TWI770631B - Biodegrable and injectable bone composite and uses thereof - Google Patents

Abstract

Disclosed herein are biodegradable injectable bone composites and uses thereof. The biodegradable injectable composite comprises a shell made of biodegradable thermoplastic polymer, and a bone substitute encapsulated in the chamber defined by the shell, wherein the biodegradable thermoplastic polymer has a molecular weight between 7,000 and 150,000, and the shell and the bone substitute are present in a weight ratio of 1:1 to 1:19 in the composite. Also disclosed herein is the use of the biodegradable injectable bone composite for the manufacture of a medicament for the treatment of bone fracture, in which the bone composite becomes molten upon exposure to heat, thereby allowing the molten bone composite be applied via injection to the bone fracture.

Description

Biodegradable injectable bone composite material and its use

The present invention generally relates to a bone composite material and its use. Specifically, the present invention relates to a biodegradable bone composite that can be injected into a treatment site and uses thereof.

Spine compression fracture is a very common form of fracture in elderly patients with osteoporosis, which causes great pain and functional impact in life. The treatment methods include conservative pain control and surgical treatment. The injection of bone cement (vertebroplasty or kyphoplasty) at the vertebral fracture is a minimally invasive surgical method. Under the positioning of the X-ray machine, a guide pin is inserted into the fracture, and polymethyl methacrylate (polymethyl methacrylate) is injected. Poly(methyl methacrylate, PMMA)), commonly known as acrylic bone cement, can support the fracture to relieve pain and prevent the fracture from continuing to collapse and deform. However, injection of acrylic bone cement also has its risks and disadvantages. Because the acrylic will flow before hardening, the bone cement will leak to the nerves and blood vessels. When hardening, it will emit high heat (60~90 degrees). Fractures occur again in adjacent condyles, and PMMA is a bioabsorbable material that affects bone formation and becomes a permanent foreign body in the body. In recent years, it has been pointed out that the effect of injection of PMMA in spinal compression fractures is not better than that of conservative treatment. Therefore, related fields have been seeking a better material for spinal injection to solve the shortcomings of the current treatment or repair of fractures with PMMA.

The inventors of the present application have unexpectedly discovered that the use of thermoplastic biocompatible polymers to encapsulate bone substitutes can form a biodegradable bone composite material, which is heated to form an injectable material that is easy to handle due to the liquefaction of the polymer, and is cooled to solidify The latter has a mechanical support close to the human body's loose bone. Therefore, in addition to replacing PMMA for the treatment of vertebral compression fractures, it can also be used in other places in the body that require bone fillers.

The first aspect of the present invention relates to a biodegradable injectable bone composite material, comprising a shell made of a biodegradable thermoplastic polymer, and a bone substitute encapsulated in the space formed by the shell; Wherein, the molecular weight of the biodegradable thermoplastic polymer is between 7,000 and 150,000, and the weight ratio and volume ratio of the shell and the bone substitute in the bone composite material are both between 1:1 and 1:19.

Examples of biodegradable thermoplastic polymers suitable for making shells according to embodiments of the present invention include, but are not limited to, silica gel, polycaprolactone (PCL), polyglycolic acid (polyglycolic acid), Lactic acid (Polylactic acid, PLA), poly (L-lactic acid), poly (D-, L-lactic acid), poly (lactic-co-glycolic acid) (Poly(lactic-co-glycolic acid), PLGA), poly Polyhydroxybutyrate (Polyhydroxybutyrate), Polydioxanone (Polydioxanone), Poly(caprolactone-co-glycolide), Polyamide (Poly( ester amide), PEA), polyethylene glycol (Polyethylene glycol, PEG), polyphosphazene (Polyphosphazene), polyorthophosphoric esters (Polyorthoesters), polyanhydrides (polyanhydrides) and combinations thereof. According to certain embodiments, suitable as The biodegradable thermoplastic polymer of the shell is PCL.

Examples of suitable bone substitutes according to embodiments of the present invention include, but are not limited to, ceramics, bioglass, silicon, strontium, magnesium, hydroxyapatite (HA), tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate, and combinations thereof. According to certain embodiments, suitable as a bone substitute is a mixture of HA and TCP.

According to a specific embodiment, the bone composite material of the present invention is made of PCL as a shell, which is filled with a bone substitute composed of HA/TCP (HA:TCP = 2:3, weight ratio), and the shell and the bone substitute are filled. The weight ratio in this bone composite was 1:4 and the volume ratio was 1:9.

According to certain embodiments, the bone composite material of the present invention may further comprise a contrast agent, an antibiotic or a combination thereof, which are coated with the bone substitute in the space formed by the shell.

The second aspect of the present invention provides a use of the above-mentioned bone composite material to prepare a medicament for treating fracture or osteoporosis. The bone composite material in the drug will form a molten state after being heated at 90°C for 1 minute, thereby enabling the bone composite material to be administered in a molten state to a fractured or osteoporotic site of an individual.

According to an embodiment of the present invention, the molten bone composite material is administered to the fractured or osteoporotic site by injection.

Other aspects and advantages of the present invention will become readily apparent upon review of the following description and claims.

In order to make the description of the present disclosure more detailed and complete, the following provides an illustrative description for the embodiments and specific embodiments of the present invention; but this is not the only form of implementing or using the specific embodiments of the present invention. The features of various specific embodiments as well as method steps and sequences for constructing and operating these specific embodiments are encompassed in the detailed description. However, other embodiments may also be utilized to achieve the same or equivalent function and sequence of steps.

In general, the present invention relates to the discovery that the use of thermoplastic biocompatible polymers to encapsulate bone substitutes results in the formation of a biodegradable bone composite which upon heating results in liquefaction of the polymer to form an easily handled injectable material, After being cooled and solidified, it has mechanical support close to the human body's loose bone. Therefore, the bone composite material of the present disclosure can not only replace PMMA for treating vertebral compression fractures, but also can be used for filling or repairing other bone fillers in the body. The place.

1. Biodegradable Bone Composite

Please refer to FIG. 1 and FIG. 2 , which respectively illustrate a biodegradable bone composite material 10 made according to the present disclosure, comprising a shell (11, 12) made of a biodegradable thermoplastic polymer, and a bone substitute 20 located in the space formed by the shells (11, 12) made of the biodegradable thermoplastic polymer.

According to the embodiment of the present disclosure, the polymer shells (11, 12) of the biodegradable bone composite material 10 are made of thermoplastic polymer materials with molecular weights between 7,000 and 150,000 through extrusion molding, injection molding, The upper and lower shells (11, 12) that can be joined to each other are formed by means of thermoforming, blow molding, rotational molding, calendering or casting to form an inner space that can accommodate the bone substitute 20 therein, for example, as shown in FIG. 1 ( A) and Figure 2(A). It should be noted that the biodegradable thermoplastic polymer shell of the present disclosure is not limited to the cylindrical shape shown in FIG. 1 or FIG. This shape does not limit the functionality of the biodegradable injectable bone composite.

According to embodiments of the present disclosure, suitable biodegradable thermoplastic polymer materials have molecular weights between 7,000 and 150,000, eg 50,000、55,000、60,000、65,000、70,000、75,000、80,000、85,000、90,000、95,000、100,000、105,000、110,000、115,000、12,000、125,000、130,000、135,000、140,000、145,000及150,000；較佳是介於10,000 至120,000 For example, 15,000, 20,000, 25,000, 30,000, 35,000, 45,000, 45,000, 50,000, 55,000, 65,000, 70,000, 75,000, 85,000, 95,000, 105,000, 105,000, 115,000, 115,000, 105,000, 105,000, 105,000, 105,000, 105,000, 105,000, 105,000, 105,000, 105,000, 105,000, 115,000, 115,000 and 115,000 and 115,000. The preferred range is between 45,000 and 90,000, such as 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, and 90,000.

Examples of suitable biodegradable thermoplastic polymer materials include, but are not limited to, silicone, polycaprolactone (PCL), polyglycolic acid (polyglycolic acid), polylactic acid (PLA) , poly(L-lactic acid), poly(D-, L-lactic acid), poly(lactic-co-glycolic acid) (Poly(lactic-co-glycolic acid), PLGA), polyhydroxybutyrate (Polyhydroxybutyrate) , Polydioxanone, Poly(caprolactone-co-glycolide), Poly(ester amide, PEA), Polyethylene glycol (PEG), polyphosphazene, polyorthoesters (polyorthoesters), polyanhydrides (polyanhydrides), and combinations thereof. According to certain embodiments, biodegradable suitable for making shells The thermoplastic polymer of the formula is PCL with a molecular weight between 10,000 and 80,000.

According to certain embodiments, the disclosed upper and lower shells (11, 12) made of the biodegradable thermoplastic polymer material together form a hollow chamber for accommodating the bone substitute 20 therein. The joint ends of the upper and lower shells (11, 12) can be bonded in any conventional manner, such as ultrasonic fusion bonding or thermal fusion bonding, thereby forming the bone composite material 10 of the present invention, as shown in FIG. 1(B). ) and shown in Figure 2(B).

Examples of suitable bone substitutes according to embodiments of the present invention include, but are not limited to, ceramics, bioglass, silicon, strontium, magnesium, hydroxyapatite (HA), tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate and combinations thereof. According to some embodiments, the bone substitute is composed of two different materials mixed in a weight ratio of 1:1 to 10:1, eg 1:1, 1:2, 1:3, 1:4, 1:1: 5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 2:3, 2:5, 2:7, 2:9, 3:1, 3:2, 3:4, 3:5, 3:7, 3:8, 3:10, 4:1, 4:3, 4:5, 4:7, 4:9, 5:1, 5:2, 5: 3, 5:4, 5:6, 5:7, 5:8, 5:9, 6:1, 6:5, 6:7, 7:1, 7:2, 7:3, 7:4, 7:5, 7:6, 7:8, 7:9, 7:10, 8:1, 8:3, 8:5, 8:7, 8:9, 9:1, 9:2, 9: 4, 9:5, 9:7, 9:8, 9:10 and 10:1. According to the preferred embodiment of the present disclosure, the bone substitute is prepared by mixing HA and TCP in a weight ratio of 2:3.

According to the embodiment of the present disclosure, the weight ratio of the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:1 to 1:19, for example, 1:1 , 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1 :14, 1:15, 1:16, 1:17, 1:18, and 1:19. According to certain embodiments, the weight ratio of the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:1. According to other embodiments, the weight ratio of the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:4. According to further other embodiments, the weight ratio of the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:19. In addition, it should be noted that the volume space ratio occupied by the thermoplastic polymer shell (11, 12) and the bone substitute 20 encapsulated therein in the bone composite material 10 is also in the range of 1:1 to 1:19 time, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12 , 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, and 1:19. According to certain embodiments, the ratio of the volume to space occupied by the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:4. According to a preferred embodiment, the ratio of the volume to space occupied by the biodegradable thermoplastic polymer shell (11, 12) and the bone substitute 20 in the bone composite material 10 is 1:9.

According to some optional embodiments, the bone composite material of the present invention may further comprise a developer, an antibiotic or a combination thereof, which is formed by coating the biodegradable thermoplastic polymer shell together with the bone substitute. within the space.

2. Use of biodegradable bone composites

The second aspect of the present invention relates to the above-mentioned biodegradable bone composite material for the treatment of fractures or osteoporosis. According to a preferred embodiment, the above-mentioned biodegradable bone composite material can be heated by special equipment to liquefy it into a molten state, and then injected into the affected part (ie, fracture or osteoporosis) by minimally invasive injection. .

According to a preferred embodiment of the present disclosure, after the biodegradable bone composite material 10 is heated at a temperature of about 90° C. for about 1 minute, the biodegradable thermoplastic polymer shell (11, 12) will liquefy and form a molten state. , and cover the bone substitute 20 in it. Therefore, the molten bone composite material 10 can be injected into the affected part by injection. To achieve the purpose of treating fractures or osteoporosis.

According to the preferred embodiment of the present disclosure, the cured bone composite material 10 has an irregular lattice-like structure inside, and its mechanical support strength is close to that of human porous bone, which is between 3-40 MPa, which is far lower than that of conventional PMMA. Therefore, it is suitable for wrapping and repairing fractures and treating osteoporosis.

In addition, compared with the conventional method of repairing fractures with a mixture of high molecular polymer (eg, PMMA) and bone powder, the stress of the polymer after curing is too high, and the mixing of the polymer system and bone powder at the filling place makes it difficult for bone cells to grow. In terms of the disadvantages of the bone composite material of the present invention, the special structure of the bone composite material of the present invention, that is, the polymer shell wraps the bone powder in it, and does not mix with each other, but when the polymer shell is heated and melted, it can wrap the bone powder originally filled therein. Then, the bone composite material of the present invention can be injected or extruded to apply the bone composite material of the present invention to the fracture by the soft and operable form formed after the polymer is melted, and the applied bone composite material can be adjusted to conform to the shape of the repaired place, because The interior of the filled bone composite material is still mostly bone powder, and only a small amount of high molecular polymer is mixed in, so that the bone cells grow easily, so there will be no disadvantages of the conventional filling place where the stress is too high or the bone cells are not easy to grow.

According to the preferred embodiment of the present disclosure, when repairing fractures or treating osteoporosis, X-ray guidance is used first, and an introducer needle and an introducer needle probe are used to determine the part to be treated in the body (that is, the fracture or bone). At the same time, a plurality of biodegradable bone composite materials of the present invention are sequentially filled in another catheter with a catheter probe, and a heating device is used to liquefy the biodegradable bone composite materials filled into the catheter into In the molten state, the catheter loaded with the biodegradable bone composite material in the molten state is placed into the introduction needle, and the biodegradable bone composite material is extruded into the site to be treated (ie, the fracture site) with the catheter probe, Unnecessarily, the extrusion can be repeated several times to make the area to be treated contain a sufficient amount of molten biodegradable bone composite material. After the molten bone composite material is solidified again, the introduction needle can be removed, and the fracture or fracture can be repaired. The purpose of strengthening the mechanical strength of bone in osteoporosis.

Embodiments of the invention may be practiced using any suitable method known in the art. The following description provides only some examples of examples. It should be understood by those skilled in the art that these embodiments are for illustration only, and modifications and changes can be made to the present invention without departing from the scope of the present invention.

Example 1 Preparation and characteristic analysis of the bone composite material of the present invention

1.1 preparation

In this example, according to the formula in Table 1, polycaprolactone (PCL) with different molecular weights was used to manufacture hollow polymer capsules by extrusion molding and demoulding. The shell diameter was 4 mm, height was 10 mm, and thickness was 0.2 mm. The internal (3.8 mm diameter x 14.6 mm) space can be filled with various bone substitutes to form the bone composite of the present invention.

Table 1 formula# composition (A) Thermoplastic polymer (B) Bone substitute A/B (weight ratio) A/B (volume ratio) 1 PCL (molecular weight 10,000) Hydroxyapatite (40%) Tricalcium Phosphate (60%) 10/90 20/80 2 PCL (molecular weight 45,000) Hydroxyapatite (40%) Tricalcium Phosphate (60%) 20/80 10/90 3 PCL (molecular weight 80,000) Hydroxyapatite (40%) Tricalcium Phosphate (60%) 30/70 5/95

1.2 analyze

The bone composite material formed according to the formula 1-3 in Table 1 is placed in the catheter and heated at 90 degrees Celsius for one minute. The polymer capsule shell will be liquefied and mixed with part of the ceramic bone powder, covering the rest of the unmixed bone powder and cooling. After curing within three minutes, the internal structure was observed and the stress it could withstand was measured.

The results show that the bone composite materials prepared according to the above formulas 1-3 have an irregular lattice-like internal structure after curing, and the mechanical support strength is close to that of human porous bone, between 3-40 MPa, much lower than Knowing the pressure that acrylic bone cement can withstand (250 MPa), it is suitable for covering and repairing fractures and treating osteoporosis.

Although the embodiments of the invention have been described in certain embodiments, those skilled in the art to which this invention pertains will have the benefit of the invention and will appreciate other devised arrangements without departing from the scope of this disclosure. implementation. Accordingly, the scope of the present invention should be subject to the appended claims.

10: Bone Composite

11: Upper shell

12: Lower shell

20: Bone Replacement

1A and 1B respectively illustrate the thermoplastic polymer upper and lower shells ( 11 , 12 ) of the biodegradable injectable bone composite material 10 made according to an embodiment of the present disclosure before joining (A) and joining (B) schematic diagram); and

2A and 2B respectively illustrate the thermoplastic polymer upper and lower shells ( 11 , 12 ) of the biodegradable injectable bone composite material 10 made according to another embodiment of the present disclosure before joining (A) and Schematic of post-bonding (B).

10: Bone Composite

11: Upper shell

12: Lower shell

20: Bone Replacement

Claims (9)

A biodegradable bone composite material, comprising: a shell made of a biodegradable thermoplastic polymer, and a bone substitute located in the space formed by the shell; wherein, the biodegradable thermoplastic polymer The molecular weight is between 7,000 and 150,000, and the weight ratio and volume ratio of the shell and the bone substitute in the bone composite material are both between 1:1 and 1:19; and the biodegradable bone composite material is in After melting and solidifying, it can withstand a stress of about 3-40MPa. The biodegradable bone composite material according to claim 1, wherein the biodegradable thermoplastic polymer is made of at least one selected from the group consisting of silica gel, polycaprolactone (PCL), polyglycolic acid (Poly( glycolic acid)), polylactic acid (PLA), poly (L-lactic acid) (Poly (L-lactic acid)), poly (D-, L-lactic acid) (Poly (D-, L-lactic acid) ), Poly(lactic-co-glycolic acid) (PLGA), Polyhydroxybutyrate, Polydioxanone, Poly(caprolactone) Ester-co-glycolic acid (poly(ε-caprolactone-co-glycolide)), Poly(ester amide, PEA), Polyethylene glycol (PEG), Polyphosphazene ( In the group consisting of Polyphosphazene, polyorthoesters, polyanhydrides, and combinations thereof; and the bone substitute is made of at least one selected from the group consisting of ceramics, bioglass, silicon, strontium, magnesium, hydroxyphosphorus In the group consisting of limestone (Hydroxyapatite, HA), tricalcium phosphate (Tricalcium phosphate, TCP), calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate and combinations thereof. The biodegradable bone composite material according to claim 2, wherein the biodegradable thermoplastic polymer is PCL, the bone substitute is composed of HA and TCP in a weight ratio of 2:3, and the shell and the The weight ratio of the bone substitute in the bone composite material is 1:4, and the volume ratio is 1:9. The biodegradable bone composite material as claimed in claim 2, wherein the bone composite material further comprises a contrast agent, an antibiotic or a combination thereof, which together with the bone substitute are coated in the space formed by the shell . A use of the biodegradable bone composite material as claimed in claim 1 for preparing a medicament for treating fractures or osteoporosis, wherein the biodegradable bone composite material will form a molten state after being heated at 90° C. for 1 minute , so that the biodegradable bone composite material can be administered to the fracture or osteoporosis in a molten state. The use of claim 5, wherein the bone composite material in the molten state is administered to the fracture or osteoporosis by injection. The use according to claim 6, wherein the biodegradable thermoplastic polymer is made of at least one selected from the group consisting of silica gel, PCL, polyglycolic acid, PLA, poly(L-lactic acid), poly(D-,L-lactic acid) ), PLGA, polyhydroxybutyrate, polydioxanone, poly(caprolactone-co-glycolic acid)), PEA, PEG, polyphosphazene, polyorthophosphate, polyanhydride and its and the bone substitute is made of at least one selected from the group consisting of ceramics, bioglass, silicon, strontium, magnesium, HA, TCP, calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate, and combinations thereof. in the group formed. The use according to claim 7, wherein the biodegradable thermoplastic polymer is PCL, the bone substitute is composed of HA and TCP in a weight ratio of 2:3, and the shell and the bone substitute are in the bone The weight ratio in the composite was 1:4 and the volume ratio was 1:9. The use as claimed in claim 7, wherein the biodegradable bone composite material further comprises a contrast agent, an antibiotic or a combination thereof, which together with the bone substitute are coated in the space formed by the shell.

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