliferation of osteocytes, ranging from 0.1ng/g to 50 ng/g.
Specifically, the growth factor that promotes the proliferation of bone cells according to the present invention may be one or a combination of two or more of the bone morphogenetic protein family (BMP), the fibroblast growth factor family (FGF), the insulin-like growth factor family (IGF), the platelet-derived growth factor (PDGF), the transforming growth factor- β family (TGF- β), and the like. The degradable polymer microspheres with osteogenic activity can be derived from one or more of gelatin, collagen, sodium alginate, chitosan, hyaluronic acid, polylactic acid, polycaprolactone, polyglycolic acid, polylactic acid-glycolic acid copolymer, polyurethane and the like. The degradable polymer microspheres can be used as carriers of growth factors for promoting osteogenesis.
In the present invention, the animal-derived bone matrix may be a demineralized bone matrix, a non-demineralized bone matrix, a defatted and deproteinized bone powder having no immunogenicity, or the like.
Preferably, the particle size of the powder component having osteogenic activity of the present invention is between 1nm and 500. mu.m, preferably between 50nm and 200. mu.m, and may be between 10nm and 400. mu.m, or may be between 100nm and 100. mu.m, etc.
The animal cartilage matrix of the present invention includes defatted deproteinized animal cartilage powder without immunogenicity.
The polymer microsphere having chondrogenic activity of the present invention is a biodegradable polymer microsphere containing a growth factor that promotes chondrocyte proliferation. Among them, the growth factor that promotes the proliferation of chondrocytes may be various growth factors that are commonly used in the art to promote the proliferation and differentiation of chondrocytes. The content of the growth factor for promoting the proliferation of the chondrocytes is 0.1 ng/g-50 ng/g based on the mass of the polymer microsphere with chondrogenic activity, for example: 0.5ng/g, 1ng/g, 10ng/g, 20ng/g, 30ng/g, 40ng/g, etc. In the present invention, the proliferation and differentiation of chondrocytes can be rapidly promoted despite the use of such a low content of growth factors that promote the proliferation of chondrocytes, ranging from 0.1ng/g to 50 ng/g.
Specifically, the growth factor that promotes the proliferation of chondrocytes according to the present invention may be one or a combination of two or more of the bone morphogenetic protein family (BMP), transforming growth factor- β family (TGF- β), platelet-derived growth factor (PDGF), insulin-like growth factor family (IGF), Wingless family (Wnt), Hedgehog family, and the like. The degradable polymer microspheres can be derived from one or more of gelatin, collagen, sodium alginate, chitosan, hyaluronic acid, polylactic acid, polycaprolactone, polyglycolic acid, polylactic acid-glycolic acid copolymer, polyurethane and the like. The degradable polymer microspheres can be used as carriers of growth factors for promoting chondrogenesis.
Preferably, the particle size of the powder component having chondrogenic activity of the invention is between 1nm and 500. mu.m, preferably between 50nm and 200. mu.m, and may be between 10nm and 400. mu.m, or may be between 100nm and 100. mu.m, etc.
< pore Structure >
The tissue repair scaffold may have, at least in part, a plurality of pore structures having an average pore size between 50 μm and 1000 μm, for example: may be 100 to 800 μm, may be 200 to 600 μm, and the like, and is preferably 50 to 400 μm; the porosity of the tissue repair scaffold may be between 20% and 95%, for example: may be 30% to 85%, may be 40% to 75%, may be 50% to 65%, and the like.
Preferably, at least part of the pore structure is formed by overlapping the fiber bundles and penetrates through the tissue repair scaffold; and/or, at least part of the pore structure is formed inside the fiber filament. For example: when the tissue repair scaffold is prepared by using a 3D printing process, the fiber yarns are formed in the printing process and are made into fiber bundles, and the fiber bundles are mutually overlapped in the printing process. The angle between the two sets of overlapping fiber bundles may be greater than 0 ° to 90 °, for example, 10 ° to 80 °, 20 ° to 60 °, 30 ° to 50 °, and preferably 70 ° to 90 °.
Preferably, in the present invention, at least a part of the pore structure may also be present inside the fiber filaments. For example: may be formed during the preparation process by drying the tissue repair scaffold to remove the solvent.
The porosity detection method of the invention can be according to the method commonly used in the prior art, and specifically can be as follows: the porosity of the sample to be tested is calculated according to the following formula,
in the formula: m is the sample mass (g);
v is the sample volume (cm)3)；
ρ s is the skeleton density (g/cm) of the sample material3) Or referred to as true density.
The active ingredients in the functional powder of the tissue repair scaffold can be separated out in a living body, and can pointedly stimulate defect local parts and promote tissue regeneration; further, the tissue repair scaffold has a suitable compressive modulus and a low probability of brittle fracture.
Second embodiment
A second embodiment of the present invention provides a method for preparing a tissue repair scaffold, comprising the steps of preparing the tissue repair scaffold using a 3D printing technique; the tissue repair scaffold of the first embodiment. The preparation method of the tissue repair scaffold by precipitation molding can correspondingly adjust the dosage proportion between the biodegradable synthetic polymer compound and the functional powder, the average diameter of a single fiber filament, the aperture and porosity of the tissue repair scaffold and other parameters according to the requirement of the defect part, thereby being beneficial to meeting the requirement of different defect parts on the mechanical property of the tissue repair scaffold and keeping the bioactivity of each component in the tissue repair scaffold in the printing process. Specifically, the method can be performed according to the following steps:
dissolving a biodegradable synthetic high molecular compound in a first solvent, and adding functional powder to obtain slurry; then, printing and extruding the slurry into a second solvent by using a 3D printing technology for precipitation molding, wherein
The second solvent is a poor solvent for the biodegradable synthetic polymer compound;
the tissue repair scaffold comprises a fiber bundle, wherein the fiber bundle comprises one or more than two fiber filaments, and functional powder is arranged on the surface and/or inside of at least one fiber filament, preferably, the particle size of the functional powder is 1 nm-500 mu m.
The 3D printing technology is a technology for constructing an object by using a bondable material such as powdered metal or plastic and the like in a layer-by-layer stacking and accumulating mode on the basis of a digital model file. For example, the printer may be instructed to print layer by modeling it with Computer Aided Design (CAD) or computer animation modeling software and "partitioning" the created three-dimensional model into layer-by-layer sections. Specifically, a printer (e.g., FDM 3D printer) reads cross-sectional information from a document, prints the cross-sectional information layer by layer using a liquid, powder, or sheet material, and bonds the layers in various ways to produce a solid body.
In the invention, the biodegradable synthetic high molecular compound also has good biocompatibility, and the mechanical property and the degradation speed of the material can be adjusted and controlled by adjusting the molecular weight and selecting different polymerization modes and forming means. Preferably, the biodegradable synthetic polymer compound may include one or a combination of two or more of polycaprolactone, polylactic acid, polyglycolic acid, and polylactic acid-glycolic acid copolymer, and the like.
In the present invention, the first solvent serves as a good solvent for the biodegradable synthetic polymer compound, so that the biodegradable synthetic polymer compound can be well dissolved therein. For example: the first solvent of the present invention may be one or a combination of two or more of dioxane, acetic acid, chloroform, hexafluoroisopropanol, dimethyl sulfoxide, and the like. In the present invention, the first solvent is not limited to the above-listed first solvents, and may be any of the first solvents in the prior art that can achieve the present invention.
In the present invention, the amount of the biodegradable synthetic polymer compound added to the first solvent is 0.05 g/mL-1 g/mL, may be 0.1 g/mL-0.8 g/mL, or may be 0.3 g/mL-0.6 g/mL. The functional powder in the present embodiment is the functional powder in the first embodiment. Preferably, in the slurry, the adding amount of the functional powder can be 0.01 g/mL-1 g/mL, for example: may be 0.05 g/mL-0.5 g/mL or 0.1 g/mL-0.5 g/mL.
In a specific printing process, a biodegradable synthetic high molecular compound is dissolved in a first solvent, and a second solvent is contained in a printing receiving platform, wherein the first solvent and the second solvent can be mixed and dissolved. Because the second solvent is a poor solvent of the biodegradable synthetic high molecular compound, when the printing ink is extruded into the second solvent, the first solvent and the second solvent can be quickly mixed and dissolved, and the biodegradable synthetic high molecular compound in the first solvent is separated out in a phase separation manner, so that the tissue repair scaffold is formed. And further removing residual organic solvent from the printed and molded tissue repair scaffold and drying the tissue repair scaffold.
Preferably, the second solvent of the present invention comprises water and/or ethanol. In the present invention, the second solvent is not limited to the above two solvents, and may be any second solvent capable of implementing the present invention in the prior art.
Preferably, the prepared tissue repair scaffold can be further subjected to gamma-ray irradiation sterilization and then packaged to obtain a finished tissue repair scaffold.
In addition, a layer of strippable film can be arranged on any side of the tissue repair scaffold prepared by the invention. The peelable film can be made of any material without changing the performance of the tissue repair scaffold.
Third embodiment
A third embodiment of the present invention provides a specific tissue repair scaffold of the first embodiment or a specific tissue repair scaffold prepared by the second embodiment, i.e., an integrated bone-cartilage repair scaffold. The bone-cartilage integrated repair scaffold comprises: a bone repair layer 1 and a cartilage repair layer 2 connected. In the present invention, the bone repair layer 1 and the cartilage repair layer 2 may be directly contacted, or may be connected through some other possible active layer.
As shown in fig. 1, the bone repair layer 1 and the cartilage repair layer 2 comprise a fiber bundle 3, and the fiber bundle 3 comprises one or more than two fiber filaments. The filament is the filament of the first embodiment. As shown in fig. 3, it can be seen from the electron microscope image that at least one of the fiber filaments has a functional powder on the surface and/or inside thereof, and preferably, the particle size of the functional powder is 1nm to 500 μm.
The functional powder is the functional powder in the first embodiment. In the present embodiment, in the bone repair layer 1, the functional powder includes a powder component having an osteogenic activity, and preferably includes one or a combination of two or more of an inorganic component having an osteogenic activity, polymer microspheres having an osteogenic activity, and an animal bone matrix. In the cartilage repair layer 2, the functional powder comprises a powder component with chondrogenic activity, preferably an animal cartilage matrix and/or a polymer microsphere with chondrogenic activity.
In this embodiment, the integrated bone-cartilage repair scaffold has, at least in part, a plurality of pore structures having an average pore diameter of between 50 μm and 1000 μm, for example: may be 100 to 800 μm, may be 200 to 600 μm, and the like, and is preferably 50 to 400 μm; the porosity of the bone-cartilage integrated repair scaffold is between 50% and 95%, for example: may be 51% to 95%, may be 60% to 85%, may be 70% to 80%, and the like.
Preferably, at least part of the pore structure is formed by overlapping the fiber bundles 3 and penetrates through the bone repair layer 1 and the cartilage repair layer 2; and/or, at least part of the pore structure is formed inside the fiber filament.
As shown in fig. 2 and 3, it can be seen from the electron microscope images that the powder component having osteogenic activity exists on the surface and/or inside of the fiber filaments of the bone repair layer 1, and the powder component having chondrogenic activity exists on the surface and/or inside of the fiber filaments of the cartilage repair layer 2. Preferably, the powder component with osteogenic activity is uniformly distributed on the surface and/or inside of the fiber filaments of the bone repair layer 1, and the powder component with chondrogenic activity is uniformly distributed on the surface and/or inside of the fiber filaments of the cartilage repair layer 2. In addition, as shown in fig. 2 and 3, the surface of the fiber filament may further have a concave structure formed by drying the bone-cartilage integrated repair scaffold to remove a solvent during the preparation process.
Generally, cartilage and subchondral bone are a whole, the former plays a role in load, the latter plays a role in mechanical support and impact absorption, and the two are interdependent and inseparable. Cartilage regeneration should not be limited to cartilage repair, and to achieve functional repair, attention should be paid to the effects of subchondral bone on cartilage repair.
In addition, in the present invention, the bone-cartilage integrated repair scaffold may further include other layer structures, and the other layer structures included in the scaffold are not particularly limited, and may achieve the functions of the present invention.
The bone-cartilage integrated repair scaffold in the present embodiment is generally used in cartilage defect repair products. For example: the cartilage defect repair article of the present invention may be directed to the repair of articular cartilage defects.
Generally, the quality of the repaired tissue is evaluated by the morphology of the new tissue, and the natural articular cartilage is hyaline cartilage and is composed of chondrocytes and ECM. Cells contained in the tissue of the native articular cartilage should be simple chondrocytes, and the secreted ECM should include type II collagen and glycosaminoglycan. The cartilage repair layer 2 of the existing repair scaffold mainly comprises fibrocartilage, which is different from natural articular cartilage. The invention considers the cartilage repair and the subchondral bone repair in the full-layer defect of the cartilage, and the cartilage repair layer 2 contains active ingredients for promoting the proliferation of chondrocytes, so that the new tissue can be hyaline cartilage.
Fourth embodiment
A fourth embodiment of the present invention provides a use of the tissue repair scaffold according to the first embodiment of the present invention or the tissue repair scaffold according to the second embodiment of the present invention, in the preparation of at least one of a craniomaxillofacial bone repair product, an alveolar bone repair product, a degradable bone connecting sheet, a alar cartilage repair product, an auricular cartilage repair replica, a bone tissue defect repair product in bone surgery, an articular cartilage defect repair product, a rib repair product in thoracic surgery, and a thoracic deformity correction repair product.
The degradable bone connecting sheet can be applied to connecting sheets of fracture parts with weak bearing force, such as the bone connecting sheet applied to craniomaxillofacial surfaces, the bone connecting sheet applied to finger joints or toe joints and the like.
The bone tissue defect repairing product in the aspect of bone surgery can be applied to bone defect filling repairing products of non-bearing parts, such as filling repairing products after necrotic bones are removed under the condition of femoral head necrosis, filling repairing products after bone tumors are removed, filling repairing products after bone cysts are removed, and the like.
Examples
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
In the embodiment, the combination of polycaprolactone and polylactic acid-glycolic acid copolymer is used as a biodegradable synthetic high molecular compound, and hexafluoroisopropanol is used as a first solvent to prepare the bone-cartilage integrated repair scaffold. The specific implementation steps are as follows:
(1) dissolving polycaprolactone and polylactic acid-glycolic acid copolymer in hexafluoroisopropanol, wherein the total addition amount of the polycaprolactone and the polylactic acid-glycolic acid copolymer is 0.7g/mL, and the mass ratio of the polycaprolactone to the polylactic acid-glycolic acid copolymer is 1: 1. And dividing the dissolved solution into two parts to obtain a first matrix solution and a second matrix solution. The non-immunogenic defatted and deproteinized bone powder with the granularity of 100 nm-500 nm is selected as a powder component with osteogenic activity, and the powder component with osteogenic activity is uniformly dispersed into a first matrix solution according to the addition amount of 0.5g/mL to form osteogenic component slurry.
(2) Selecting non-immunogenic defatted deproteinized cartilage powder with the granularity of 50-100 microns as a powder component with chondrogenic activity, and uniformly dispersing the powder component with chondrogenic activity into a second matrix solution according to the addition amount of 0.5g/mL to form chondrogenic component slurry.
(3) And establishing a cylindrical bracket model by adopting modeling software. And adding a second solvent, namely absolute ethyl alcohol, into the receiving groove of the printing receiving platform, and sequentially printing the bone repair layer and the cartilage repair layer. After the printing ink is extruded into absolute ethyl alcohol, hexafluoroisopropanol is quickly dissolved into the absolute ethyl alcohol, the average diameter of fibers formed in the printing process is 300 mu m, and polycaprolactone and polylactic acid-glycolic acid copolymer are subjected to phase separation and then are molded to obtain the bone-cartilage integrated repair scaffold I. Soaking the bone-cartilage integrated repair scaffold I in absolute ethyl alcohol for 3d to remove residual solvent, and then carrying out air drying treatment. And finally, carrying out gamma-ray irradiation sterilization on the air-dried bone-cartilage integrated repair bracket I.
Example 2
In the embodiment, polycaprolactone is selected as a biodegradable synthetic polymer compound, and acetic acid is selected as a first solvent to prepare the cartilage scaffold. The specific implementation steps are as follows:
(1) dissolving polycaprolactone in acetic acid, wherein the addition amount of the polycaprolactone is 0.5g/mL, and obtaining a matrix solution.
(2) Selecting non-immunogenic defatted deproteinized cartilage powder with particle size of 500nm-50 μm as powder component with chondrogenic activity, and uniformly dispersing the powder component with chondrogenic activity into matrix solution according to the addition amount of 0.2g/mL to form slurry.
(3) And establishing an ear cartilage support model by adopting modeling software. And adding a second solvent deionized water into the receiving groove of the printing receiving platform to print the ear cartilage support. After the slurry is extruded into deionized water, the acetic acid is quickly dissolved in the deionized water, the average diameter of the fiber formed in the printing process is 500 mu m, and the polycaprolactone is separated out in a phase separation manner and then is molded to obtain the auricular cartilage repair scaffold II. And (3) soaking the ear cartilage repairing support II in deionized water for 3d to remove residual solvent, then carrying out freeze-drying treatment, and finally carrying out gamma-ray irradiation sterilization on the freeze-dried ear cartilage repairing support II.
Example 3
In the embodiment, polylactic acid and polycaprolactone are selected as biodegradable synthetic high molecular compounds, and hexafluoroisopropanol is selected as a first solvent to prepare the alveolar bone repair scaffold. The specific implementation steps are as follows:
(1) and (2) dissolving polylactic acid and polycaprolactone in hexafluoroisopropanol, wherein the adding amount of the polylactic acid and the polycaprolactone is 0.7g/mL, and the mass ratio of the polylactic acid to the polycaprolactone is 1:1, so as to obtain a matrix solution.
(2) Hydroxyapatite with the granularity of 500 nm-100 mu m is selected as a powder component with osteogenic activity, and the powder component with osteogenic activity is uniformly dispersed into a matrix solution according to the addition amount of 0.5g/mL to form slurry.
(3) And establishing an alveolar bone scaffold model by adopting modeling software. And adding a second solvent, namely absolute ethyl alcohol, into the receiving groove of the printing receiving platform to print the alveolar bone bracket. After the printing slurry is extruded into the absolute ethyl alcohol, the hexafluoroisopropanol is quickly dissolved into the absolute ethyl alcohol, the average diameter of fibers formed in the printing process is 700 mu m, and the polylactic acid and the polycaprolactone are separated out in a phase separation manner and then are molded to obtain the alveolar bone repair scaffold III. Soaking the alveolar bone repair support III in absolute ethyl alcohol for 3d to remove residual solvent, then carrying out air drying treatment, and finally carrying out gamma-ray irradiation sterilization on the air-dried alveolar bone repair support III.
Performance testing
The average pore size, average diameter, porosity and compressive modulus test data for the tissue repair scaffolds I-III of examples 1-3 above are set forth in Table 1 below.
TABLE 1
As can be seen from Table 1, the tissue repair scaffolds I-III of examples 1-3 of the present application have a porosity and pore size suitable for tissue growth, and facilitate precipitation of bone-promoting active ingredients and/or cartilage-promoting active ingredients in the scaffold; the compression modulus is large, and the possibility of brittle fracture of the bone-cartilage integrated repair scaffold I-III is low.
Animal experiments
The integrated bone-cartilage repair scaffold of example 1 was implanted under the skin of nude mice, removed 1 month after the operation, and the cartilage site was sectioned and analyzed for immunohistochemical staining of cartilage matrix type II collagen and staining of acid glycosaminoglycan with aliskiren blue. As shown in particular in fig. 4 and 5.
As can be seen from FIGS. 4 and 5, the cells secreted a certain amount of the cartilage matrix type II collagen and acidic glycosaminoglycan after the cell-containing cartilage layer scaffold was implanted subcutaneously in nude mice for 1 month. Indicating that the scaffold has good chondrogenic activity.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (18)
1. A method of making a tissue repair scaffold comprising the steps of:
dissolving a biodegradable synthetic high molecular compound in a first solvent, and adding functional powder to obtain slurry; then the slurry is printed and extruded into a second solvent by using a 3D printing technology to be separated and formed,
wherein the second solvent is a poor solvent for the biodegradable synthetic polymer compound, and the first solvent and the second solvent are miscible;
the tissue repair scaffold comprises a bone repair layer and a cartilage repair layer which are connected; the bone repair layer and the cartilage repair layer comprise fiber bundles, the fiber bundles comprise one or more than two fiber yarns, and functional powder is arranged on the surface and/or inside of at least one fiber yarn;
the tissue repair scaffold is at least partially provided with a plurality of hole structures, and at least part of the hole structures are formed by overlapping the fiber bundles and penetrate through the bone repair layer and the cartilage repair layer.
2. The method according to claim 1, wherein the particle size of the functional powder is 1nm to 500 μm.
3. The method according to claim 1, wherein the biodegradable synthetic polymer compound is added to the first solvent in an amount of 0.05 to 1 g/mL.
4. The preparation method according to claim 3, wherein the functional powder is added in an amount of 0.01-1 g/mL.
5. The method for preparing a tissue repair scaffold according to any one of claims 1 to 4, wherein the second solvent comprises water and/or ethanol; the first solvent comprises one or the combination of more than two of dioxane, acetic acid, chloroform, hexafluoroisopropanol and dimethyl sulfoxide.
6. The method of any one of claims 1-4, wherein the tissue repair scaffold has, at least in part, a plurality of pore structures, and the tissue repair scaffold has an average pore size of between 50 μm and 1000 μm and a porosity of between 20% and 95%.
7. The method of claim 6, wherein at least a portion of the pore structure is formed by overlapping the fiber bundles and extends through the tissue repair scaffold; and/or, at least part of the pore structure is formed inside the fiber filament.
8. The method according to any one of claims 1 to 4, wherein the biodegradable synthetic polymer compound comprises one or a combination of two or more of polycaprolactone, polylactic acid, polyglycolic acid, and a polylactic acid-glycolic acid copolymer.
9. The method according to any one of claims 1 to 4, wherein a surface of at least one of the filaments has a depressed structure.
10. The preparation method according to claim 9, wherein the average diameter of the individual fiber filaments is between 50 μm and 1000 μm.
11. The method according to any one of claims 1 to 4, wherein the functional powder comprises a powder component having osteogenic activity and/or a powder component having chondrogenic activity.
12. The preparation method according to claim 11, wherein the powder component having osteogenic activity comprises one or a combination of two or more of an inorganic component having osteogenic activity, polymeric microspheres having osteogenic activity, and an animal-derived bone matrix; the powder component with chondrogenic activity comprises animal cartilage matrix and/or high molecular microspheres with chondrogenic activity.
13. The method according to claim 12, wherein the polymeric microspheres having osteogenic activity contain growth factors that promote osteoblast proliferation; the polymer microsphere with chondrogenic activity contains growth factors which promote the proliferation of chondrocytes.
14. The method according to claim 13, wherein the osteoblast proliferation-promoting growth factor is present in an amount of 0.1ng/g to 50ng/g, based on the mass of the polymer microspheres.
15. The method according to claim 13, wherein the growth factor that promotes chondrocyte proliferation is contained in an amount of 0.1ng/g to 50ng/g, based on the mass of the polymer microsphere having chondrogenic activity.
16. The method for preparing a tissue repair scaffold according to any one of claims 1 to 4, wherein the compressive modulus of the tissue repair scaffold is 0.1MPa to 15 MPa.
17. Use of a tissue repair scaffold prepared according to the method of preparing a tissue repair scaffold according to any one of claims 1 to 16 in the preparation of a degradable bone attachment patch or an article for bone tissue defect repair in bone surgery.
18. Use according to claim 17, wherein the degradable bone connecting sheet or orthopedic bone tissue defect repair article comprises at least one of a cranio-maxillofacial bone repair article, an alveolar bone repair article, a alar cartilage repair article, an auricular cartilage repair replica, an articular cartilage defect repair article, a thoracic rib repair article, and a thoracic deformity correction repair article.
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