CN115671400B - 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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- CN115671400B CN115671400B CN202211328196.8A CN202211328196A CN115671400B CN 115671400 B CN115671400 B CN 115671400B CN 202211328196 A CN202211328196 A CN 202211328196A CN 115671400 B CN115671400 B CN 115671400B
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- degradable
- absorbable
- degradable composite
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- 239000002131 composite material Substances 0.000 title claims abstract description 237
- 239000007943 implant Substances 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000002513 implantation Methods 0.000 title abstract description 7
- 239000000835 fiber Substances 0.000 claims abstract description 101
- 229910052751 metal Inorganic materials 0.000 claims abstract description 67
- 239000002184 metal Substances 0.000 claims abstract description 66
- 239000011159 matrix material Substances 0.000 claims abstract description 58
- 229920000642 polymer Polymers 0.000 claims abstract description 48
- 238000002844 melting Methods 0.000 claims abstract description 13
- 230000008018 melting Effects 0.000 claims abstract description 13
- 230000003014 reinforcing effect Effects 0.000 claims abstract description 12
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 39
- 229910052749 magnesium Inorganic materials 0.000 claims description 31
- 239000011777 magnesium Substances 0.000 claims description 31
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 24
- 229920001577 copolymer Polymers 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- 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
- 239000000203 mixture Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 12
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical class O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000919 ceramic Substances 0.000 claims description 10
- 239000004626 polylactic acid Substances 0.000 claims description 10
- 229910052742 iron Inorganic materials 0.000 claims description 9
- 239000000155 melt Substances 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 9
- 229920001610 polycaprolactone Chemical class 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 230000002787 reinforcement Effects 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000004632 polycaprolactone Chemical class 0.000 claims description 7
- 238000010008 shearing Methods 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 229920000331 Polyhydroxybutyrate Polymers 0.000 claims description 6
- 229910045601 alloy Inorganic materials 0.000 claims description 6
- 239000000956 alloy Substances 0.000 claims description 6
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- 239000005015 poly(hydroxybutyrate) Substances 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
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- 229910052727 yttrium Inorganic materials 0.000 claims description 3
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- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 2
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical class O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 229920001651 Cyanoacrylate Polymers 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920002732 Polyanhydride Polymers 0.000 claims description 2
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- 229910052712 strontium Inorganic materials 0.000 claims description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims 1
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
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- 239000000395 magnesium oxide Substances 0.000 description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 4
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
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- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
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- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 2
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- HECLRDQVFMWTQS-UHFFFAOYSA-N Dicyclopentadiene Chemical compound C1C2C3CC=CC3C1C=C2 HECLRDQVFMWTQS-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Materials For Medical Uses (AREA)
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% wt of metal wire, 15-60% wt of degradable composite fiber and 15-60% wt of degradable composite matrix; the metal wires are arranged in parallel in the degradable composite matrix, the degradable composite fibers are dispersed in parallel in the degradable composite matrix 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, good mechanical property in the later degradation period, controllable degradation and uniform degradation speed; the polymer chain segment diastole and ordered arrangement and orientation composite reinforcing phase provides binding points for interaction with human tissues, promotes adhesion of tissues and implantation, and promotes cell proliferation and growth.
Description
Technical Field
The invention belongs to the technical field of medical implants, and relates to a composite absorbable implant, a preparation method and application thereof.
Background
Currently, medical implants are widely used in human tissue repair, and these implant products have a high degree of tissue compatibility in the human body. Often these implants are implanted in the human body for therapeutic purposes, but are not degradable in the human body and need to be removed by a further surgery. Therefore, even if a material having high biocompatibility is implanted in the human body for a long period of time, rejection reaction may occur.
In order to solve a series of problems caused by non-degradable materials after surgery, one approach is to develop implants that are degradable in vivo. The degradable implant interacts with physiological processes or tissues of the medium in the body, resulting in progressive degradation of the implant material. These materials decrease over time in the body and the implant eventually degrades and the degradation products are absorbed by the body without the need for secondary surgery. However, the mechanical properties of the artificially synthesized or natural absorbable polymer are insufficient, the high mechanical strength cannot be born, the degradable polymer represented by the high mechanical property of the levorotatory polylactic acid has high brittleness, the impact resistance is poor, and the brittleness of the material is further increased after the activity of the inorganic biological material is enhanced; degradable polymers, represented by polycaprolactone, which are superior in softness, have low tensile strength and low elastic modulus, while implants must meet specific requirements of elastic modulus, toughness and plasticity. Unfortunately, most polymers cause inflammation during the absorption process of degradable polymers, resulting in severe intimal hyperplasia or thrombotic occlusion.
Some researchers have attempted to develop a metallic alloy for absorbable bioerodible metals to overcome the shortcomings of degradable polymers. Corrodible metal alloys are selected from alkali metals, alkaline earth metals, iron, zinc and aluminum, while metals or alloys of magnesium, iron, zinc are particularly suitable as implant materials, these metals being used in combination with manganese, cobalt, nickel, chromium, copper, cadmium, lead, tin, thorium, zirconium, silver, gold, palladium, platinum, silicon, calcium, lithium, aluminum for improving the metal properties. Although advances have been made in the field of bioerodible metal alloys, it is known that alloys have limited use in applications due to material properties such as strength and corrosion behavior. Compared with other metals, the magnesium alloy has relatively high biological corrosion speed, uneven relative corrosion, higher corrosion speed towards the later stage and relatively low strength.
US20040098108A1 discloses a metal implant which, after having completed a temporary support function, degrades at a suitable rate so as to avoid the negative effects of long-term implantation. The main components of the material are self-alkali metals, alkaline earth metals comprise 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 taken as auxiliary components.
US20080103594 discloses an absorbable medical implant composite material, 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 magnesium base, firstly, adopting micro-arc oxidation technology to prepare porous magnesium oxide coating containing phosphorus and calcium on the surface of magnesium or magnesium alloy, then using spin-coating deposition method to spin-coat a layer of F-msns@plla coating on the porous magnesium oxide coating containing phosphorus and calcium, finally using dipping deposition method to obtain DCPD coating with high osseointegration effect on the surface. According to the invention, a layer of magnesium oxide and F-MSNs@PLLA are coated on the surface of the magnesium material in sequence to form the dicalcium phosphate layer for slowing down the early-stage excessively rapid degradation of magnesium.
CN105377318A discloses a bioabsorbable biomedical implant. The implant includes a tubular stent comprising a plurality of interconnected polymeric struts. The interconnected polymeric 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 implants, including methods for making fiber-reinforced polymer composites for tubular stents.
However, the absorbable polymer in the prior art has poor mechanical properties, some degradation products are slightly acidic, the metal degradation is too fast, the degradation is not uniform, the degradation products are alkaline, the solubility is poor, the metal degradation speed is low and fast, and the supporting effect in the early stage and the middle stage cannot be met; the local acidity of some polyester-based polymer degradation and the local basicity of metal degradation products can lead to tissue damage. Currently, ceramic reinforced composites, especially anisotropic ceramic and polymer composites, are disordered in the arrangement of the anisotropic ceramic, the polymer segments are entangled, unable to stretch, and the properties of the absorbable implanted surface are very important, they affect subsequent interactions between the material and tissues 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 that has relatively stable mechanical properties during repair, controllable metal degradation, uniform degradation rate, and can interact with tissue microenvironment, and promote better proliferation and growth of cells, and a method for preparing the same, and uses 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, the mechanical property in the implanted human body is relatively stable in the repairing process, the mechanical property still has good mechanical property in the later degradation period, the metal degradation is controllable and the degradation speed is uniform, can interact with the tissue microenvironment, promote better proliferation of cells, facilitate cell adhesion and reduce inflammatory reaction of the cells.
One of the purposes of the present invention is to provide a composite absorbable implant, which adopts the following technical scheme:
a composite absorbable implant comprising wire, degradable composite reinforcing fibers and degradable composite matrix, comprising, in mass percent, 10% to 70% of wire, 15% to 60% of degradable composite fibers and 15% to 60% of degradable composite matrix, the sum of the mass percentages of the above components being 100%;
the metal wires are arranged in parallel in the degradable composite matrix, 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.
In the invention, the composite absorbable implant comprises a metal wire, degradable composite fibers and a degradable composite matrix, wherein the melting temperature of a polymer in the degradable composite fibers is higher than that of the degradable composite matrix, so that the composite absorbable implant has unique performance, the metal wire provides higher strength and modulus, and the metal wire provides higher strength and modulus for fixing an implantation part; as the subsequent degradation of the composite absorbable implant proceeds, the strength and modulus of the wire gradually decrease, the degradable composite fibers in the implant maintain the strength and modulus of the implant, providing strong mechanical strength for later healing in the implantation site, and the melting temperature of the degradable composite fibers is higher than the melting temperature of the degradable composite matrix, so that the degradable composite material does not soften or melt in shear fluid in the degradable polymer matrix, maintaining a solid shape; meanwhile, the metal wires are arranged in the degradable composite matrix for orientation or parallel arrangement, the degradable composite fibers are oriented in the degradable composite matrix, the orientation direction is parallel to the metal wires, and polymer chain segments in the degradable composite fibers are relaxed according to the same direction, so that the longitudinal mechanical strength and toughness of the material are greatly improved, and the synergistic improvement of the strength, plasticity and degradation performance of the composite material is realized; meanwhile, polymer chain segments arranged in a stretching orientation mode of the implant are optimized, so that the surface is more compact, and particularly the degradable composite fiber is provided, bonding points for interaction with human tissues are provided, adhesion between the tissues and the implant is promoted, and cell proliferation and growth are promoted.
Wherein 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 parallel to the stretching direction of the metal wire, and the reinforcing phases in the degradable composite fiber are arranged in parallel and are parallel to the processing stretching direction of the metal wire.
The degradable composite reinforcing fiber comprises an absorbable polymer and a composite reinforcing phase, wherein the absorbable polymer accounts for 40-90% of the mass of the degradable composite fiber, such as 40%, 50%, 60%, 70%, 80%, 90% and the like.
The segments of the absorbable polymer relax and are arranged in order along the stretching direction of the wire; the composite reinforcement phase is oriented in the wire shear direction.
The shape of the degradable composite fiber is anisotropic rod, strip or sheet.
The absorbable polymer comprises any one or a mixture of at least two of Polyglycolide (PGA), glycolide copolymer, polylactic acid (PLA), polylactic acid copolymer, polydipeptide, asymmetric 3, 6-substituted poly-1, 4-dioxane-2, 5-dione, polyhydroxyalkanoate, poly-p-dioxanone (PDS), poly-d-valerolactone, polycaprolactone, methyl methacrylate-N-vinylpyrrolidone copolymer, polyesteramide, oxalic acid polyester, polydihydropyran, polyalkyl-2-cyanoacrylate, polyurethane (PU), polyvinyl alcohol (PVA), polypeptide, poly-b-malic acid (PM-LA), poly-b-alkanoic acid, polycarbonate, polycarboxylate, polyphosphate, polyanhydride.
Preferably, the glycolide copolymer comprises a glycolide/L-lactide copolymer (PGA/PLLA) and/or a glycolide/trimethyl carbonate copolymer (PGA/TMC).
Preferably, the polylactic acid copolymer comprises any one 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, polylactic acid/polyethylene oxide copolymer.
Preferably, the polyhydroxyalkanoate comprises any one or a mixture of at least two of Polyhydroxybutyrate (PHB), polyhydroxybutyrate/b-hydroxyvalerate copolymer (PHB/PHV), poly-b-hydroxypropionic acid (PHPA).
In the present 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 reinforcement phase has a dimension of 20 nm-50 microns, for example 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 microns, 10 microns, 15 microns, 20 microns, 25 microns, 30 microns, 35 microns, 40 microns, 45 microns, 50 microns, etc.; further 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, and the metal fibers are parallel to each other, and comprise any one or a mixture of at least two of magnesium fibers, zinc fibers, or iron fibers.
Preferably, the metal particles comprise any one or a mixture of at least two of magnesium particles, iron particles, zinc particles.
Preferably, the metal oxide particles are any one or a mixture of at least two of magnesium oxide particles, iron oxide particles and zinc oxide particles.
Preferably, the absorbable ceramic comprises any one or a mixture of at least two of hydroxyapatite, calcium carbonate, bioactive glass and bioactive microcrystalline glass, and has an anisotropic rod-like, strip-like, sheet-like, wire-like or tubular shape with an aspect ratio of more than 6; if the absorbable ceramic is hydroxyapatite, it is preferably rod-or bar-shaped hydroxyapatite, and it is preferably low-crystalline hydroxyapatite prepared by hot water method, biological template method, sol-gel method without calcination.
The degradable composite fiber can be processed into a long rod-shaped or strip-shaped material by a processing method of micro-fluidic fluid shearing, and if the composite reinforcing phase fiber in the degradable composite material is a rod-shaped material, the processing method of conical or wedge-shaped micro-fluidic fluid shearing is preferred.
In the present invention, the degradable composite matrix comprises any one or a mixture of at least two of absorbable polymers, copolymers, polymer alloys. The degradable matrix may be complexed with collagen, bacterial cellulose, and other bioactive substances.
As a preferred embodiment of the present invention, the degradable composite fiber and the degradable matrix may incorporate an active agent.
In the invention, the melting temperature of the absorbable polymer in the degradable composite reinforced fiber is higher than the melting temperature 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 invention, the metal wire is selected from any one of magnesium, iron, zinc, calcium, strontium, zirconium and yttrium or an alloy of at least two metals. The wire may be a round wire, a strip wire, or the like.
Preferably, the diameter of the wire is 10-1000 μm, for example 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, etc.
Another object of the present invention is to provide a method for preparing a composite absorbable implant according to one of the objects, comprising the steps of: and (3) stretching the metal wire in a microfluidic channel containing the degradable composite fiber and the degradable composite matrix according to the proportion, and cooling and fixing in situ orientation to obtain the composite absorbable implant.
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 flowing of a micro-channel, cooling and solidifying in situ on a conveyor belt, and cutting into long rod-like, sheet-like, thread-like, strip-like and other shapes to obtain the degradable composite fiber; the long-rod-shaped, sheet-shaped, thread-shaped and strip-shaped degradable composite fibers and the degradable composite matrix are mixed by known mixing equipment such as an internal mixer, a double screw and the like and conveyed to the conical micro-channel. The melting temperature of the polymer in the degradable composite fiber is greater than the melting temperature of the degradable composite matrix.
The degradable composite fiber can effectively and rapidly stretch the polymer chain segments by utilizing the fluid shear force and promote the ordered arrangement of the polymer chain segments; at the same time, the anisotropic composite reinforcement phase is oriented in the shear direction (melt flow direction), the composite melt cools and the orientation is fixed.
The metal wires, 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 the polymer are preformed into a material (prepreg) by coating or using a solvent as an intermediate.
Preferably, the wire is one or more, is woven or knitted into a two-dimensional or three-dimensional structure, is pultruded, melt extruded, tapered or wedge shaped, and is shaped into the desired shape by machining.
Preferably, the method of preparing the composite absorbable implant comprises the steps of:
and (3) stretching one or more metal wires through a conical micro-channel, mixing the metal wires with the cooled degradable composite matrix and the degradable composite fibers on a conveyor belt, wherein the stretching rate of the metal wires is higher than the melt flow rate, and realizing the orientation of the degradable composite fibers and the degradable composite matrix to obtain the composite absorbable implant.
It is a further object of the present invention to provide the use of a composite absorbable implant as defined in one of the objects for the preparation of sutures, vascular stents, bone repair screws, bone defects, interbody fusion bioabsorbable materials and devices.
The composite absorbable implant of the present invention may be further mechanically and/or thermally treated into more complex implant forms to obtain screws, bone plates, nails, staples, suture anchors, bolts, clamps, wedges, blood vessels, vascular stents, etc., for use in different implant sites for treatment, 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 tensile strength of the composite absorbable implant prepared by the invention is 158-213MPa, the elongation at break is 26.0-38.9%, the bending strength is 392-441MPa, and the bending modulus is 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 of FIG. 1;
the reference numerals are as follows:
1-a metal wire; 2-degradable composite fibers; 21-an absorbable polymer; 22-composite reinforcement phase; 3-degradable composite matrix.
Detailed Description
The technical scheme of the invention is further described below by means of specific embodiments with reference to the accompanying drawings 1-3.
The various starting materials of the present invention are commercially available, or may be prepared according to methods conventional in the art, unless specifically indicated.
In the examples and comparative examples of the present invention, the raw material sources were as follows: polylactic acid PLLA is PURASRB PL65 from CORBION of Netherlands; polycaprolactone PCL was from PURASRB PC17; the metal wire is prepared into a metal magnesium wire with the diameter of 30-50 mu m according to the WO2011/125887 patent; the bioactive low-crystallization nano-hydroxyapatite has a diameter of 20 nanometers and a 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 distributed in the degradable composite matrix 3, the degradable composite fibers 2 are dispersed in the degradable composite matrix 3 and are distributed 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 comprises 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 wire 1, as shown in fig. 2.
As another preferred embodiment of the present invention, the degradable composite fiber 2 comprises a particulate composite reinforcing phase 22 and an absorbable polymer 21, the composite reinforcing phase 22 being dispersed in the absorbable polymer 21 and arranged parallel to the wire 1, as shown in fig. 3.
Example 1
The composite absorbable implant of this example was prepared by the following method:
and (3) preparing degradable composite fibers: and adding the polylactic acid PLLA and the low-crystallization nano-hydroxyapatite into a chloroform solution according to the mass ratio of 80/20, mixing, and removing the solvent. And (3) injecting the melt into a microfluidic device for shearing the melt, performing wire drawing processing, wherein the diameter of a microfluidic channel is 10 micrometers, the length of the microfluidic channel is 1 meter, cooling and granulating. Cut into a rod-shaped material with the diameter of 10 micrometers and the length of 2 millimeters to obtain the degradable composite fiber.
Adding the degradable composite fiber and polycaprolactone PCL into a double-screw extruder for melt mixing, wherein the highest temperature zone of the screw is lower than 130 ℃, mixing uniformly, injecting the melt into a 10-hole conical microfluidic device, wherein the diameter of a channel of the microfluidic device is 200 micrometers, the length of the channel is 1m, and the melt temperature of the microfluidic channel is 120 ℃. The metal magnesium wires with the diameter of 30 micrometers are stretched from the microfluidic channel in parallel and equidistantly, and the pulling speed is 20.0mm/min. 30% of magnesium metal wires, 30% of degradable composite fibers, 40% of degradable composite matrix, and cooling and in-situ solidification to obtain the composite absorbable implant with the diameter of 2 mm.
Example 2
This example differs from example 1 in that the magnesium metal wire is 40%, the degradable composite fiber is 30% and the degradable composite matrix is 30%.
Example 3
This example differs 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
This example differs from example 1 in that the magnesium metal wire is 60%, the degradable composite fiber is 25% and the degradable composite matrix is 15%.
Example 5
This example differs from example 1 in that the metal magnesium wire is 70%, the degradable composite fiber is 15% and the degradable composite matrix is 15%.
Example 6
This example differs from example 1 in that the magnesium metal wire is 30%, the degradable composite fiber is 50% and the degradable composite matrix is 20%.
Example 7
This example differs from example 1 in that the PLLA and the low-crystalline nano-hydroxyapatite in the degradable composite fiber are mixed in a mass ratio of 50/50.
Example 8
This example differs from example 1 in that the mass ratio of PLLA to low-crystalline nano-hydroxyapatite in the degradable composite fiber is 40/60.
Example 9
And (3) preparing degradable composite fibers: magnesium filaments with the diameter of 30 micrometers are processed into 1-2 micrometer superfine magnesium filaments by 0.1mol/L dilute hydrochloric acid solution, and cut into 1 millimeter short superfine magnesium filaments. And uniformly mixing and dispersing the PLLA with the prepared superfine magnesium fiber and chloroform according to the mass ratio of 80:20:200, and removing the chloroform. And (3) injecting the melt into a microfluidic device for shearing the melt, performing wire drawing processing, wherein the diameter of a microfluidic channel is 4 microns, the length of the microfluidic channel is 0.5 meter, cooling, and cutting into a rodlike degradable composite fiber with the diameter of 4 microns and the length of 2 mm.
This example differs from example 1 in that the degradable composite fiber of example 1 is replaced with the degradable composite fiber described above.
Example 10
This example differs from example 1 in that each wire is equally spaced parallel from the microfluidic device at a draw speed of 60.0 mm/min.
Example 11
This example differs from example 1 in that the diameter of the metal magnesium wire is 50 microns, and the other is the same as example 1.
Comparative example 1
The comparative example does not contain metal magnesium wires, 60% of degradable composite fibers and 40% of degradable composite matrix are added into a mold, the above composite materials are added, the mold is heated to 120 ℃, the temperature is kept for 5 minutes by 5MP pressure, the pressure is raised to 10MPa, the temperature is kept for 2 minutes, and the mold is cooled.
Comparative example 2
The implant of this comparative example was prepared by the following method:
adding PLLA and low-crystallization nano-hydroxyapatite into a double-screw extruder according to the mass part ratio of 80/20 for melt mixing, spinning and granulating to prepare the degradable composite fiber with the diameter of 10 micrometers and the length of 2mm, wherein the hydroxyapatite of the degradable composite fiber is randomly arranged and is unoriented.
The degradable composite fiber, polycaprolactone and 30-micrometer magnesium wires are distributed in parallel at equal intervals and placed into a die, the metal wires are 30%, the degradable composite fiber is 30%, and the degradable composite matrix is 40%. The mold was heated to 120℃and held at 5MP for 5 minutes, the pressure was raised to 10MPa and held for 2 minutes, and the mold was cooled.
Comparative example 3
Adding PLLA and low-crystallization nano-hydroxyapatite into a double-screw extruder according to the mass part ratio of 80/20 for melt mixing, spinning and granulating to prepare the degradable composite fiber with the diameter of 10 micrometers and the length of 2mm, wherein the hydroxyapatite of the degradable composite fiber is randomly arranged and is unoriented.
This comparative example differs from example 1 in that the degradable composite fiber of example 1 was replaced with a non-oriented degradable composite fiber of the above-described hydroxyapatite.
Comparative example 4
The degradable composite fiber, polycaprolactone and 30-micrometer magnesium wires in example 1 are equidistantly and parallelly arranged and placed into a die, the metal wires are 30%, the degradable composite fiber is 30% and the degradable composite matrix is 40%. The mold was heated to 120℃and held at 5MP for 5 minutes, the pressure was raised to 10MPa and held for 2 minutes, and the mold was cooled. The degradable composite fibers of this comparative example were unoriented in the implant.
Comparative example 5
This comparative example differs from example 1 in that the metal magnesium wire is 5%, the degradable composite fiber is 65% and the degradable composite matrix is 30%.
Comparative example 6
This comparative example differs from example 1 in that the magnesium metal wire is 75%, the degradable composite fiber is 20%, and the degradable composite matrix is 5%.
Comparative example 7
This comparative example differs 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 with a diameter of 2 mm.
(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, tensile strength and elongation at break are measured with reference to ASTM D3039M, flexural strength and flexural modulus are measured with reference to ASTM D790-17, and degradation time is measured as follows: the mechanical strength was tested and hydrogen was collected using a 0.1mol/L, pH TRI-HCl buffer solution of 7.4.+ -. 0.2, and the percentage of the total amount of actual hydrogen evolution was calculated as shown in Table 3.
TABLE 1
| Sequence 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 metal magnesium wire was completely degraded within 6 months and could not be tested.
As can be seen from Table 1, the inventive implants significantly improved the tensile strength, elongation at break, flexural strength and flexural modulus of the composite materials using the preparation methods for examples 1-11 and comparative examples 1-8. In the degradation liquid after 6 months, the mechanical property of the implant is still maintained to be more than 70 percent.
As can be seen from the data of examples 1-5, changing the ratio of magnesium metal increases the tensile strength, flexural modulus.
Example 6 increasing the amount of degradable composite fibers will result in a significant increase in flexural strength, flexural modulus.
Examples 7-8 the increase in nano-hydroxyapatite in the degradable composite fiber resulted in improved flexural strength and flexural modulus.
Example 9 tensile strength and flexural strength were improved after substituting hydroxyapatite in the degradable composite fiber with short ultrafine magnesium filaments.
Example 10 changes the drawing speed, magnesium filament drawing speed, favoring polymer and hydroxyapatite orientation, and improves the tensile strength and bending strength.
Compared with the single organic polymer and ceramic composite material, the metal magnesium wire composite material has the advantages that the metal wires are not added in the comparative example 1, the metal magnesium wire composite material is added, the mechanical property tensile strength, the bending strength and the bending modulus of the implant are greatly improved, and the requirement of the implanted medical instrument on the mechanical property is met.
Comparative examples 2 to 4 show that the elongation at break, flexural strength and flexural modulus of the composite implant are significantly improved, regardless of the orientation of the degradable composite fibers or the nano-hydroxyapatite.
Comparative examples 5-8 show that the metal magnesium wires have a low content and low mechanical properties for implantation, and cannot provide high mechanical properties; too high metallic magnesium and too low degradable composite fibers result in faster degradation of the implant in vivo.
(2) Cell Activity test
The composite absorbable implants prepared in examples 1 to 11 and comparative examples 1 to 8 were subjected to cell activity test, and the test results are shown in table 3.
The test method is as follows: mesenchymal stem cells extracted from corneal epithelial cells and rat leg bones were inoculated onto the surface of the implant of the present invention. Cell proliferation was measured 36 hours after inoculation using the CCK-8 kit.
TABLE 3 Table 3
As can be seen from the data of table 3, the polymer segments are relaxed and ordered and the nano hydroxyapatite is oriented to promote cell proliferation, and the polymer segments are relaxed and ordered and the hydroxyapatite is arranged unordered to inhibit 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 cell adhesion rate test, and the test results are shown in table 4.
The test method is as follows:
taking rat osteoblasts for culturing, adding 2.5g/L trypsin 5ml into the osteoblasts according to a 6-hole plate for culturing for 10 hours after culturing, digesting for 3-5min, centrifuging to remove supernatant, and counting by blowing. The adhesion rate per well of cells 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 Table 4
| Sequence 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 segment is relaxed and the ordered arrangement of polymer segments provides binding sites for cell adhesion to the human body, increasing the viscosity of the cells.
The invention increases the affinity between the cells or proteins and the surface of the implant through the surface improvement of the implant, reduces the inflammatory reaction between the implant and the cells or proteins, promotes the proliferation of 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 detailed process equipment and process flow of the present invention are described by the above embodiments, but the present invention is not limited to, i.e., it does not mean that the present invention must be practiced depending on the detailed process equipment and process flow. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.
Claims (22)
1. A composite absorbable implant comprising, in mass percent, 10 to 70% by weight of metal filaments, 15 to 60% by weight of degradable composite fibers and 15 to 60% by weight of degradable composite matrix, the sum of the mass percentages of the above components being 100%;
the metal wires are arranged in parallel in the degradable composite matrix, 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;
the degradable composite fiber comprises an absorbable polymer and a composite reinforcing phase;
the mass percentage of the absorbable polymer to the degradable composite fiber is 40-90%;
the segments of the absorbable polymer relax and are arranged in order along the stretching direction of the wire; the composite reinforcement phase is oriented in a wire shear direction;
the degradable composite matrix comprises an absorbable polymer and/or polymer alloy;
the absorbable polymer in the degradable composite fiber has a melting temperature that is greater than or equal to 15 ℃ greater than the melting temperature of the absorbable polymer in the degradable composite matrix.
2. The composite absorbable implant of claim 1, wherein the degradable composite fiber is in the shape of an anisotropic rod, bar, sheet, wire, or tube.
3. The composite absorbable implant of claim 1, wherein the absorbable polymer comprises any one or a mixture of at least two of polyglycolide, glycolide copolymers, polylactic acid copolymers, polydipeptides, unsymmetrical 3, 6-substituted poly-1, 4-dioxane-2, 5-dione, poly-p-dioxanone, poly-d-valerolactone, polycaprolactone, methyl methacrylate-N-vinylpyrrolidone copolymers, polyesteramides, oxalic acid polyesters, polydihydropyrans, polyalkyl-2-cyanoacrylates, polyurethanes, polyvinyl alcohol, polypeptides, poly-b-malic acid, poly-b-alkanoic acid, polycarbonates, polycarboxylates, polyphosphates, polyanhydrides.
4. A composite absorbable implant according to claim 3, wherein the glycolide copolymer comprises a glycolide/L-lactide copolymer and/or a glycolide/trimethyl carbonate copolymer.
5. The composite absorbable implant of claim 3, wherein the polylactic acid copolymer comprises any one or a mixture of at least two of 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, polylactic acid/polyethylene oxide copolymer.
6. The composite absorbable implant of claim 3, wherein the polyhydroxyalkanoate comprises any one or a mixture of at least two of polyhydroxybutyrate, polyhydroxybutyrate/b-hydroxyvalerate copolymer, and poly-b-hydroxypropionic acid.
7. The composite absorbable implant of claim 1, wherein the composite reinforcement phase comprises any one or a mixture of at least two of metal fibers, metal particles, metal oxide particles, absorbable ceramic, or bacterial cellulose.
8. The composite absorbable implant of claim 1, wherein the composite reinforcement phase has a dimension of 20 nanometers to 50 micrometers.
9. The composite absorbable implant of claim 8, wherein the composite reinforcement phase has a dimension of 50 nm-500 nm.
10. The composite absorbable implant of claim 7, wherein the metal fibers comprise any one or a mixture of at least two of magnesium, zinc, or iron fibers.
11. The composite absorbable implant of claim 7, wherein the absorbable ceramic comprises any one or a mixture of at least two of hydroxyapatite, calcium carbonate, bioactive glass-ceramic.
12. The composite absorbable implant of claim 7, wherein the absorbable ceramic is shaped as an anisotropic rod, bar, sheet, wire, or tube having an aspect ratio greater than 6.
13. The composite absorbable implant of claim 11, wherein the hydroxyapatite is a low crystalline hydroxyapatite.
14. The composite absorbable implant of claim 13, wherein the hydroxyapatite is a low crystalline hydroxyapatite prepared by hydrothermal reaction, gel-sol, bio-templating without calcination.
15. The composite absorbable implant of claim 1, wherein the polymer of the degradable composite matrix is in a wire stretch direction, and wherein the segments of the polymer are relaxed and ordered.
16. The composite absorbable implant of claim 1, wherein said metal wire is selected from any one or an alloy of at least two metals of magnesium, iron, zinc, calcium, strontium, zirconium, yttrium.
17. The composite absorbable implant of claim 1, wherein the wire has a diameter of 10-1000 μιη.
18. A method of preparing a composite absorbable implant as set forth in any one of claims 1-17 wherein the method comprises the steps of: and (3) stretching the metal wire in a microfluidic channel containing the degradable composite fiber and the degradable composite matrix according to the proportion, and cooling and fixing in situ orientation to obtain the composite absorbable implant.
19. The method of preparing the degradable composite fiber according to claim 18, wherein the method of preparing the degradable composite fiber comprises the steps of: and mixing the absorbable polymer and the composite reinforcing phase to form a composite material, shearing the melt of the composite material through flowing of a micro-channel, cooling and solidifying in situ on a conveyor belt, and cutting to obtain the degradable composite fiber.
20. The method of preparing a composite absorbable implant of claim 18, comprising the steps of:
and stretching one or more metal wires through a conical micro-fluidic channel containing a degradable composite matrix and degradable composite fibers, mixing the metal wires with the cooled degradable composite matrix and the degradable composite fibers on a conveyor belt, wherein the stretching rate of the metal wires is higher than the melt flow rate, and realizing the orientation of the degradable composite fibers and the degradable composite matrix to obtain the composite absorbable implant.
21. The method of claim 20, wherein the degradable composite matrix is in a molten state and the degradable composite fiber is in a solid state in the microfluidic channel.
22. Use of a composite absorbable implant as set forth in any one of claims 1-17 for the preparation of sutures, vascular stents, bone repair screws, bone defects or interbody fusion bioabsorbable materials and devices.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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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| WO2006002366A2 (en) * | 2004-06-24 | 2006-01-05 | Surmodics, Inc. | Biodegradable ocular devices, methods and systems |
| EP2243749B1 (en) * | 2009-04-23 | 2015-04-08 | PURAC Biochem BV | Resorbable and biocompatible fibre glass compositions and their uses |
| AU2018392252A1 (en) * | 2017-12-20 | 2020-06-11 | Ossio Ltd. | Fiber bundle reinforced biocomposite medical implants |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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