CN115671400A - Composite absorbable implant and preparation method and application thereof - Google Patents
Composite absorbable implant and preparation method and application thereof Download PDFInfo
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- CN115671400A CN115671400A CN202211328196.8A CN202211328196A CN115671400A CN 115671400 A CN115671400 A CN 115671400A CN 202211328196 A CN202211328196 A CN 202211328196A CN 115671400 A CN115671400 A CN 115671400A
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- degradable composite
- degradable
- absorbable
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- 239000002131 composite material Substances 0.000 title claims abstract description 225
- 239000007943 implant Substances 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000002513 implantation Methods 0.000 title description 4
- 239000000835 fiber Substances 0.000 claims abstract description 104
- 229910052751 metal Inorganic materials 0.000 claims abstract description 66
- 239000002184 metal Substances 0.000 claims abstract description 65
- 239000011159 matrix material Substances 0.000 claims abstract description 58
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- 238000002844 melting Methods 0.000 claims abstract description 11
- 230000008018 melting Effects 0.000 claims abstract description 11
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 40
- 229910052749 magnesium Inorganic materials 0.000 claims description 27
- 239000011777 magnesium Substances 0.000 claims description 27
- 229920001577 copolymer Polymers 0.000 claims description 25
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- 239000000463 material Substances 0.000 claims description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 230000003014 reinforcing effect Effects 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 15
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- 239000011701 zinc Substances 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
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Abstract
The invention provides a composite absorbable implant, a preparation method and application thereof. The composite absorbable implant of the present invention comprises, in mass percent, 10-70% by weight of wire, 15-60% by weight of degradable composite fiber and 15-60% by weight of degradable composite matrix; the metal wires are arranged in the degradable composite matrix in parallel, the degradable composite fibers are dispersed in the degradable composite matrix in parallel and are arranged in parallel with the metal wires, and the melting temperature of the polymer in the degradable composite fibers is higher than that of the degradable composite matrix. The composite absorbable implant has good strength and toughness, still has good mechanical property in the later degradation period, is controllable in degradation and uniform in degradation speed; the polymer chain section relaxation and orderly arrangement and orientation composite reinforced phase provides a binding point for interaction with human tissues, promotes the adhesion of tissues and implants, and promotes the propagation and growth of cells.
Description
Technical Field
The invention belongs to the technical field of medical implants, and relates to a composite absorbable implant, and a preparation method and application thereof.
Background
Medical implants are currently widely used in human tissue repair, and these implant products have a high degree of tissue compatibility within the human body. These implants are typically implanted in the body for therapeutic purposes, but are not degradable in the body and require re-surgery for removal. Therefore, even if a material having high biocompatibility is implanted for a long period of time in the human body, rejection reaction may occur.
To address the problems that result after surgery with non-degradable materials, one approach has been to develop implants that are degradable in vivo. Degradable implants interact with the body medium physiological processes or tissues, resulting in gradual degradation of the implant material. These materials will decrease in vivo over time, the implant will eventually degrade and the degradation products will be absorbed by the body without the need for a secondary operation. However, the mechanical properties of artificially synthesized or natural absorbable polymers are insufficient and cannot bear higher mechanical strength, and the material brittleness is large and poor in impact resistance due to the degradable polymers represented by the high-mechanical-property levorotatory polylactic acid, and the material brittleness is further increased after the activity of the inorganic biological material is enhanced; the degradable polymer represented by polycaprolactone with excellent flexibility is low in tensile strength and elastic modulus, and the implant needs to meet the special requirements of elastic modulus, toughness and plasticity. Unfortunately, most polymers cause inflammation during the absorption of degradable polymers, resulting in severe intimal hyperplasia or thrombotic occlusion.
Some researchers have attempted to develop absorbable bio-corrodible metal alloys to overcome the disadvantages of degradable polymers. The corrodible metal alloy is selected from alkali metals, alkaline earth metals, iron, zinc and aluminum, while metals or alloys of magnesium, iron, zinc, which can be used with manganese, cobalt, nickel, chromium, copper, cadmium, lead, tin, thorium, zirconium, silver, gold, palladium, platinum, silicon, calcium, lithium, aluminum for improving the metal properties, are particularly suitable as implant materials. Although there have been some advances in the field of bioerodible metal alloys, the use of known alloys is limited due to material properties, such as strength and corrosion behavior. Compared with other metals, the magnesium alloy has relatively high biological corrosion speed and relatively uneven corrosion, and the later period is higher in corrosion speed and relatively lower in strength.
US20040098108A1 discloses a metal implant that degrades at a suitable rate after completing a temporary support function, thereby avoiding the negative effects of long-term implantation. The main component of the material is alkali metal, the alkaline earth metal comprises magnesium, iron, zinc and aluminum, and manganese, cobalt, nickel, chromium, copper, cadmium, lead, tin, thorium, zirconium, silver, gold, palladium, platinum, rhenium, silicon, calcium and lithium are used as auxiliary components.
US20080103594 discloses an absorbable medical implant composite, the implant being made of a bioerodible alloy selected from the group consisting of magnesium, calcium, iron, and yttrium. Suitable metallic elements which provide higher strength and delayed in vivo corrosion.
CN109881238A discloses an active coating with self-healing function coated on the surface of a magnesium-based material, which is prepared by firstly adopting micro-arc oxidation technology to prepare a porous magnesium oxide coating containing phosphorus and calcium on the surface of the magnesium or magnesium alloy, then using a spin-coating deposition method to spin-coat an F-MSNs @ PLLA coating on the porous magnesium oxide coating containing phosphorus and calcium, and finally using a dipping deposition method to obtain a DCPD coating with high osseointegration effect on the surface. The magnesium material is coated with a layer of magnesium oxide, a F-MSNs @ PLLA coating and dicalcium phosphate in sequence to slow down the early-stage over-rapid degradation of magnesium.
CN105377318A discloses a bioabsorbable biomedical implant. The implant includes a tubular scaffold comprising a plurality of interconnected polymer struts. The interconnected polymer struts define a plurality of deformable cells. The polymer struts have an average thickness of no more than 150 μm. Also disclosed are methods for making the bioabsorbable biomedical implant, including methods of making fiber reinforced polymer composites for tubular stents.
However, the absorbable polymer in the prior art has poor mechanical property, some degradation products are acidic, the metal degradation is too fast and nonuniform, the degradation products are alkaline, the solubility is poor, the metal degradation is fast and slow before and after, and the support effect in the early stage and the middle stage cannot be met; the local acidity of some polyester-based polymer degradation and the generation of local alkalinity as metal degradation products can lead to tissue damage. At present, ceramic reinforced composites, especially anisotropic ceramic and polymer composites, are disordered in arrangement, the polymer segments are entangled and cannot be stretched, and the ability to absorb the implanted surface is very important, which affects the subsequent interaction between the material and the tissue and cells, such as cell adhesion, protein adsorption and tissue inflammation, thus limiting the good function of the composite in the human body.
Therefore, there is an urgent need to develop a composite absorbable implant with relatively stable mechanical properties in the repair process, controllable metal degradation, uniform degradation speed, capability of interacting with the tissue microenvironment and promoting better cell propagation and growth, and a preparation method and application thereof.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a composite absorbable implant, a preparation method and application thereof, wherein the composite absorbable implant has good strength and toughness, relatively stable mechanical properties in the process of being implanted into a human body in the repair process, good mechanical properties in the later degradation period, controllable metal degradation, uniform degradation speed, capability of interacting with a tissue microenvironment, promotion of better cell propagation, contribution to cell adhesion and reduction of inflammatory response of cells.
One of the objectives of the present invention is to provide a composite absorbable implant, and to achieve the objective, the present invention adopts the following technical solutions:
a composite absorbable implant comprising metal wire, degradable composite reinforcing fiber and a degradable composite matrix, comprising, in percent by mass, 10-70% wt of metal wire, 15-60% wt of degradable composite fiber and 15-60% wt of degradable composite matrix, the sum of the above-mentioned components total percent by mass being 100%;
the metal wires are arranged in the degradable composite matrix in parallel, the degradable composite fibers are dispersed in the degradable composite matrix in parallel and are arranged in parallel with the metal wires, and the melting temperature of polymers in the degradable composite fibers is higher than that of the degradable composite matrix.
According to the invention, the composite absorbable implant comprises the metal wire, the degradable composite fiber and the degradable composite matrix, wherein the melting temperature of a polymer in the degradable composite fiber is higher than that of the degradable composite matrix, so that the composite absorbable implant has unique performance, and the metal wire provides higher strength and modulus and higher strength and modulus for fixing an implanted part; the strength and modulus of the metal wire are gradually reduced along with the subsequent degradation of the composite absorbable implant, the degradable composite fiber in the implant maintains the strength and modulus of the implant, powerful mechanical strength is provided for the healing of the middle and later periods of the implanted part, and the melting temperature of the degradable composite fiber is higher than that of the degradable composite matrix, so that the degradable composite material does not soften or melt in shear fluid in the biodegradable polymer matrix and maintains a solid shape; meanwhile, the metal wires are arranged in the degradable composite matrix in an oriented or parallel manner, the degradable composite fibers are oriented in the degradable composite matrix, the orientation direction is arranged in parallel with the metal wires, polymer chain segments in the degradable composite fibers relax in the same direction, the longitudinal mechanical strength and toughness of the material are greatly improved, and the strength, plasticity and degradation performance of the composite material are synergistically improved; meanwhile, the polymer chain segments arranged in the unfolding orientation of the implant are optimized, the surface is more compact, particularly, the composite fiber can be degraded, a binding point interacting with human tissues is provided, the tissue and implant adhesion is promoted, and the cell reproduction and growth are promoted.
Among other things, the composite absorbable implant of the present invention comprises a wire phase, a composite material, and a matrix phase. The metal wires are arranged and oriented in a certain direction; the degradable composite fiber is oriented in the degradable composite matrix and is parallel to the stretching direction of the metal wire, and the reinforcing phases in the degradable composite fiber are arranged in parallel and are all parallel to the processing and stretching direction of the metal wire.
The degradable composite reinforcing fiber comprises absorbable polymers and a composite reinforcing phase, wherein the absorbable polymers account for 40-90% of the degradable composite fiber by mass, such as 40%, 50%, 60%, 70%, 80%, 90% and the like.
The chain segments of the absorbable polymer relax and are orderly arranged along the stretching direction of the metal wire; the composite reinforcing phase is oriented in the wire shearing direction.
The shape of the degradable composite fiber is anisotropic rod-shaped, strip-shaped or sheet-shaped.
The absorbable polymer comprises any one or a mixture of at least two of Polyglycolide (PGA), glycolide copolymers, polylactic acid (PLA), polylactic acid copolymers, polydipeptides, asymmetric 3, 6-substituted poly-1, 4-dioxane-2, 5-dione, polyhydroxyalkanoates, polydioxanone (PDS), poly-d-valerolactone, polycaprolactone, methyl methacrylate-N-vinylpyrrolidone copolymers, polyesteramides, oxalic acid polyesters, polydihydropyrans, polyalkyl-2-cyanoacrylates, polyurethanes (PU), polyvinyl alcohol (PVA), polyhydropeptides, poly b-malic acid (PM-LA), poly-b-alkanoic acid, polycarbonates, polycarboxylates, polyphosphates, polyanhydrides.
Preferably, the glycolide copolymer comprises glycolide/L-lactide copolymer (PGA/PLLA) and/or glycolide/trimethyl carbonate copolymer (PGA/TMC).
Preferably, the polylactic acid copolymer comprises any one of or a mixture of at least two of poly L-lactide (PLLA), poly DL-lactide (PDLLA), L-lactide/DL-lactide copolymer, lactide/tetramethylglycolide copolymer, lactide/trimethyl carbonate copolymer, lactide/d-valerolactone copolymer, lactide/epsilon-caprolactone copolymer, lactide/glycolide/trimethyl carbonate terpolymer, lactide/glycolide/epsilon-caprolactone terpolymer, and polylactic acid/polyethylene oxide copolymer.
Preferably, the polyhydroxyalkanoate comprises any one of Polyhydroxybutyrate (PHB), polyhydroxybutyrate/b-hydroxyvalerate copolymer (PHB/PHV), poly-b-hydroxypropionic acid (PHPA), or a mixture of at least two thereof.
In the invention, the composite reinforcing phase in the absorbable composite material comprises any one or a mixture of at least two of metal fibers, metal particles, metal oxide particles, absorbable ceramics or bacterial cellulose.
Preferably, the composite reinforcing phase has a dimension of 20 nm to 50 microns, such as 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1 micron, 5 micron, 10 micron, 15 micron, 20 micron, 25 micron, 30 micron, 35 micron, 40 micron, 45 micron, 50 micron, or the like; more preferably 50 nm to 500 nm, for example, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, etc.
Preferably, the metal fibers may be long metal fibers, short metal fibers, the metal fibers being parallel to each other, the metal fibers comprising any one of magnesium fibers, zinc fibers, or iron fibers, or a mixture of at least two of them.
Preferably, the metal particles comprise any one of magnesium particles, iron particles, zinc particles or a mixture of at least two thereof.
Preferably, the metal oxide particles are any one of magnesium oxide particles, iron oxide particles, zinc oxide particles or a mixture of at least two of them.
Preferably, the absorbable ceramic comprises any one of hydroxyapatite, calcium carbonate, bioactive glass and bioactive microcrystalline glass or a mixture of at least two of the hydroxyapatite, the calcium carbonate, the bioactive glass and the bioactive microcrystalline glass, and is in the shape of an anisotropic rod, a strip, a sheet, a wire or a tube, and the length-diameter ratio of the absorbable ceramic is more than 6; if the absorbable ceramic is hydroxyapatite, rod-shaped or strip-shaped hydroxyapatite is preferred, and low-crystallization hydroxyapatite prepared by a hot-water method, a biological template method and a sol-gel method without calcination is preferred.
The degradable composite fiber can be processed into a long rod-shaped or strip-shaped material by a microfluidic fluid shearing processing method, and if the composite reinforcing phase fiber in the degradable composite material is a rod-shaped material, the processing is preferably performed in a conical or wedge-shaped microfluidic fluid shearing mode.
In the present invention, the degradable composite matrix comprises any one of absorbable polymers, copolymers, polymer alloys or a mixture of at least two thereof. The degradable matrix can be compounded with collagen, bacterial cellulose and other bioactive substances.
As a preferable scheme of the invention, active drugs can be added into the degradable composite fiber and the degradable matrix.
In the invention, the melting temperature of the absorbable polymer in the degradable composite reinforced fiber is higher than that of the absorbable polymer in the degradable composite matrix by more than 15 ℃, so that the absorbable polymer in the degradable composite reinforced fiber is prevented from softening due to overhigh temperature.
In the present invention, the metal wire is selected from any one of magnesium, iron, zinc, calcium, strontium, zirconium, yttrium or an alloy of at least two metals. The metal wires can be round wires, strip wires and the like.
Preferably, the diameter of the wire is 10-1000 μm, such as 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, and the like.
The second purpose of the present invention is to provide a method for preparing the composite absorbable implant, which comprises the following steps: according to the proportion, the metal wire is stretched in a micro-fluidic channel containing degradable composite fibers and a degradable composite matrix, and after the micro-fluidic channel is cooled and fixed in situ, the composite absorbable implant is obtained.
The preparation method of the degradable composite fiber comprises the following steps: mixing an absorbable polymer and a composite reinforcing phase to form a composite material, shearing a composite material melt through micro-flow channel flowing, cooling and solidifying in situ on a conveyor belt, and cutting into shapes of long rods, sheets, filaments, strips and the like to obtain the degradable composite fiber; mixing the long rod-shaped, flaky, filamentous and strip degradable composite fibers and the degradable composite matrix by known mixing equipment such as an internal mixer, a twin-screw and the like, and conveying the tapered micro-channel. The melting temperature of the polymer in the degradable composite fiber is higher than that of the degradable composite matrix.
The degradable composite fiber can effectively and quickly stretch polymer chain segments by utilizing fluid shearing force and promote the ordered arrangement of the polymer chain segments; at the same time, the anisotropic composite reinforcing phase is oriented in the shearing direction (melt flow direction), the composite melt is cooled, and the orientation is fixed.
The metal wire, the degradable composite material and the degradable composite matrix are mixed in a shearing flow mode.
Preferably, the degradable composite fibers and the degradable composite matrix are mixed by means of mechanical mixing, melt mixing or solvent mixing. The matrix and polymer are preformed into a material (prepreg) by coating or using a solvent as an intermediate.
Preferably, the metal wire is one or more, woven or knitted into a two or three dimensional structure, pultruded through a taper or wedge, melt extruded, and shaped into a desired shape by machining.
Preferably, the preparation method of the composite absorbable implant comprises the following steps:
and drawing one or more metal wires through a conical micro-channel, mixing the metal wires with the cooled degradable composite matrix and the degradable composite fiber on a conveyor belt, wherein the drawing speed of the metal wires is higher than the flow speed of the melt, so that the orientation of the degradable composite fiber and the degradable composite matrix is realized, and the composite absorbable implant is obtained.
The invention also aims to provide the application of the composite absorbable implant, which is used for preparing the bioabsorbable materials and the instruments of the suture, the vascular stent, the bone repair screw, the bone defect and the intervertebral fusion.
The composite absorbable implants of the present invention may be further mechanically and/or thermally processed into more complex implant forms to achieve screws, bone plates, nails, staples, suture anchors, bolts, clamps, wedges, vessels, vascular stents, and the like, for application to various implant sites, for therapeutic purposes, such as tissue fixation, or to aid or guide tissue regeneration.
Compared with the prior art, the invention has the beneficial effects that:
the composite absorbable implant has good strength and toughness, controllable degradation and uniform degradation speed. Specifically, the composite absorbable implant prepared by the invention has the tensile strength of 158-213MPa, the elongation at break of 26.0-38.9 percent, the bending strength of 392-441MPa and the bending modulus of 28.6-41.2GPa; the prepared composite absorbable implant has the tensile strength of 133-151MPa, the elongation at break of 20.2-32.3%, the bending strength of 277-331MPa and the bending modulus of 20.6-32.0GPa after 6 months.
Drawings
FIG. 1 is a schematic structural view of a composite absorbable implant of the present invention;
FIG. 2 is a schematic structural view of a preferred embodiment of the degradable composite fiber of FIG. 1;
FIG. 3 is a schematic structural view of another preferred embodiment of the degradable composite fiber in FIG. 1;
the reference numbers are as follows:
1-a metal wire; 2-degradable composite fibers; 21-an absorbable polymer; 22-a composite reinforcing phase; 3-degradable composite matrix.
Detailed Description
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached figures 1-3.
Unless otherwise specified, various starting materials of the present invention are commercially available or prepared according to conventional methods in the art.
In the examples and comparative examples of the present invention, the raw materials are as follows: polylactic acid PLLA is PURASRB PL65 from CORBION, the Netherlands; the polycaprolactone PCL is derived from PURASRB PC17; preparing a magnesium metal wire with the diameter of 30-50 mu m from the metal wire according to the WO2011/125887 patent; the nano hydroxyapatite with low bioactivity and crystallization has the diameter of 20 nanometers and the length of 200 nanometers.
As shown in fig. 1, the composite absorbable implant of the invention comprises metal wires 1, degradable composite fibers 2 and a degradable composite matrix 3, wherein the metal wires 1 are arranged in the degradable composite matrix 3, the degradable composite fibers 2 are dispersed in the degradable composite matrix 3 and are arranged in parallel with the metal wires 1, and the melting temperature of the degradable composite fibers 2 is higher than that of the degradable composite matrix 3.
As a preferred embodiment of the present invention, the degradable composite fiber 2 includes a rod-shaped composite reinforcing phase 22 and an absorbable polymer 21, and the composite reinforcing phase 22 is dispersed in the absorbable polymer 21 and arranged parallel to the metal wire 1, as shown in fig. 2.
As another preferred embodiment of the present invention, the degradable composite fiber 2 includes a particulate composite reinforcing phase 22 and an absorbable polymer 21, and the composite reinforcing phase 22 is dispersed in the absorbable polymer 21 and arranged in parallel to the metal wire 1, as shown in fig. 3.
Example 1
The composite absorbable implant of the embodiment is prepared by the following method:
preparing degradable composite fibers: adding 80/20 parts by mass of polylactic acid PLLA and low-crystalline nano-hydroxyapatite into a chloroform solution, mixing, and removing the solvent. Injecting the melt into a microfluidic device for shearing the melt, drawing a line, processing, cooling and granulating, wherein the diameter of a microfluidic channel is 10 micrometers, the length of the microfluidic channel is 1 meter. Cutting into rod-shaped material with diameter of 10 micrometer and length of 2mm to obtain degradable composite fiber.
Adding the degradable composite fiber and polycaprolactone PCL into a double-screw extruder for melting and mixing, wherein the maximum temperature zone of the screw is lower than 130 ℃, uniformly mixing, injecting a melt into a 10-hole conical microfluidic device, the diameter of a channel of the microfluidic device is 200 micrometers, the length of the channel is 1m, and the temperature of the melt of the microfluidic channel is 120 ℃. And (3) parallelly and equidistantly arranging metal magnesium wires with the diameter of 30 micrometers, and drawing the metal magnesium wires from the microfluidic channel at the drawing speed of 20.0mm/min. The magnesium metal wire is cooled and solidified in situ according to the proportion of 30 percent of degradable composite fiber and 40 percent of degradable composite matrix to obtain the composite absorbable implant with the diameter of 2 mm.
Example 2
The difference between the present embodiment and embodiment 1 is that the magnesium metal wire is 40%, the degradable composite fiber is 30%, and the degradable composite matrix is 30%.
Example 3
The present example is different from example 1 in that the magnesium metal wire is 50%, the degradable composite fiber is 30%, and the degradable composite matrix is 20%.
Example 4
The difference between this example and example 1 is that the magnesium metal wire is 60%, the degradable composite fiber is 25%, and the degradable composite matrix is 15%.
Example 5
The difference between the embodiment and the embodiment 1 is 70% of magnesium metal wires, 15% of degradable composite fibers and 15% of degradable composite matrix.
Example 6
The difference between this example and example 1 is that 30% of magnesium metal wires, 50% of degradable composite fibers and 20% of degradable composite matrix.
Example 7
The present example is different from example 1 in that PLLA and low-crystalline nano-hydroxyapatite in the degradable composite fiber are in a mass part ratio of 50/50.
Example 8
The present example is different from example 1 in that PLLA and low-crystalline nano-hydroxyapatite in the degradable composite fiber are in a mass part ratio of 40/60.
Example 9
Preparing degradable composite fibers: the magnesium wire with the diameter of 30 micrometers is processed in 0.1mol/L dilute hydrochloric acid solution to prepare the superfine magnesium wire with the diameter of 1-2 micrometers, and the superfine magnesium wire is cut into the superfine magnesium wire fiber with the length of 1 millimeter. Uniformly mixing and dispersing polylactic acid PLLA, the prepared superfine magnesium filament fiber and chloroform according to the mass ratio of 80. And injecting the melt into a microfluidic device for shearing the melt, drawing a line, wherein the diameter of a microfluidic channel is 4 micrometers, the length of the microfluidic channel is 0.5 meter, cooling, and cutting into rod-shaped degradable composite fibers with the diameter of 4 micrometers and the length of 2 millimeters.
This example is different from example 1 in that the degradable composite fiber in example 1 was replaced with the above degradable composite fiber.
Example 10
This example differs from example 1 in that each wire is arranged equidistantly and in parallel from the microfluidic device at a drawing speed of 60.0 mm/min.
Example 11
This example differs from example 1 in that the magnesium metal wire has a diameter of 50 μm, and is otherwise the same as example 1.
Comparative example 1
The comparative example does not contain metal magnesium wires, 60 percent of degradable composite fibers and 40 percent of degradable composite matrix are added into a mould, the composite material is added, the mould is heated to 120 ℃, the temperature is kept for 5 minutes by 5MP pressure, the pressure is increased to 10MPa, the temperature is kept for 2 minutes, and the mould is cooled.
Comparative example 2
The implant of this comparative example was prepared by the following method:
adding PLLA and low-crystalline nano-hydroxyapatite into a double-screw extruder according to the mass part ratio of 80/20 for melt mixing, spinning, granulating and preparing degradable composite fibers with the diameter of 10 microns and the length of 2mm, wherein the hydroxyapatite of the degradable composite fibers is randomly arranged and is not oriented.
The degradable composite fiber, the polycaprolactone and the magnesium wire with the diameter of 30 microns are arranged in parallel at equal intervals and put into a die, wherein the metal wire accounts for 30 percent, the degradable composite fiber accounts for 30 percent, and the degradable composite matrix accounts for 40 percent. Heating the mould to 120 ℃, preserving heat for 5 minutes by using 5MP pressure, increasing the pressure to 10MPa, preserving heat for 2 minutes, and cooling the mould.
Comparative example 3
Adding PLLA and low-crystalline nano-hydroxyapatite into a double-screw extruder according to the mass part ratio of 80/20 for melt mixing, spinning, and granulating to prepare degradable composite fibers with the diameter of 10 microns and the length of 2mm, wherein the hydroxyapatite of the degradable composite fibers is randomly arranged and is not oriented.
This comparative example is different from example 1 in that the degradable composite fiber of example 1 is replaced with the above-mentioned hydroxyapatite non-oriented degradable composite fiber.
Comparative example 4
The degradable composite fiber, polycaprolactone and 30-micron magnesium wire in the embodiment 1 are arranged in parallel at equal intervals and placed in a mold, and the metal wire, the degradable composite fiber and the degradable composite matrix are 30% and 30% respectively. Heating the mould to 120 ℃, preserving heat for 5 minutes by using 5MP pressure, increasing the pressure to 10MPa, preserving heat for 2 minutes, and cooling the mould. The degradable composite fibers of this comparative example were not oriented in the implant.
Comparative example 5
The comparative example is different from example 1 in that the magnesium metal wire is 5%, the degradable composite fiber is 65%, and the degradable composite matrix is 30%.
Comparative example 6
The comparative example is different from example 1 in that 75% of magnesium metal wires, 20% of degradable composite fibers and 5% of degradable composite matrix.
Comparative example 7
The comparative example is different from example 1 in that the magnesium metal wire is 50%, the degradable composite fiber is 10%, and the degradable composite matrix is 40%.
Comparative example 8
The comparative example is a pure metal magnesium wire of 2mm diameter.
(1) Mechanical Property test
The mechanical properties of the composite absorbable implants prepared in examples 1 to 11 and comparative examples 1 to 8 were tested, and the test results are shown in table 1.
The mechanical properties of the composite absorbable implants prepared in examples 1 to 11 and comparative examples 1 to 8 were tested after 6 months, and the test results are shown in table 2.
Wherein the tensile strength and elongation at break are according to ASTM D3039M, the flexural strength and flexural modulus are tested according to ASTM D790-17, and the degradation time is tested as follows: the percentage of the total amount of actual hydrogen evolution was calculated as shown in Table 3 using 0.1mol/L TRI-HCl buffer solution with pH 7.4. + -. 0.2 to test the mechanical strength and collect hydrogen.
TABLE 1
| Serial number | Tensile strength/MPa | Elongation at break/% | Flexural Strength/MPa | Flexural modulus/GPa |
| Example 1 | 158 | 37.8 | 392 | 28.6 |
| Example 2 | 187 | 35.7 | 412 | 31.2 |
| Example 3 | 192 | 34.9 | 419 | 33.6 |
| Example 4 | 201 | 32.4 | 437 | 36.5 |
| Example 5 | 213 | 28.2 | 441 | 41.2 |
| Example 6 | 167 | 26.0 | 432 | 37.3 |
| Example 7 | 169 | 35.2 | 421 | 33.2 |
| Example 8 | 172 | 33.2 | 429 | 32.5 |
| Example 9 | 167 | 36.2 | 421 | 35.4 |
| Example 10 | 162 | 38.9 | 399 | 29.8 |
| Example 11 | 160 | 37.2 | 395 | 29.4 |
| Comparative example 1 | 18.9 | 91.2 | 4.5 | 2.1 |
| Comparative example 2 | 132 | 17 | 298 | 17.8 |
| Comparative example 3 | 136 | 29.7 | 297 | 18.2 |
| Comparative example 4 | 142 | 26.1 | 214 | 19.2 |
| Comparative example 5 | 52.2 | 30.2 | 114 | 12.4 |
| Comparative example 6 | 186 | 4.2 | 430 | 42.1 |
| Comparative example 7 | 192 | 25.2 | 280 | 30.2 |
| Comparative example 8 | 185 | 25.0 | 326 | 43.6 |
TABLE 2
Note that "-" indicates that the pure metallic magnesium wire was completely degraded within 6 months and could not be tested.
As can be seen from Table 1, the implants of the present invention, prepared using the methods of examples 1-11 and comparative examples 1-8, significantly improved the tensile strength, elongation at break, flexural strength and flexural modulus of the composite material. In the degradation liquid after 6 months, the mechanical property of the implant is still maintained to be more than 70%.
The data of examples 1-5 show that varying the magnesium metal ratio results in improved tensile strength, flexural strength, and flexural modulus.
Example 6 increasing the amount of degradable composite fiber significantly increases the flexural strength and flexural modulus.
Examples 7-8 increase of nano-hydroxyapatite in degradable composite fibers resulted in improved flexural strength and flexural modulus.
Example 9 the tensile strength and the bending strength were improved by replacing hydroxyapatite in the degradable composite fiber with a short ultra-fine magnesium filament.
Example 10 changes the drawing speed, the magnesium wire drawing speed, and is beneficial to the orientation of the polymer and the hydroxyapatite, and the tensile strength and the bending strength are improved.
Compared with the single organic polymer and ceramic composite material, the composite material of the invention has the advantages that the metal magnesium wire is added for compounding, the mechanical properties of the implant are greatly improved, the tensile strength, the bending strength and the bending modulus are greatly improved, and the requirements of the implanted medical instrument on the mechanical properties are met.
Comparative examples 2-4 show that both degradable composite fibers and nano-hydroxyapatite orientation significantly improve the elongation at break, flexural strength, and flexural modulus of composite implants.
Comparative examples 5 to 8 show that the content of the metal magnesium wire is low, the implantation mechanical property is low, and high mechanical property cannot be provided; too high magnesium metal and too low degradable composite fibers result in faster degradation of the implant in vivo.
(2) Cell viability assay
The composite absorbable implants prepared in examples 1 to 11 and comparative examples 1 to 8 were subjected to cell activity tests, and the results are shown in Table 3.
The test method is as follows: corneal epithelial cells and mesenchymal stem cells extracted from rat leg bones were seeded on the surface of the implant of the present invention. After 36 hours of inoculation, cell proliferation was measured using the CCK-8 kit.
TABLE 3
As can be seen from the data in Table 3, the polymer chain segments relax and orderly arrange and orient the nano-hydroxyapatite to promote the cell proliferation, and the polymer chain segments with disordered arrangement relax and orderly arrange and the hydroxyapatite inhibit the cell proliferation.
(3) Cell adhesion Rate test
The composite absorbable implants prepared in examples 1 to 11 and comparative examples 1 to 8 were subjected to a cell adhesion rate test, and the test results are shown in Table 4.
The test method is as follows:
culturing rat osteoblasts, adding 5ml of 2.5g/L trypsin into the osteoblasts according to a 6-well plate cultured for 10h, digesting for 3-5min, centrifuging to remove supernatant, and performing air-assisted counting. The adhesion rate of the cells per well was calculated as follows:
cell adhesion rate = (number of cells before seeding-number of residual cells after seeding)/number of cells before seeding.
TABLE 4
| Serial number | Cell adhesion rate/%) |
| Example 1 | 89.3 |
| Example 2 | 88.2 |
| Example 3 | 88.8 |
| Example 4 | 88.7 |
| Example 5 | 88.9 |
| Example 6 | 87.7 |
| Example 7 | 85.3 |
| Example 8 | 92.4 |
| Example 9 | 89.9 |
| Example 10 | 84.2 |
| Example 11 | 89.5 |
| Comparative example 1 | 60.2 |
| Comparative example 2 | 61.3 |
| Comparative example 3 | 60.8 |
| Comparative example 4 | 60.7 |
| Comparative example 5 | 62.5 |
| Comparative example 6 | 63.5 |
| Comparative example 7 | 58.2 |
| Comparative example 8 | 50.3 |
As can be seen from table 4, the polymer segments relax and the ordered arrangement of the polymeric segments provides binding sites for adhesion to human cells, increasing the viscosity of the cells.
The invention improves the surface of the implant, increases the affinity of cells or proteins with the surface of the implant, reduces the inflammatory reaction of the implant and the cells or proteins, promotes the propagation of the cells and the proliferation of epithelial cells, provides a proper way for the adhesion of the cells on the surface of the implant, and is beneficial to the adhesion of the cells.
The present invention is illustrated by the above-mentioned examples, but the present invention is not limited to the above-mentioned detailed process equipment and process flow, i.e. it is not meant to imply that the present invention must rely on the above-mentioned detailed process equipment and process flow to be practiced. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of the raw materials of the product of the present invention, and the addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (10)
1. A composite absorbable implant which comprises, in percent by mass, 10-70% wt of metal wire, 15-60% wt of degradable composite fibers and 15-60% wt, 37-60% wt of degradable composite matrix, the sum of the total mass percentages of the aforementioned components being 100%;
the metal wires are arranged in the degradable composite matrix in parallel, the degradable composite fibers are dispersed in the degradable composite matrix in parallel and are arranged in parallel with the metal wires, and the melting temperature of the polymer in the degradable composite fibers is higher than that of the degradable composite matrix.
2. The composite absorbable implant of claim 1, wherein the degradable composite fibers comprise absorbable polymers and composite reinforcing phase, the absorbable polymers account for 40-90% of the degradable composite fibers by mass;
preferably, the segments of the absorbable polymer relax and align in the direction of stretching of the wire; the composite reinforcing phase is oriented along the shearing direction of the metal wire;
preferably, the degradable composite fiber has the shape of an anisotropic rod, a strip, a sheet, a filament or a tube.
3. The composite absorbable implant of claim 2, wherein the absorbable polymer comprises any one or a mixture of at least two of polyglycolide, copolymers of glycolide, polylactic acid, copolymers of polylactic acid, polydipeptides, unsymmetrical 3, 6-substituted poly-1, 4-dioxane-2, 5-dione, polyhydroxyalkanoates, polydioxanones, poly-d-valerolactone, polycaprolactone, methyl methacrylate-N-vinylpyrrolidone copolymer, polyesteramides, oxalates, polydihydropyrans, polyalkyl-2-cyanoacrylates, polyurethanes, polyvinyl alcohols, polyhypeptides, poly-b-malic acid, poly-b-alkanoic acid, polycarbonates, polycarboxylates, polyphosphates, polyanhydrides;
preferably, the glycolide copolymer comprises a glycolide/L-lactide copolymer and/or a glycolide/trimethyl carbonate copolymer;
preferably, the polylactic acid copolymer comprises any one of or a mixture of at least two of poly L-lactide, poly DL-lactide, L-lactide/DL-lactide copolymer, lactide/tetramethyl glycolide copolymer, lactide/trimethyl carbonate copolymer, lactide/d-valerolactone copolymer, lactide/epsilon-caprolactone copolymer, lactide/glycolide/trimethyl carbonate terpolymer, lactide/glycolide/epsilon-caprolactone terpolymer and polylactic acid/polyethylene oxide copolymer;
preferably, the polyhydroxyalkanoate comprises any one of polyhydroxybutyrate, polyhydroxybutyrate/b-hydroxyvaleric acid copolymer, poly-b-hydroxypropionic acid or a mixture of at least two of them.
4. The composite absorbable implant of claim 2 or 3, wherein the composite reinforcing phase comprises any one of metal fibers, metal particles, metal oxide particles, absorbable ceramics or bacterial cellulose or a mixture of at least two thereof;
preferably, the composite reinforcing phase has dimensions of 20 nm to 50 μm, preferably 50 nm to 500 nm;
preferably, the metal fibers comprise any one of magnesium fibers, zinc fibers or iron fibers or a mixture of at least two thereof;
preferably, the absorbable ceramic comprises any one of hydroxyapatite, calcium carbonate, bioactive glass-ceramics or a mixture of at least two of the above;
preferably, the shape of the absorbable ceramic is anisotropic rod, strip, sheet, wire or tube, and the length-diameter ratio is more than 6;
preferably, the hydroxyapatite is low-crystalline hydroxyapatite, preferably low-crystalline hydroxyapatite prepared by a hydrothermal reaction method, a gel-sol method and a biological template method without calcination.
5. The composite absorbable implant of any of claims 1-4, wherein the degradable composite matrix comprises a mixture of any one or at least two of absorbable polymers, copolymers, polymer alloys;
preferably, the polymer of the degradable composite matrix is stretched along the wire, and the segments of the polymer are relaxed and orderly arranged.
6. The composite absorbable implant of claim 5, wherein the melting temperature of the absorbable polymer in the degradable composite reinforcing fibers is more than 15 ℃ higher than the melting temperature of the absorbable polymer in the degradable composite matrix.
7. The composite absorbable implant of any of claims 1-6, wherein the wires are selected from the group consisting of magnesium, iron, zinc, calcium, strontium, zirconium, yttrium, or alloys of at least two metals;
preferably, the diameter of the wire is 10-1000 μm.
8. A method of making a composite absorbable implant of any of claims 1-7, characterized in that the method of making comprises the steps of: according to the proportion, the metal wire is stretched in a micro-fluidic channel containing degradable composite fibers and a degradable composite matrix, and after the micro-fluidic channel is cooled and fixed in situ, the composite absorbable implant is obtained.
9. The method for preparing the degradable composite fiber according to claim 8, wherein the method for preparing the degradable composite fiber comprises the following steps: mixing an absorbable polymer and a composite reinforcing phase to form a composite material, shearing a composite material melt through micro-flow channel flowing, cooling and solidifying in situ on a conveyor belt, and cutting to obtain the degradable composite fiber;
preferably, the preparation method of the composite absorbable implant comprises the following steps:
drawing one or more metal wires through a tapered micro-fluidic channel containing a degradable composite matrix and a degradable composite fiber, mixing the metal wires with the cooled degradable composite matrix and the cooled degradable composite fiber on a conveyor belt, wherein the drawing rate of the metal wires is higher than the melt flow rate, so that the orientation of the degradable composite fiber and the degradable composite matrix is realized, and the composite absorbable implant is obtained;
preferably, the degradable composite matrix in the microfluidic channel is in a molten state, and the degradable composite fiber is in a solid state.
10. Use of a composite absorbable implant according to any of claims 1 to 7, characterized in that it is used for the preparation of bioabsorbable materials and instruments for sutures, vascular stents, bone repair screws, bone defects, intervertebral fusions.
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| WO2013071862A1 (en) * | 2011-11-15 | 2013-05-23 | 东南大学 | High-strength absorbable intrabony fixing implanted composite device and preparation method thereof |
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| CN114272437A (en) * | 2021-12-28 | 2022-04-05 | 同光(昆山)生物科技有限公司 | Medical composite material and preparation method and application thereof |
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|---|---|---|---|---|
| US20060024350A1 (en) * | 2004-06-24 | 2006-02-02 | Varner Signe E | Biodegradable ocular devices, methods and systems |
| US20120040002A1 (en) * | 2009-04-23 | 2012-02-16 | Timo Lehtonen | Resorbable and biocompatible fibre glass compositions and their uses |
| EP2512539A1 (en) * | 2009-12-18 | 2012-10-24 | Skulle Implants OY | An implant system |
| WO2013071862A1 (en) * | 2011-11-15 | 2013-05-23 | 东南大学 | High-strength absorbable intrabony fixing implanted composite device and preparation method thereof |
| US20200345895A1 (en) * | 2017-12-20 | 2020-11-05 | Ossio Ltd | Fiber bundle reinforced biocomposite medical implants |
| CN114272437A (en) * | 2021-12-28 | 2022-04-05 | 同光(昆山)生物科技有限公司 | Medical composite material and preparation method and application thereof |
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