Implants containing biodegradable polymers, methods for manufacturing the same, and compositions therefor

Abstract

The present invention provides an implant comprising a first biodegradable polymer and a second biodegradable polymer, wherein the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), and the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

Description

Technical Field

[0001] The present disclosure relates to an implant containing a biodegradable polymer and a method for manufacturing the same. More specifically, the present disclosure relates to a shaping implant containing a biodegradable polymer, which is excellent in osteoblast differentiation and osteoconductivity, and a method for manufacturing the same.

Background Art

[0002] Biodegradable polymers are materials that have attracted attention in various fields such as medicine, agriculture, and the environment due to their unique degradation characteristics. In particular, in the medical field, unlike non-degradable polymers such as metals and ceramics, they have the advantage of being decomposed by in vivo metabolism after their function is completed and assisting in vivo healing, eliminating the need for removal surgery after healing.

[0003] Such biodegradable polymers are broadly classified into natural biodegradable polymers and synthetic biodegradable polymers. Since natural biodegradable polymers are made from natural materials, they are excellent in biocompatibility and biocompatibility and have relatively few immune responses in the body. However, since their physical strength and durability are weaker than those of synthetic biodegradable polymers, it is necessary to select an appropriate material according to the application.

[0004] Currently, polyglycolide (PGA), polylactic acid (PLLA), and polycaprolactone (PCL) are used as the main materials for absorbable implants, and synthetic biodegradable polymers are the most widely used. Generally, the most commonly used PLLA has high strength but is weak against impact, so there are many materials copolymerized with PGA or PCL (PLGA or PLCL). For example, Korean Patent Laid-Open Publication No. 2022-0047788 discloses an implant made of a biodegradable composite material composed of PLLA, PGA, PCL, or a copolymer thereof.

[0005] Polyhydroxyalkanoates (PHAs) are naturally biodegradable polymers produced within microorganisms, which decompose in the human body and are considered non-toxic. Due to these advantages, they can be applied to various medical materials such as fracture treatment, cardiovascular materials, artificial joints, and surgical instruments. PHAs come in various forms, including PHB, P3HB, P4HB, PHV, and PHH. Each type has different properties, so the appropriate type should be selected according to the application, or copolymers such as P(3HB-4HB) may be prepared and used.

[0006] The development of absorbable implants for fracture treatment containing such bio-derived polymers is expected to play a crucial role in improving the quality of fracture treatment, shortening patient recovery times, and reducing the burden during rehabilitation. Furthermore, it is expected to contribute to reducing medical costs related to fracture treatment, which is a growing concern in an aging society. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Korean Patent Publication No. 2022-0047788 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The purpose of this disclosure is to provide implants containing biodegradable polymers, possessing strength and stability suitable for orthopedic surgery, and exhibiting excellent osteoblast differentiation and bone fusion properties, as well as methods for manufacturing the same and compositions for the same. [Means for solving the problem]

[0009] The present disclosure provides an implant comprising a first biodegradable polymer and a second biodegradable polymer, wherein the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), and the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0010] In one embodiment, the implant may include a blend of a first biodegradable polymer and a second biodegradable polymer.

[0011] In another embodiment, the implant comprises a core and a covering, the covering comprising a first biodegradable polymer and the core comprising a second biodegradable polymer.

[0012] In another embodiment, the implant comprises a core and a covering, the covering and the core each comprising a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in the covering relative to the total weight of the blend in the covering may be greater than the content of the first biodegradable polymer in the core relative to the total weight of the blend in the core.

[0013] In another embodiment, the implant includes at least one intermediate portion positioned between a core and a covering portion, the at least one intermediate portion comprising a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in the covering portion relative to the total weight of the blend in the covering portion is greater than the content of the first biodegradable polymer in the intermediate portion relative to the total weight of the blend in the intermediate portion, and the content of the first biodegradable polymer in the intermediate portion relative to the total weight of the blend in the intermediate portion is greater than the content of the first biodegradable polymer in the core portion relative to the total weight of the blend in the core portion.

[0014] In another embodiment, the implant may have a porous structure with pores having a size of 10 nm to 10 μm.

[0015] In another embodiment, the copolymerized polyhydroxyalkanoic acid (PHA) may further contain repeating units derived from at least one monomer selected from the group consisting of 2-hydroxybutyric acid (2-HB), 3-hydroxybutyric acid (3-HB), 3-hydroxypropionic acid (3-HP), 3-hydroxyvaleric acid (3-HV), 3-hydroxyhexanoic acid (3-HH), 3-hydroxyheptanoic acid (3-HHep), 3-hydroxyoctanoic acid (3-HO), 3-hydroxynonanoic acid (3-HN), 3-hydroxydecanoic acid (3-HD), 3-hydroxydodecanoic acid (3-HDd), 4-hydroxyvaleric acid (4-HV), 5-hydroxyvaleric acid (5-HV), and 6-hydroxyhexanoic acid (6-HH).

[0016] In another embodiment, the first biodegradable polymer may further comprise at least one polymer selected from the group consisting of poly(3-hydroxybutyric acid) (P3HB), poly(4-hydroxybutyric acid) (P4HB), poly(3-hydroxyhexanoic acid) (P3HH), poly(3-hydroxybutyric acid-co-3-hydroxyhexanoic acid) (P3HB-3HH), poly(3-hydroxyoctanoic acid) (P3HO), and poly(3-hydroxybutyric acid-co-3-hydroxyoctanoic acid) (P3HB-3HO).

[0017] In another embodiment, the second biodegradable polymer is a mixture of one or more synthetic biodegradable polymers and natural biodegradable polymers, excluding polyhydroxyalkanoic acid (PHA), wherein the synthetic biodegradable polymer may include polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic acid-co-caprolactone) (PLCL), poly(lactic acid-co-glycolic acid) (PLGA), polybutylene succinate (PBS), or poly(butylene adipate-co-terephthalate) (PBAT), and the natural biodegradable polymer may include starch, silk fibroin, chitosan, chitin, cellulose, collagen, or gelatin.

[0018] In another embodiment, copolymerized polyhydroxyalkanoic acid (PHA) may be present in an amount of 10% to 50% by weight relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0019] In another embodiment, the implant may further include at least one additive selected from bioactive glass fibers and ceramics.

[0020] In another embodiment, the implant further comprises at least one agent for promoting bone regeneration, the agent may be applied to the surface of the implant, blended with a first biodegradable polymer and a second biodegradable polymer, or included in a concentration gradient from the surface to the interior of the implant.

[0021] In another embodiment, the implant may have a tensile strength of 40 MPa to 70 MPa and an elongation of 3.2% to 10%, as measured using a test specimen with a diameter of 1.5 mm and a length of 50 mm.

[0022] In another embodiment, the implant may have a surface roughness of 1 μm to 10 μm in depth, or a grid pattern, wave pattern, or stripe pattern with spacing of 1 μm to 10 μm.

[0023] In another embodiment, in the cytotoxicity test using the eluate, the implant may exhibit a cell viability of 70% or more with respect to 100% of the cell viability of the elution solvent control group.

[0024] In another embodiment, when the implant is implanted into the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected two months after implantation can be 120 N / mm or more.

[0025] The present disclosure also includes preparing a biodegradable polymer including a first biodegradable polymer and a second biodegradable polymer, and molding an implant using the biodegradable polymer. The first biodegradable polymer includes a copolymerized polyhydroxyalkanoate (PHA), and the copolymerized polyhydroxyalkanoate (PHA) includes a repeating unit derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight based on the total weight of the copolymerized polyhydroxyalkanoate (PHA). A method for manufacturing an implant is provided.

[0026] In one embodiment, the molding may be injection molding or 3D printing molding.

[0027] In another embodiment, the injection molding may be performed under the conditions of an extrusion temperature of 100 to 210 °C, an injection temperature of 150 to 200 °C, and an annealing temperature of 80 to 110 °C.

[0028] In another embodiment, the 3D printing molding may be performed under the conditions of a printing temperature of 150 °C to 200 °C, an injection rate of 200 mm / min to 400 mm / min, a pressure of 200 kPa to 400 kPa, and a printing duration of 60 minutes or less.

[0029] In another embodiment, the method may further include at least one surface treatment step of imparting roughness or a pattern to the surface by blasting, molding, or laser treatment, or imparting hydrophilicity to the surface by plasma treatment, after the molding.

[0030] Furthermore, this disclosure provides an implant composition comprising a first biodegradable polymer and a second biodegradable polymer, wherein the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), and the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA). [Effects of the Invention]

[0031] The implant of this disclosure comprises a first biodegradable polymer containing copolymerized polyhydroxyalkanoic acid (PHA) and a second biodegradable polymer, thereby exhibiting appropriate strength and stability for orthopedic implants, such as pins, screws, and fixation plates, and also exhibiting excellent ossogenesis and osseointegration. [Brief explanation of the drawing]

[0032] [Figure 1a] An implant (11) according to an embodiment is shown. [Figure 1b] Another embodiment of the implant (12) (100: core portion, 300: covering portion) is shown. [Figure 1c] An implant (13) (100: core, 200: middle, 300: covering) according to another embodiment is shown. [Figure 2] This diagram schematically shows the surface roughness of the implant. [Figure 3] The results of the tensile test on the implant are shown. [Figure 4] The results of the cytotoxicity test on the implant are shown. [Figure 5] The results of the WST-1 analysis of the implant are shown. [Figure 6] The results of the osteoblast differentiation induction test for implants are shown. [Figure 7] This outlines the rat femoral fracture test. [Figure 8] The histological analysis results of the rat femoral fracture test are shown. [Figure 9] Micro-CT 2D and 3D images of rat femoral fracture tests are shown. [Figure 10a] The results of the radiographic analysis of rat femur samples taken after two months are shown. [Figure 10b] The results of the radiographic analysis of rat femur samples taken after two months are shown. [Figure 11a] The results of radiographic analysis of rat femur samples taken at 4 months of age are shown. [Figure 11b] The results of radiographic analysis of rat femur samples taken at 4 months of age are shown. [Figure 12a] The results of the biomechanical analysis of rat femoral fracture tests are shown. [Figure 12b] The results of the biomechanical analysis of rat femoral fracture tests are shown. [Modes for carrying out the invention]

[0033] The present disclosure will be described in detail below with reference to the drawings of embodiments. The embodiments are not limited to those described below. Rather, the embodiments can be modified in various ways without departing from the spirit of the invention.

[0034] In this specification, the term “equipped with” is used to explicitly identify specific characteristics, areas, processes, treatments, elements, and / or components. Unless explicitly stated otherwise, this does not preclude the presence or addition of other characteristics, areas, processes, treatments, components, elements, and / or components.

[0035] In this specification, terms such as "1," "2," etc., are used to describe various components. However, these components should not be bound by these terms. These terms are used to distinguish one element from another.

[0036] In the numerical ranges that limit the size and physical properties of the components described herein, if numerical ranges limited only by an upper limit and numerical ranges limited only by a lower limit are given as separate examples, it is sufficient to understand within the scope of the examples that numerical ranges consisting of both the upper and lower limits are also included.

[0037] Biodegradable polymers The implants of this disclosure include biodegradable polymers. For example, they may include bio-derived polymers.

[0038] Specifically, the implant may contain two or more biodegradable polymers.

[0039] In one embodiment, the implant comprises a first biodegradable polymer and a second biodegradable polymer.

[0040] In another embodiment, the implant may include a blend of a first biodegradable polymer and a second biodegradable polymer.

[0041] The first biodegradable polymer and the second biodegradable polymer may be different polymers from each other.

[0042] The first biodegradable polymer and the second biodegradable polymer may each contain one or more types of biodegradable polymers.

[0043] In one embodiment, the first biodegradable polymer may be polyhydroxyalkanoic acid (PHA).

[0044] Polyhydroxyalkanoates (PHAs) possess similar physical properties to conventional petroleum-derived synthetic polymers such as polybutylene adipate terephthalate (PBAT), polybutylene succinate (PBS), polybutylene succinate terephthalate (PBST), and polybutylene succinate adipate (PBSA), exhibiting complete biodegradability and excellent biocompatibility.

[0045] PHA, specifically, is a natural polyester polymer that accumulates within microbial cells. Ultimately, it decomposes into carbon dioxide, water, and organic matter. In particular, because PHA can be broken down within the body, implants manufactured using biodegradable polymer compositions containing PHA can be used in the medical field as absorbable medical devices.

[0046] PHA may be formed in vivo by the enzymatic polymerization of one or more monomer repeating units.

[0047] In one embodiment, the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA).

[0048] For example, the first biodegradable polymer may contain one, two, or more copolymerized polyhydroxyalkanoates (PHAs).

[0049] Copolymerized polyhydroxyalkanoic acid (PHA) may include copolymers containing two or more different repeating units, and in which the different repeating units are randomly distributed.

[0050] In one embodiment, the copolymerized polyhydroxyalkanoic acid (PHA) may contain repeating units derived from 4-hydroxybutyric acid (4-HB).

[0051] In this disclosure, it is important to adjust the content of 4-HB repeating units in copolymerized PHA. In other words, in order to achieve the desired physical properties in this disclosure, and especially to enhance biodegradability in vivo and achieve excellent physical properties, the content of 4-HB repeating units in copolymerized PHA may be important.

[0052] The content of repeating units derived from 4-HB (4-hydroxybutyric acid) may be 0.1% or more by weight, 5% or more by weight, 10% or more by weight, 12% or more by weight, 13% or more by weight, 15% or more by weight, 17% or more by weight, 18% or more by weight, 20% or more by weight, or 25% or more by weight, 50% or less by weight, 45% or less by weight, 43% or less by weight, 42% or less by weight, 40% or less by weight, or 35% or less by weight, based on the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0053] For example, the content of repeating units derived from 4-hydroxybutyric acid (4-HB) may be, but is not limited to, 0.1% to 50% by weight, 1% to 50% by weight, 2% to 50% by weight, 3% to 50% by weight, 5% to 50% by weight, 10% to 50% by weight, 1% to 40% by weight, 1% to 30% by weight, 1% to 29% by weight, 1% to 25% by weight, 1% to 24% by weight, 2% to 20% by weight, 2% to 23% by weight, 3% to 20% by weight, 3% to 15% by weight, 4% to 18% by weight, 5% to 15% by weight, 8% to 12% by weight, 9% to 12% by weight, 15% to 50% by weight, 20% to 50% by weight, or 25% to 50% by weight, relative to the total weight of copolymerized polyhydroxyalkanoic acid (PHA).

[0054] In one embodiment, the copolymerized polyhydroxyalkanoic acid (PHA) may comprise repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0055] More specifically, the copolymerized polyhydroxyalkanoic acid (PHA) may contain repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 3% to 20% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0056] As described above, copolymerized PHA comprises one or more 4-HB repeating units, and the crystallinity of copolymerized PHA can be adjusted by controlling the content of the 4-HB repeating units. In other words, copolymerized PHA may be a polymer with controlled crystallinity.

[0057] Copolymerized PHAs with adjusted crystallinity may have their crystalline and amorphous properties adjusted as the disorder in the molecular structure increases. Specifically, this can be done by adjusting the type and proportion of monomers, or the type and / or content of isomers.

[0058] Furthermore, copolymerized polyhydroxyalkanoic acid (PHA) may further contain repeating units derived from at least one monomer selected from the group consisting of 2-hydroxybutyric acid (2-HB), 3-hydroxybutyric acid (3-HB), 3-hydroxypropionic acid (3-HP), 3-hydroxyvaleric acid (3-HV), 3-hydroxyhexanoic acid (3-HH), 3-hydroxyheptanoic acid (3-HHep), 3-hydroxyoctanoic acid (3-HO), 3-hydroxynonanoic acid (3-HN), 3-hydroxydecanoic acid (3-HD), 3-hydroxydodecanoic acid (3-HDd), 4-hydroxyvaleric acid (4-HV), 5-hydroxyvaleric acid (5-HV), and 6-hydroxyhexanoic acid (6-HH).

[0059] The copolymerized polyhydroxyalkanoic acid (PHA) may specifically contain at least one repeating unit selected from the group consisting of 3-hydroxybutyric acid (3-HB), 3-hydroxypropionic acid (3-HP), 3-hydroxyvaleric acid (3-HV), 3-hydroxyhexanoic acid (3-HH), 4-hydroxyvaleric acid (4-HV), 5-hydroxyvaleric acid (5-HV), and 6-hydroxyhexanoic acid (6-HH).

[0060] More specifically, the copolymerized PHA may be a copolymer containing repeating units derived from 3-HB and repeating units derived from 4-HB. For example, the copolymerized PHA may contain poly(3-hydroxybutyrate-co-4-hydroxybutyrate)(3HB-co-4HB).

[0061] For example, the content of repeating units derived from 3-HB may be 50% or more by weight, 55% or more by weight, 60% or more by weight, 64% or more by weight, 70% or more by weight, or 75% or more by weight, relative to the total weight of copolymerized PHA, and may be 99.9% or less by weight, 99% or less by weight, 95% or less by weight, 90% or less by weight, 85% or less by weight, 80% or less by weight, or 75% or less by weight.

[0062] Furthermore, copolymerized PHA may contain isomers. For example, copolymerized PHA may contain structural isomers, enantiomers, or geometric isomers. Specifically, PHA may contain structural isomers.

[0063] Copolymerized PHA may have glass transition temperatures (Tg) of, for example, -45°C to 80°C, -35°C to 80°C, -30°C to 80°C, -25°C to 75°C, -20°C to 70°C, -35°C to 5°C, -25°C to 5°C, -35°C to 0°C, -25°C to 0°C, -30°C to -10°C, -35°C to -15°C, -35°C to -20°C, -20°C to 0°C, -15°C to 0°C, or -15°C to -5°C.

[0064] The crystallization temperature (Tc) of copolymerized PHA may be, for example, unmeasurable, or it may be in the range of 70°C to 120°C, 75°C to 120°C, 75°C to 115°C, 75°C to 110°C, or 90°C to 110°C.

[0065] The melting temperature (Tm) of copolymerized PHA may be, for example, unmeasurable, or it may be in the range of 100°C to 170°C, 110°C to 150°C, or 120°C to 140°C.

[0066] The weight-average molecular weight (Mw) of copolymerized PHA can be, for example, 10,000 g / mol to 1,200,000 g / mol. The weight-average molecular weight of copolymerized PHA can be, for example, 50,000 g / mol to 1,200,000 g / mol, 100,000 g / mol to 1,200,000 g / mol, 50,000 g / mol to 1,000,000 g / mol, 100,000 g / mol to 1,000,000 g / mol, 100,000 g / mol to 900,000 g / mol, 200,000 g / mol. 00g / mol~1,200,000g / mol, 250,000g / mol~1,150,000g / mol, 300,000g / mol~1,100,000g / mol, 350,000g / mol~1,000,000g / mol, 350,000g / mol~950,000g / mol, 100,000g / mol~900,000g / mol, 200, 000g / mol to 800,000g / mol, 200,000g / mol to 700,000g / mol, 250,000g / mol to 650,000g / mol, 200,000g / mol to 400,000g / mol, 300,000g / mol to 800,000g / mol, 300,000g / mol to 600,000g / mol, 400,000g / mol It can be ~800,000 g / mol, 500,000 g / mol ~1,200,000 g / mol, 500,000 g / mol ~1,000,000 g / mol, 550,000 g / mol ~1,050,000 g / mol, 550,000 g / mol ~900,000 g / mol, or 600,000 g / mol ~900,000 g / mol.

[0067] In one embodiment, the copolymerized PHA can be crystalline or semi-crystalline PHA. For example, the crystalline or semi-crystalline PHA may contain 4-HB repeating units in an amount of, for example, 1% to 25% by weight relative to the total weight of the copolymerized PHA. Furthermore, the crystalline or semi-crystalline PHA may have, for example, a glass transition temperature (Tg) of -20 to 0°C, a crystallization temperature (Tc) of 75 to 115°C, and a melting temperature (Tm) of 110 to 160°C.

[0068] In another embodiment, the first biodegradable polymer may further comprise at least one polymer selected from the group consisting of poly(3-hydroxybutyric acid) (P3HB), poly(4-hydroxybutyric acid) (P4HB), poly(3-hydroxyhexanoic acid) (P3HH), poly(3-hydroxybutyric acid-co-3-hydroxyhexanoic acid) (P3HB-3HH), poly(3-hydroxyoctanoic acid) (P3HO), and poly(3-hydroxybutyric acid-co-3-hydroxyoctanoic acid) (P3HB-3HO).

[0069] In another embodiment, the first biodegradable polymer may further include, in addition to the above, at least one short-chain or intermediate-chain copolymerized polyhydroxyalkanoic acid (PHA).

[0070] The second biodegradable polymer is one or more selected from synthetic biodegradable polymers and naturally biodegradable polymers, excluding polyhydroxyalkanoic acid (PHA).

[0071] Examples of synthetic biodegradable polymers include polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic acid-co-caprolactone) (PLCL), poly(lactic acid-co-glycolic acid) (PLGA), polybutylene succinate (PBS), and poly(butylene adipate-co-terephthalate) (PBAT).

[0072] Examples of natural biodegradable polymers include starch, silk fibroin, chitosan, chitin, cellulose, collagen, and gelatin.

[0073] In one embodiment, the second biodegradable polymer may be polylactic acid (PLA).

[0074] For example, the second biodegradable polymer may contain one, two, or more types of polylactic acid (PLAs).

[0075] Specifically, the second biodegradable polymer may include poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-DL-lactic acid (PDLLA), or a blend thereof.

[0076] Polylactic acid (PLA) is prone to breakage due to its high strength and low flexibility. However, when mixed with copolymerized polyhydroxyalkanoic acid (PHA), flexibility is imparted. As a result, the stability, osteogenesis, and osteogenesis of implant surgery can be improved.

[0077] Additives and drugs In addition to the biodegradable polymer described above, the implant may further contain at least one additive and / or drug.

[0078] In one embodiment, the implant may further contain, but is not limited to, at least one additive selected from bioactive glass fibers and ceramics.

[0079] Examples of bioactive ceramics include hydroxyapatite (HAP), wollastonite, tricalcium phosphate (TCP), dicalcium phosphate dihydrate (DCPD), tetracalcium phosphate (TTCP), octacalcium phosphate (OCP), and amorphous calcium phosphate (ACP).

[0080] In another embodiment, the implant may further include at least one agent for promoting bone regeneration.

[0081] Examples of drugs include tricalcium phosphate (TCP), β-tricalcium phosphate (β-TCP), hydroxyapatite-tricalcium phosphate (HTCP), deoxyribonucleic acid triphosphates (dNTPs), bone morphogenetic proteins (BMPs), calcium (Ca), and magnesium (Mg).

[0082] In one embodiment, the drug may be coated onto the surface of the implant.

[0083] In another embodiment, the agent may be blended with a first biodegradable polymer and a second biodegradable polymer.

[0084] In another embodiment, the drug may be contained in a concentration gradient from the surface to the interior of the implant. For example, the concentration of the drug may be contained such that it gradually decreases from the surface to the interior. In this case, the amount of drug released may be high at first and gradually decrease.

[0085] Implant composition Figure 1a shows an implant according to an embodiment.

[0086] Referring to Figure 1a, the implant (11) may have a single-layer structure.

[0087] In one embodiment, the implant may include a blend of a first biodegradable polymer and a second biodegradable polymer.

[0088] The content of the first biodegradable polymer may be 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 3% by weight or more, 5% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, or 25% by weight or more, based on the total weight of the first biodegradable polymer and the second biodegradable polymer (i.e., the total weight of the blend), or it may be 50% by weight or less, 45% by weight or less, 40% by weight or less, 35% by weight or less, 30% by weight or less, or 25% by weight or less.

[0089] Specifically, the content of the first biodegradable polymer can be 0.1% to 50% by weight, 1% to 50% by weight, 5% to 50% by weight, 10% to 50% by weight, 15% to 50% by weight, 20% to 50% by weight, 25% to 50% by weight, 0.1% to 40% by weight, 5% to 40% by weight, 15% to 40% by weight, 25% to 40% by weight, 5% to 35% by weight, 15% to 35% by weight, or 25% to 35% by weight, relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0090] Furthermore, the content of the second biodegradable polymer may be 50% or more by weight, 55% or more by weight, 60% or more by weight, 64% or more by weight, 70% or more by weight, or 75% or more by weight, relative to the total weight of the first biodegradable polymer and the second biodegradable polymer, and may also be 99.9% or less by weight, 99% or less by weight, 95% or less by weight, 90% or less by weight, 85% or less by weight, 80% or less by weight, or 75% or less by weight, specifically between 50% and 90% by weight.

[0091] For example, the weight ratio of the first biodegradable polymer to the second biodegradable polymer may be 0.1:99.9~50:50, 1:99~50:50, 5:95~50:50, 5:95~40:60, 10:90~50:50, 15:85~40:60, 20:80~40:60, or 25:75~40:60.

[0092] In one embodiment, the implant may include a blend of a first biodegradable polymer containing copolymerized polyhydroxyalkanoic acid (PHA) and the second biodegradable polymer.

[0093] The content of copolymerized polyhydroxyalkanoic acid (PHA) may be 0.1% or more, 0.5% or more, 1% or more, 3% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 25% or more by weight, relative to the total weight of the first biodegradable polymer and the second biodegradable polymer, or it may be 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, or 25% or less by weight, relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0094] The content of copolymerized polyhydroxyalkanoic acid (PHA) can be 0.1% to 50% by weight, 1% to 50% by weight, 5% to 50% by weight, 10% to 50% by weight, 15% to 50% by weight, 20% to 50% by weight, 25% to 50% by weight, 0.1% to 40% by weight, 5% to 40% by weight, 15% to 40% by weight, 25% to 40% by weight, 5% to 35% by weight, 15% to 35% by weight, or 25% to 35% by weight, relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0095] For example, copolymerized polyhydroxyalkanoic acid (PHA) may be present in an amount of 10% to 50% by weight relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0096] In one embodiment, the first biodegradable polymer may be copolymerized polyhydroxyalkanoic acid (PHA), and the second biodegradable polymer may be polylactic acid (PLA).

[0097] For example, the weight ratio of copolymerized polyhydroxyalkanoic acid (PHA) to polylactic acid (PLA) may be 0.1:99.9~50:50, 1:99~50:50, 5:95~50:50, 5:95~40:60, 10:90~50:50, 15:85~40:60, 20:80~40:60, or 25:75~40:60.

[0098] Figure 1b shows an implant according to another embodiment.

[0099] Referring to Figure 1b, the implant (12) of another embodiment comprises a core portion (100) and a covering portion (300).

[0100] In one embodiment, the coating portion may contain a first biodegradable polymer, and the core portion may contain a second biodegradable polymer.

[0101] In another embodiment, the coating portion and the core portion each comprise a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in the coating portion relative to the total weight of the blend in the coating portion may be greater than the content of the first biodegradable polymer in the core portion relative to the total weight of the blend in the core portion.

[0102] In another embodiment, the core and the coating each comprise the first biodegradable polymer, the second biodegradable polymer, or a blend thereof, wherein the weight ratio of the first biodegradable polymer to the second biodegradable polymer contained in the coating is greater than the weight ratio of the first biodegradable polymer to the second biodegradable polymer contained in the core.

[0103] Furthermore, the size and thickness of the core and covering portion may vary depending on the proportion of the first biodegradable polymer and the second biodegradable polymer contained in the implant.

[0104] Figure 1c shows an implant according to another embodiment.

[0105] Referring to Figure 1c, the implant (13) according to another embodiment comprises a core portion (100), a covering portion (300), and at least one intermediate portion (200) interposed between them.

[0106] For example, the coating portion may have the highest content of the first biodegradable polymer, the core portion may have the highest content of the second biodegradable polymer, and at least one intermediate portion may have a configuration in which the content of the first biodegradable polymer increases as it approaches the coating portion, and the content of the second biodegradable polymer increases as it approaches the core portion.

[0107] In one embodiment, the coating portion may contain a first biodegradable polymer, and the core portion may contain a second biodegradable polymer.

[0108] In another embodiment, the coating portion and the core portion each comprise a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in the coating portion relative to the total weight of the blend in the coating portion may be greater than the content of the first biodegradable polymer in the core portion relative to the total weight of the blend in the core portion.

[0109] The implant includes at least one intermediate portion positioned between a core portion and a covering portion, the at least one intermediate portion comprising a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in the covering portion relative to the total weight of the blend in the covering portion is greater than the content of the first biodegradable polymer in the intermediate portion relative to the total weight of the blend in the intermediate portion, and the content of the first biodegradable polymer in the intermediate portion relative to the total weight of the blend in the intermediate portion is greater than the content of the first biodegradable polymer in the core portion relative to the total weight of the blend in the core portion.

[0110] In another embodiment, the core, intermediate, and coating portions may each contain a first biodegradable polymer, a second biodegradable polymer, or a blend thereof. The weight ratios described above allow the coating portion to have the highest weight ratio of the first biodegradable polymer to the second biodegradable polymer in each of the core, intermediate, and coating portions, and the core portion to have the lowest weight ratio.

[0111] In another embodiment, the implant includes at least two intermediate parts interposed between the core and the covering, each of which contains a blend of a first biodegradable polymer and a second biodegradable polymer, wherein the content of the first biodegradable polymer in each intermediate part relative to the total weight of the blend is higher as the intermediate part approaches the covering. Furthermore, the content of the second biodegradable polymer in the intermediate part relative to the total weight of the blend is higher as the intermediate part approaches the core.

[0112] For example, the coating portion may be composed of a first biodegradable polymer (e.g., PHA), and the mixing ratio of the second biodegradable polymer (e.g., PLA) may gradually increase towards the core. The difference in the content of the first or second biodegradable polymer in each intermediate portion may be, for example, 5% to 50% by weight.

[0113] Furthermore, the size and thickness of the core, intermediate, and covering portions may vary depending on the ratio of the first biodegradable polymer and the second biodegradable polymer contained in the implant.

[0114] The shape of the implant is not particularly limited. For example, it may be cylindrical (or pin-shaped), prismatic, or plate-shaped.

[0115] The implant may have a porous structure.

[0116] For example, an implant may have multiple holes.

[0117] Specifically, the implant may have a porous structure with pores ranging in size from 10 nm to 10 μm.

[0118] Furthermore, the implant may have a rough or patterned surface.

[0119] In one embodiment, the implant may have a certain degree of roughness on its surface.

[0120] In one embodiment, the implant may have a surface roughness of 1 μm to 10 μm in depth. More specifically, the implant may have fine irregularities on its surface with a depth of 1 μm to 10 μm and spacing of 1 μm to 10 μm.

[0121] In one embodiment, the implant may have small surface roughness on top of large surface roughness. More specifically, the implant may have first micro-irregularities with a depth of 1 μm to 10 μm and spacing of 1 μm to 10 μm, and the surface of the first micro-irregularities may have second micro-irregularities with a depth of 0.1 μm to 1 μm and spacing of 0.1 μm to 1 μm (see Figure 2).

[0122] In another embodiment, the implant may have a certain pattern on its surface.

[0123] Specifically, the implant may have a grid-like, wave-like, or stripe-like pattern on its surface, spaced at intervals of 1 μm to 10 μm.

[0124] The implant of this disclosure comprises a first biodegradable polymer containing copolymerized polyhydroxyalkanoic acid (PHA) and a second biodegradable polymer, thereby exhibiting appropriate strength and stability for orthopedic implants, such as pins, screws, and fixation plates, and also exhibiting excellent ossogenesis and osseointegration.

[0125] For example, the implant may have a tensile strength of 35 MPa or more, 40 MPa or more, 45 MPa or more, or 50 MPa or more, and 75 MPa or less, 70 MPa or less, 65 MPa or less, or 60 MPa or less. Specifically, the tensile strength of the implant can be 40 MPa to 70 MPa. More specifically, the tensile strength of the implant may be 40 MPa to 60 MPa, or 50 MPa to 60 MPa.

[0126] The elongation of the implant can be 2% or more, 3% or more, 3.2% or more, or 4% or more, and 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, or 5% or less. Specifically, the elongation of the implant can be 3.2% to 10%. More specifically, the elongation of the implant can be 3.2% to 7%.

[0127] The tensile strength and elongation of the implant can be measured by, for example, preparing a test specimen with a diameter of 1.5 mm and a length of 50 mm.

[0128] The implant may exhibit a cell viability of 70% or higher in a cytotoxicity test using the elution solution, relative to a cell viability of 100% in the control group treated with the elution solvent. Furthermore, the implant may exhibit a cell viability of 75% or higher, 80% or higher, or 81% or higher in a cytotoxicity test using the elution solution, relative to a cell viability of 100% in the control group treated with the elution solvent. Additionally, the implant may exhibit a cell viability of 70-90%, 80-90%, or 81-90% in a cytotoxicity test using the elution solution, relative to a cell viability of 100% in the control group treated with the elution solvent. Specifically, in a cytotoxicity test, the implant is eluted with an elution solvent (e.g., cell culture medium), cells are treated with the elution solution, and the cell viability is measured over 48 hours. A relative value is calculated, with the cell viability of the control group treated with only the elution solvent set to 100%.

[0129] Furthermore, when an implant is placed in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected two months after implantation can be 120 N / mm or higher. Specifically, when an implant is placed in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected two months after implantation can be 130 N / mm or higher. For example, when an implant is placed in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected two months after implantation may be 120 N / mm to 500 N / mm, 130 N / mm to 500 N / mm, 130 N / mm to 400 N / mm, or 150 N / mm to 300 N / mm.

[0130] Furthermore, when an implant is placed in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected four months after implantation can be 170 N / mm or higher. For example, when an implant is placed in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected four months after implantation may be 170 N / mm to 700 N / mm, 200 N / mm to 600 N / mm, or 250 N / mm to 500 N / mm.

[0131] The stiffness of femoral tissue can be measured, for example, by a three-point bending test using a biomechanical testing machine. The test may be carried out using standards commonly used for testing ceramics or crushed composite materials (ASTM F1161 and ASTM F382). In one embodiment, the test specimen is placed on a test fixture with a support span spacing of 16 mm, such that the fracture site is located on the upper fixture, and a load of 3 kN is applied at a speed of 5 mm / min. The test may be carried out until the test specimen fractures, and the stiffness at that time may be measured.

[0132] Implant manufacturing methods The present disclosure relates to a method for manufacturing an implant comprising: preparing a biodegradable polymer comprising a first biodegradable polymer and a second biodegradable polymer; and molding an implant using the biodegradable polymer, wherein the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), and the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0133] In one embodiment, the molding can be performed by injection molding.

[0134] Injection molding may be carried out by extruding using a twin-screw or single-screw extruder, then injecting using an injection molding machine, and subsequently performing post-processing such as annealing. The mold used for injection molding may be, for example, a cold runner mold, a hot runner mold, or a pinpoint mold.

[0135] The extrusion temperature can be, for example, 100°C to 210°C, the spindle speed can be, for example, 100 rpm to 250 rpm, and the feeder speed can be, for example, 4 rpm to 40 rpm.

[0136] The injection temperature is, for example, 150°C to 200°C, the injection pressure is, for example, 1000 bar to 1800 bar, the injection rate is, for example, 0.5 mm / sec to 100 mm / sec, the holding pressure range is, for example, 300 bar to 1200 bar, and the holding time is, for example, 1 second to 10 seconds.

[0137] The annealing temperature can be, for example, 80°C to 110°C, and the annealing time can be, for example, 30 minutes to 2 hours.

[0138] In another embodiment, the molding may be 3D printing.

[0139] 3D printing may be performed under conditions such as a printing temperature of 150°C to 200°C, an injection rate of 200 mm / min to 400 mm / min, a pressure of 200 kPa to 400 kPa, and a printing duration of 60 minutes or less.

[0140] In another embodiment, the surface of the implant can be modified to enhance cell adhesion and improve fixation within the tissue.

[0141] In one embodiment, the method may impart roughness or a pattern to the surface after molding by blasting, molding, or laser treatment.

[0142] In another embodiment, the process may further include imparting hydrophilicity to the surface by plasma treatment after formation.

[0143] In another embodiment, the method may further include, after molding, imparting surface roughness or a pattern to the surface by blasting, molding, or laser treatment, and imparting hydrophilicity by plasma treatment.

[0144] Composition for implants The implant composition of the present disclosure comprises a first biodegradable polymer and a second biodegradable polymer, wherein the first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), and the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

[0145] In one embodiment, the implant composition may include a blend of a first biodegradable polymer and a second biodegradable polymer.

[0146] In another embodiment, the copolymerized polyhydroxyalkanoic acid (PHA) may further contain repeating units derived from at least one monomer selected from the group consisting of 2-hydroxybutyric acid (2-HB), 3-hydroxybutyric acid (3-HB), 3-hydroxypropionic acid (3-HP), 3-hydroxyvaleric acid (3-HV), 3-hydroxyhexanoic acid (3-HH), 3-hydroxyheptanoic acid (3-HHep), 3-hydroxyoctanoic acid (3-HO), 3-hydroxynonanoic acid (3-HN), 3-hydroxydecanoic acid (3-HD), 3-hydroxydodecanoic acid (3-HDd), 4-hydroxyvaleric acid (4-HV), 5-hydroxyvaleric acid (5-HV), and 6-hydroxyhexanoic acid (6-HH).

[0147] In another embodiment, the first biodegradable polymer may further comprise at least one polymer selected from the group consisting of poly(3-hydroxybutyric acid) (P3HB), poly(4-hydroxybutyric acid) (P4HB), poly(3-hydroxyhexanoic acid) (P3HH), poly(3-hydroxybutyric acid-co-3-hydroxyhexanoic acid) (P3HB-3HH), poly(3-hydroxyoctanoic acid) (P3HO), and poly(3-hydroxybutyric acid-co-3-hydroxyoctanoic acid) (P3HB-3HO).

[0148] In another embodiment, the second biodegradable polymer is a mixture of one or more synthetic biodegradable polymers and natural biodegradable polymers, excluding polyhydroxyalkanoic acid (PHA), wherein the synthetic biodegradable polymer may include polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic acid-co-caprolactone) (PLCL), poly(lactic acid-co-glycolic acid) (PLGA), polybutylene succinate (PBS), or poly(butylene adipate-co-terephthalate) (PBAT), and the natural biodegradable polymer may include starch, silk fibroin, chitosan, chitin, cellulose, collagen, or gelatin.

[0149] In another embodiment, copolymerized polyhydroxyalkanoic acid (PHA) may be present in an amount of 10% to 50% by weight relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

[0150] In another embodiment, the implant composition may further include at least one additive selected from bioactive glass fibers and ceramics.

[0151] In another embodiment, the implant composition may further include at least one agent for promoting bone regeneration.

[0152] Specific details regarding the first biodegradable polymer, the second biodegradable polymer, the mixing ratio of the two, the content of repeating units derived from 4-hydroxybutyric acid (4-HB) in the copolymerized polyhydroxyalkanoic acid (PHA), and the types and content of additives and drugs are illustrated in the above-mentioned description of the implant.

[0153] The implant composition can be used in the manufacture of implants according to the embodiments of this disclosure. For example, it can be used when manufacturing implants according to the method described above.

[0154] Mode of the invention The present disclosure will be further described below with reference to examples. However, the following examples are for illustrative purposes only and do not limit the scope of the present disclosure to these examples alone.

[0155] Examples 1-3 and Comparative Example 1: Manufacturing of Implants The materials and equipment used are as follows: PLA: PLLA (BBCA) ·PHA:P(3HB-4HB)(4-HB 10%, CJ CheilJedang) • Extruders (STEER OMEGA20, Bautech BA19) • Injection molding machine (Engel's E-victory 170 / 80)

[0156] As shown in the table below, PLLA and P(3HB-4HB) were blended in different weight ratios.

[0157] [Table 1]

[0158] The mixing process was carried out using the following two types of twin-helix extruders. BA19 Temperature range: 100~170℃, Main screw rpm: 150, Feeder rpm: 7~8, Torque range: 36~42 Omega 20 - Temperature range: 120~195℃, Main screw rpm: 250, Feeder rpm: 25~35, Torque range: 39~46

[0159] It was dried at 60°C overnight, then at 80°C for 6 hours.

[0160] The injection conditions are as follows: Temperature: 160-180°C, Mold temperature: 30-70°C, Pressure: 1100-1500 bar, Injection speed: 5-120 mm / sec, Holding pressure: 300-600 bar, Holding pressure time: 3 seconds, Measuring value: 12-15 mm, Feed speed: 40 rpm, Back pressure: 40 bar, Holding pressure switching time: 10 seconds, Cooling time: 15-30 seconds.

[0161] This allowed us to manufacture needle-shaped implants with a diameter of 1.5 mm and a length of 50 mm in various compositions.

[0162] Test Example 1: Strength and Elongation The equipment used was a UTM (Instron 34SC-1), and pin-shaped implant test specimens with a diameter of 1.5 mm and a length of 50 mm were fabricated. The test conditions were a load cell load of 1 kN, a jig distance of 20 mm, and a tensile speed of 20 mm / min. The test results are shown in the table and Figure 3 below.

[0163] [Table 2]

[0164] The test results showed that Examples 1-3, which contained 10-30% by weight of P(3HB-4HB), exhibited greater elongation compared to Comparative Example 1, which did not contain P(3HB-4HB), with little difference in tensile strength, and the material was given flexibility. Therefore, it is suitable as an implant material.

[0165] Furthermore, tests were also conducted using P(3HB-4HB) (CJ CheilJedang) with varying 4HB content of 6%, 8%, and 10%. Implants were manufactured in the same manner as in Example 1, using P(3HB-4HB) and PLLA with different polymer compositions in a weight ratio of 3:7. The tensile strength and elongation of the fabricated implants were tested in the same manner as described above, and the results are shown in the table below.

[0166] [Table 3]

[0167] Test Example 2: Cytotoxicity (in vitro) (1) Test method Cytotoxicity evaluation was conducted in accordance with the international standard ISO 10993-1:12 and the "Considerations for Applying GLP to Medical Device Biosafety Testing (Cytotoxicity Testing Guidelines)" published by the Ministry of Food and Drug Safety. Positive control materials, negative control materials, elution conditions, cell lines, etc., were used in accordance with the guidelines as follows. • Positive control group: Polyurethane stabilized with organosin • Negative control group: High-density polyethylene (standard for cytotoxicity evaluation) ·Elution solvent: Cell culture medium (RPMI-1640 + 10% fetal bovine serum + 1% antibiotics) ·Elution conditions: 0.2g / mL, 37±2℃, 24±2 hours • Cell line: WI-38 (human lung fibroblast cell line)

[0168] Cytotoxicity assessments are divided into direct and indirect methods. Direct methods involve directly contacting the sample with cells to observe changes in the cells. Indirect methods involve eluting the sample into a cell culture medium, treating the cells with the eluate, and observing the changes in the cells after 48 hours.

[0169] First, cells were distributed into 24-well plates and left in an incubator for 24 hours. The cells were checked to see if they had grown to 80%. Then, for the direct method, the sample was injected into a cell culture plate. For the indirect method, the supernatant was replaced with cell culture medium. After 48 hours of incubation, changes in the cells were observed.

[0170] After 48 hours, direct analysis was performed using fluorescent staining of live and dead cells. For indirect analysis, qualitative analysis was performed by observing cell morphology, followed by quantitative analysis using the WST-1 assay. Evaluation during analysis was performed according to the above guidelines.

[0171] (2) Test results The results of direct fluorescence staining of live and dead cells are shown in the table and Figure 4 below. The test results showed that Comparative Example 1 and Example 1, which contained biodegradable polymers, both had fewer dead cells than the positive control group and were similar to the negative control group.

[0172] [Table 4]

[0173] Furthermore, Figure 4 shows the results of cell morphology observations after indirect testing. The test results showed that in Example 1, fibroblasts maintained their shape and proliferated by more than 80%. In Comparative Example 1, similar to the negative control group, it was confirmed that cells proliferated in large quantities, filling the culture plate.

[0174] Furthermore, cell viability was measured after indirect testing (WST-1 assay), as shown in Figure 5. The test results showed that, compared to the cell viability of the elution solvent control group (set at 100%), Comparative Example 1 (PLA 100%) had a viability of 80.9%, and Example 1 (PLA:PHA = 7:3) had a viability of 81.1%. A decrease of 30% or more in cell viability is considered cytotoxicity according to the guidelines of the Ministry of Food and Drug Safety. Neither Comparative Example 1 nor Example 1 showed cytotoxicity.

[0175] Test Example 3: Induction of osteoblast differentiation (in vitro) (1) Test method The osteoblast differentiation induction test is performed to confirm the degree of osteoblast differentiation when the test sample is brought into direct contact with osteocytes. It was conducted using the SaOS-2 cell line (human osteosarcoma cell line). The cell culture medium (using bone induction-promoting medium) was changed every three days, and the cells were cultured for two weeks. Alizarin red staining was performed to confirm calcium production and to evaluate the degree of osteoblast differentiation.

[0176] (2) Test results The results of the osteoblast differentiation induction test are shown in Figure 6. The test results showed that in the first week, Example 1 (PLA / PHA=7:3) exhibited slightly more calcium deposition staining than the other groups, indicating that osteoblast differentiation progressed slightly faster than in the other groups. However, in the second week, there was no difference in the results across all groups, and bone formation and differentiation were confirmed to be induced.

[0177] Test Example 4: Rat femoral fracture (in vivo) (1) Test method In vivo studies were conducted using PHA-based orthopedic pin-type implants in a rat fracture model. Based on existing literature and prior research, the femurs of Sprague Dawley rats were osteotomized and implants were inserted. Femoral samples from Comparative Example 1 (100% PLA) and Example 1 (PLA / PHA=7:3) were collected 2 and 4 months after implantation, respectively, and histological, radiological, and biomechanical analyses were performed. These results are compared.

[0178] The above procedure was performed on a femoral fracture model of 12-week-old rats. As shown in the table below, out of a total of 25 rats, 12 were implanted with PLA implants and the remaining 13 were implanted with the implants from Example 1 (PLA / PHA=7:3), and observed for 4 months. At 2 months, tissue slides were prepared by sacrificing 3 rats with PLA implants and 3 rats with the implants from Example 1 (PLA / PHA=7:3). Micro-CT imaging and evaluation of femoral flexion strength were performed by sacrificing 3 rats with the implants from Comparative Example 1 (100% PLA) and 4 rats with the implants from Example 1 (PLA / PHA=7:3). Femoral tissue was collected from a total of 13 rats. At 4 months, tissue slides were prepared using three rats implanted with PLA implants and three rats implanted with the implant from Example 1 (PLA / PHA=7:3). Micro-CT scans and femoral flexion strength evaluations were then performed using three rats implanted with PLA implants and three rats implanted with the implant from Example 1 (PLA / PHA=7:3). Femoral tissue was collected from a total of 12 rats. Subsequently, histological, radiological, and biomechanical evaluations were performed, including tissue staining, micro-CT scans, and flexion strength evaluations.

[0179] The rat femoral fracture test model is explained in Figure 7 and summarized in the table below.

[0180] [Table 5]

[0181] For histological analysis, femoral samples were stained with H&E, and microscopic examination was performed to observe basic bone morphology, changes in fracture site, implant bone contact surface, and new bone formation. For radiological analysis, the degree of femoral bone union was evaluated based on micro-CT images. For biomechanical analysis, femoral samples were fixed to a biomechanical testing machine, and a three-point bending experiment was performed.

[0182] In Comparative Example 1, the pin-type implant procedure (100% PLA) resulted in a very serious problem: the pin broke during bone fixation. Therefore, it was determined that it was unsuitable for use as a surgical implant. In Example 1 (PLA / PHA=7:3), the problem that occurred in Comparative Example 1 (100% PLA) did not occur, confirming that Example 1 (PLA / PHA=7:3) is more suitable as a surgical implant. In other words, the pin-type implant of Example 1 (PLA / PHA=7:3) had improved physical properties compared to Comparative Example 1 (100% PLA), and it was confirmed during the surgical process that it is more suitable as a surgical implant.

[0183] None of the 25 rats used in the experiment showed any visual signs of inflammation at the wound site. They survived without any particular problems for 2 to 4 months. Femoral specimens were collected from all 25 rats at 2 and 4 months post-surgery.

[0184] (2) Histological evaluation The collected femoral samples underwent histopathological analysis at the Department of Pathology, Hanyang University. Slides were prepared using paraffin blocks and microtomes, focusing on the femoral transsection site. H&E staining was performed to observe the arrangement of bone tissue stroma and osteocyte nuclei and cytoplasm, and the progress of bone fusion was compared between the control group and the experimental group. In addition, the pin insertion site and the contact surface with the femur were examined to determine whether or not a foreign body reaction occurred. The results are shown in Figure 8.

[0185] H&E staining of femoral samples collected at the second month revealed that the bone matrix of Example 1 (PLA / PHA=7:3) was more regularly and neatly organized than that of Comparative Example 1 (PLA100%), with smaller osteocytoplasm and a spindle shape, indicating that mature bone formation was more advanced in Example 1 compared to Comparative Example 1.

[0186] Furthermore, the femoral bone sample taken at 4 months showed that the bone matrix of Example 1 (PLA / PHA=7:3) was more regularly and well-organized compared to Comparative Example 1 (PLA100%), and the cytoplasm of the osteocytes was smaller and showed a uniform spindle shape, indicating that mature bone formation was more advanced in Example 1 compared to Comparative Example 1.

[0187] (3) Radiological imaging diagnosis The radiographic image analysis of the collected femoral specimens was entrusted to the analysis team at the Korea Medical and Health Policy Institute (KBio Health). The radiographic image analysis was performed using micro-CT. Using 2D and 3D images, bone union at the osteotomy site was observed, and the fracture surface gap, bone bridge, and thickening patterns were analyzed. Furthermore, using micro-CT, the degree of bone union was analyzed by measuring the scar volume of the ROI region (a quantitative parameter of bone union) and the bone marrow density (BMD) (a qualitative parameter).

[0188] Figure 9 shows micro-CT2D and 3D images of samples from the second and fourth months. Figure 9(a) shows an image of a sample implanted with the Comparative Example 1 implant (100% PLA), and Figure 9(b) shows an image of a sample implanted with the Example 1 implant (PLA / PHA=7:3).

[0189] At the 2-month follow-up examination, gaps were observed on the fracture surface in all three samples of Comparative Example 1 (100% PLA), and no bone bridge was observed. In particular, one sample of Comparative Example 1 showed displacement of the fracture surface and pin, indicating that a re-fracture had occurred. In contrast, in Example 1 (PLA / PHA=7:3), a bone bridge was observed in two of the four samples, and not in the other two. Therefore, in Comparative Example 1, bone union was not achieved in any of the three samples, while in Example 1, bone union was achieved in two out of four samples (50%).

[0190] In the 4-month follow-up examination, gaps were observed on the bone surface in 2 of the 3 samples in Comparative Example 1, and a bone bridge was observed in 1 of the 3 samples. In Example 1, a gap was observed on the fracture surface in 1 of the 3 samples, and a bone bridge was observed in 2 of the 4 samples. Therefore, bone union was achieved in 1 of the 3 samples in Comparative Example 1, whereas bone union was achieved in 2 of the 4 samples in Example 1.

[0191] The results of the radiographic analysis of the 2-month sample are shown in the table and Figures 10a and 10b below. Analysis of the 2-month sample revealed no significant differences in scar volume or BMD between Example 1 and Comparative Example 1.

[0192] [Table 6]

[0193] [Table 7]

[0194] The results of the radiographic analysis of the 4-month sample are shown in the table and Figures 11a to 11b below. Analysis of the 4-month sample showed that Example 1 had a slight increase in scar volume and BMD compared to Comparative Example 1.

[0195] [Table 8]

[0196] [Table 9]

[0197] (4) Biomechanical analysis Three-point bending tests were performed on femoral samples collected using a biomechanical testing machine. The rigidity (N / mm), maximum load (N), and maximum deformation (mm) of the samples were measured to evaluate their biomechanical properties.

[0198] The three-point bending biomechanical test was performed in accordance with standards commonly used for testing ceramics or fracture-resistant composite materials (ASTM F1161 Standard Test Method for Flexural Strength of Advanced Ceramics at Ambient Temperature, ASTM F382 Standard Specification and Test Method for Metallic Bone Plates).

[0199] The specific test conditions and test methods are as follows: • Support span: 16mm • Loading rate: 5mm / min • Test environment: Room temperature, natural drying • Testing equipment: MTS Acumen Test system (MTS System Corp., Mn, USA) ·Load capacity: 3kN The test specimen was placed on a test fixture with a support span spacing of 16 mm, with the fracture point positioned on the upper fixture. A load of 3 kN was applied to the test specimen at a speed of 5 mm / min. The test was carried out until the test specimen fractured, and the load and deformation were measured.

[0200] The results of the biomechanical analysis of the 2-month sample are shown in the table below. The results of the stiffness measurement of the 2-month sample are shown in Figure 12a.

[0201] [Table 10]

[0202] [Table 11]

[0203] The results of the biomechanical analysis of the 4-month sample are shown in the table below. Additionally, the results of the stiffness measurements for the 4-month to 2-month samples are shown in Figure 12b.

[0204] [Table 12]

[0205] [Table 13]

[0206] Biomechanical analysis revealed that the biomechanical strength of Example 1 (PLA / PHA=7:3) was superior to that of Comparative Example 1 (PLA100%) at both the 2nd and 4th month.

Claims

1. The present invention comprises a first biodegradable polymer and a second biodegradable polymer. The first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), An implant comprising the copolymerized polyhydroxyalkanoic acid (PHA) containing repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

2. The implant according to claim 1, comprising a blend of the first biodegradable polymer and the second biodegradable polymer.

3. The implant according to claim 1, comprising a core portion and a covering portion, wherein the covering portion comprises the first biodegradable polymer and the core portion comprises the second biodegradable polymer.

4. Including a core and a covering, The core portion and the covering portion each comprise a blend of the first biodegradable polymer and the second biodegradable polymer. The implant according to claim 1, wherein the content of the first biodegradable polymer contained in the covering portion relative to the total weight of the blend contained in the covering portion is greater than the content of the first biodegradable polymer contained in the core portion relative to the total weight of the blend contained in the core portion.

5. It includes at least one intermediate portion disposed between the core portion and the covering portion, The at least one intermediate portion comprises a blend of the first biodegradable polymer and the second biodegradable polymer, The content of the first biodegradable polymer contained in the coating portion relative to the total weight of the blend contained in the coating portion is greater than the content of the first biodegradable polymer contained in the intermediate portion relative to the total weight of the blend contained in the intermediate portion. The implant according to claim 4, wherein the content of the first biodegradable polymer contained in the intermediate portion relative to the total weight of the blend contained in the intermediate portion is greater than the content of the first biodegradable polymer contained in the core portion relative to the total weight of the blend contained in the core portion.

6. The implant according to claim 1, having a porous structure with pores having a size of 10 nm to 10 μm.

7. The implant according to claim 1, wherein the copolymerized polyhydroxyalkanoic acid (PHA) further comprises repeating units derived from at least one monomer selected from the group consisting of 2-hydroxybutyric acid (2-HB), 3-hydroxybutyric acid (3-HB), 3-hydroxypropionic acid (3-HP), 3-hydroxyvaleric acid (3-HV), 3-hydroxyhexanoic acid (3-HH), 3-hydroxyheptanoic acid (3-HHep), 3-hydroxyoctanoic acid (3-HO), 3-hydroxynonanoic acid (3-HN), 3-hydroxydecanoic acid (3-HD), 3-hydroxydodecanoic acid (3-HDd), 4-hydroxyvaleric acid (4-HV), 5-hydroxyvaleric acid (5-HV), and 6-hydroxyhexanoic acid (6-HH).

8. The implant according to claim 1, wherein the first biodegradable polymer further comprises at least one polymer selected from the group consisting of poly(3-hydroxybutyrate) (P3HB), poly(4-hydroxybutyrate) (P4HB), poly(3-hydroxyhexanoic acid) (P3HH), poly(3-hydroxybutyrate-co-3-hydroxyhexanoic acid) (P3HB-3HH), poly(3-hydroxyoctanoic acid) (P3HO), and poly(3-hydroxybutyrate-co-3-hydroxyoctanoic acid) (P3HB-3HO).

9. The second biodegradable polymer is a mixture of one or more synthetic biodegradable polymers and natural biodegradable polymers, excluding polyhydroxyalkanoic acid (PHA). The synthetic biodegradable polymer includes polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic acid-co-caprolactone) (PLCL), poly(lactic acid-co-glycolic acid) (PLGA), polybutylene succinate (PBS), or poly(butylene adipate-co-terephthalate) (PBAT), The implant according to claim 1, wherein the natural biodegradable polymer comprises starch, silk fibroin, chitosan, chitin, cellulose, collagen, or gelatin.

10. The implant according to claim 1, wherein the copolymerized polyhydroxyalkanoic acid (PHA) is present in an amount of 10% to 50% by weight relative to the total weight of the first biodegradable polymer and the second biodegradable polymer.

11. The implant according to claim 1, further comprising at least one additive selected from bioactive glass fibers and ceramics.

12. It further comprises at least one agent for promoting bone regeneration, The implant according to claim 1, wherein the drug is applied to the surface of the implant, blended with the first biodegradable polymer and the second biodegradable polymer, or contained in the implant in a concentration gradient from the surface to the interior.

13. The implant according to claim 1, wherein the tensile strength measured using a test piece with a diameter of 1.5 mm and a length of 50 mm is 40 MPa to 70 MPa, and the elongation is 3.2% to 10%.

14. The implant according to claim 1, having a surface roughness of 1 μm to 10 μm in depth, or a grid pattern, wave pattern, or stripe pattern with intervals of 1 μm to 10 μm.

15. The implant according to claim 1, wherein, in a cytotoxicity test using the eluate, the cell viability is 70% or more compared to 100% in the control group of the eluting solvent.

16. The implant according to claim 1, wherein when the implant is implanted in the fractured femoral tissue of a rat, the rigidity of the femoral tissue collected two months after implantation is 120 N / mm or more.

17. To prepare a biodegradable polymer comprising a first biodegradable polymer and a second biodegradable polymer, This includes molding an implant using the aforementioned biodegradable polymer. The first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), wherein the copolymerized polyhydroxyalkanoic acid (PHA) contains repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA). A method for manufacturing dental implants.

18. The method for manufacturing an implant according to claim 17, wherein the molding is injection molding or 3D printing.

19. The method for manufacturing an implant according to claim 18, wherein the injection molding is performed under the conditions of an extrusion temperature of 100°C to 210°C, an injection temperature of 150°C to 200°C, and an annealing temperature of 80°C to 110°C.

20. The method for manufacturing an implant according to claim 18, wherein the 3D printing is performed under the conditions of a printing temperature of 150°C to 200°C, an injection speed of 200 mm / min to 400 mm / min, a pressure of 200 kPa to 400 kPa, and a printing duration of 60 minutes or less.

21. The method for manufacturing an implant according to claim 17, further comprising at least one surface treatment step after the molding, which includes imparting roughness or a pattern to the surface by blasting, molding, or laser treatment, and imparting hydrophilicity to the surface by plasma treatment.

22. The present invention comprises a first biodegradable polymer and a second biodegradable polymer. The first biodegradable polymer comprises copolymerized polyhydroxyalkanoic acid (PHA), An implant composition comprising the copolymerized polyhydroxyalkanoic acid (PHA) containing repeating units derived from 4-hydroxybutyric acid (4-HB) in an amount of 0.1% to 50% by weight relative to the total weight of the copolymerized polyhydroxyalkanoic acid (PHA).

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