WO2022140954A1

WO2022140954A1 - Biodegradable and injectable bone composite and uses thereof

Info

Publication number: WO2022140954A1
Application number: PCT/CN2020/140296
Authority: WO
Inventors: Yi-Ho Hsieh; Ming-Fa Hsieh; Shang-Ting Tsai
Original assignee: Brilliance Biomedicine Co., Ltd.
Priority date: 2020-12-28
Filing date: 2020-12-28
Publication date: 2022-07-07

Abstract

Disclosed herein are biodegradable and injectable bone composites and uses thereof. The biodegradable and 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 or volume 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 to be applied via injection to the fractured bone.

Description

BIODEGRADABLE AND INJECTABLE BONE COMPOSITE AND USES THEREOF

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

The present disclosure in general relates to bone composites and uses thereof. Specifically, the present disclosure relates to biodegradable bone composites that may be administered to a treatment site via injection, and methods for using the same.

2. DESCRIPTION OF RELATED ART

Spine compression fracture (SCF) is a common form of bone fracture found in elders or people having osteoporosis and causes the subject extreme pain and discomfort. Currently, SCF may be treated by conservative pain management; or by surgery such as vertebroplasty or kyphoplasty. Vertebroplasty are procedures that involve injecting bone cement mixture (e.g., poly (methyl methacrylate) , PMMA) to the spine column under the guidance of X-ray to support the fractured spine, thereby reducing pain and preventing the fractured spine column from continued deformation. However, injecting bone cement mixture such as PMMA has its own risk and disadvantages. For example, to achieve the injectability of the bone cement, the viscosity of bone cement mixture needs to maintain at a relatively low level, which runs the risk of having the liquid-like bone cement mixture overflows to non-treatment site, such as neurons, blood vessels and etc. Further, PMMA emits high level of heat when solidifying, in which the temperature often reaches 60 to 90℃. Additionally, the high stress of the solidified PMMA at the treatment site may further lead to subsequent fracture of its neighboring spine column. Last but not least, PMMA is not biodegradable, thus would remain as a foreign material to its recipient. Over the years, it has been reported that treating SCF with non-degradable bone cement mixture (i.e., PMMA) does not necessary give rise to a better therapeutic effect as compared to that of pain management.

Accordingly, there exists in the related art, a need of an improved material for treating SCF, such material not only is biodegradable, but also may cure the defect resulting from treating SCF with PMMA.

SUMMARY

This invention relates to the unexpected discovery that bone substituents may be encapsulated within certain thermoplastic biocompatible polymeric compounds thereby forming a biodegradable bone composite, which converts into a workable injectable form (e.g., a molten) after heating and a solid form after cooling, in which the solid form possesses mechanical strength substantially same as that of a human cancellous bone. Accordingly, the biodegradable bone composite of the present invention may replace poly (methyl methacrylate) (PMMA) in the treatment of compression fracture of the vertebrae, and/or serve as fillers in sites that require bone filling.

Accordingly, the first aspect of present disclosure relates to a biodegradable bone composite. The biodegradable bone composite includes a shell made of a biodegradable thermoplastic polymer; and a bone substituent disposed within the shell; wherein, the biodegradable thermoplastic polymer has a molecular weight about 7,000 to 150,000 dalton; and the shell and the bone substituent are present in a weight or volume ratio about 1: 1 to 1: 19 in the biodegradable bone composite.

According to embodiments of the present disclosure, the biodegradable thermoplastic polymer may be one or more of a material selected from the group consisting of silicone, polycaprolactone (PCL) , poly (glycolic acid) , polylactic acid (PLA) , poly (L-lactic acid) , poly (D-, L-lactic acid) , poly (lactic-co-glycolic acid) (PLGA) , polyhydroxybutyrate, polydioxanone, poly (ε-caprolactone-co-glycolide) , polyester amide (PEA) , polyethylene glycol (PEG) , polyphosphazene, polyorthoesters, polyanhydrides, and a combination thereof.

According to embodiments of the present disclosure, the bone substituent may be one or more of a material selected from the group consisting of ceramic, bioglass, silica, strontium, magnesium, hydroxyapatite (HA) , tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate (TTCP) , and a combination thereof.

According to preferred embodiments of the present disclosure, the biodegradable thermoplastic polymer is PCL; the bone substituent is composed of HA and TCP in a ratio of 2: 3 by weight; and the shell and the bone substituent are present at the weight ratio of 1: 4 or the volume ratio of 1: 9 in the biodegradable bone composite.

According to optional embodiments of the present disclosure, the biodegradable bone composite further includes an agent selected from the group consisting of a contrast agent, an antibiotic, and a combination thereof. Preferably, the agent is encapsulated together with the bone substituent within the cavity enclosed by the shell.

The second aspect of the present disclosure relates to uses of the biodegradable bone composite described above. Accordingly, the present disclosure also provides a method of treating a subject having a fractured bone or osteoporosis. The method includes steps of, heating the present biodegradable bone composite until it converts into a molten mixture; and applying a sufficient amount of the molten mixture to a site in need of such treatment (e.g., a fractured bone) . According to preferred embodiments of the present disclosure, the present biodegradable bone composite is heated at a temperature of about 90℃ for 1 minute.

According to preferred embodiments of the present disclosure, the molten mixture of the biodegradable bone composite is administered to the site in need of such treatment (e.g., the fractured bone) via injection.

Many of the attendant features and advantages of the present disclosure will become better understood with reference to the following detailed description considered in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The present description will be better understood from the following detailed description read in light of the accompanying drawings, where:

FIG 1 are schematic diagrams depicting the thermoplastic polymeric upper and lower shells (11, 12) of the present biodegradable and injectable bone composite 10 before (A) and after (B) coupling in accordance with one embodiment of the present disclosure;

FIG 2 are schematic diagrams depicting the thermoplastic polymeric upper and lower shells (11, 12) of the present biodegradable and injectable bone composite 10 before (A) and after (B) coupling in accordance with another embodiment of the present disclosure; and

FIG 3 are photos of computer tomography (CT) and Hemotoxylin &Eosin staining of bone defects of Lanyu miniature pigs repaired with the bone composite of Example 1 (A and C) or let untreated (B and D) for a period of 12 months in accordance with one embodiment of the present disclosure.

DESCRIPTION

The detailed description provided below in connection with the appended drawings is intended as a description of the present examples and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

In general, the present invention relates to the unexpected discovery that bone substituents may be encapsulated within certain thermoplastic biocompatible polymeric compounds thereby forming a biodegradable bone composite, which converts into a workable injectable form (e.g., a molten) after heating and a solid form after cooling, in which the solid form possesses mechanical strength substantially same as that of a human cancellous bone. Accordingly, the biodegradable bone composite of the present invention may replace PMMA in the treatment of compression fracture of the vertebrae, and/or serve as fillers in sites that require bone filling.

1. Biodegradable bone composite

References are made to FIGs 1 and 2, which independently depict a biodegradable bone composite 10 of the present disclosure. The biodegradable bone composite 10 comprises a shell consists of an upper half shell 11 and a lower half shell 12 independently made of a biodegradable thermoplastic polymer, and a bone substituent 20 disposed within the cavity enclosed by the two

half shells

11, 12.

According to embodiments of the present disclosure, the polymeric shell (11, 12) of the biodegradable bone composite 10 may be formed by compression molding, injection molding, thermo molding, rotational molding, calendaring or casting a biodegradable thermoplastic polymer having a molecular weight about 7,000 to 150,000 dalton into two half shells (i.e., the upper half shell 11 and the lower half shell 12) that can be joined together to form the shell. As exemplified in FIGs 1 (A) and 2 (A) , coupling of the two half shells (11, 12) creates an internal space suitable for housing bone substituent 20 therein. Note that the biodegradable thermoplastic polymeric shell may be in the shape of a cylinder as depicted in FIGs 1 or 2. Alternatively or optionally, the biodegradable thermoplastic polymeric shell may be in the shape of a rectangular prism, hexagonal prism, pyramid, hexagonal pyramid, rectangular pyramid, sphere, and the like.

Biodegradable thermoplastic polymer suitable for use in the present invention may have a molecular weight between 7,000 to 150,000 dalton (Da) , such as 7,000, 8,000, 9,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 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, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, and 150,000 Da; preferably between 10,000 to 120,000 Da, such as 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 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, and 120,000 Da; more preferably, between 45,000 to 90,000 Da, such as 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, and 90,000 Da.

Examples of biodegradable thermoplastic polymer suitable for use in the present invention include, but are not limited to, silicone, polycaprolactone (PCL) , poly (glycolic acid) , polylactic acid (PLA) , poly (L-lactic acid) , poly (D-, L-lactic acid) , poly (lactic-co-glycolic acid) (PLGA) , polyhydroxybutyrate, polydioxanone, poly (ε-caprolactone-co-glycolide) , polyester amide (PEA) , polyethylene glycol (PEG) , polyphosphazene, polyorthoesters, polyanhydrides, and the like. According to some preferred embodiments of the present disclosure, the biodegradable thermoplastic polymer is PCL, which has a molecular weight ranges from 10,000 to 80,000 Da.

According to embodiments of the present disclosure, the present biodegradable thermoplastic polymer (e.g., PCL) is compression molded into an upper half shell 11 and a lower half shell 12. The upper and lower half shells (11, 12) are joined together to form a complete outer shell 10, which encloses a hollow space for housing a bone substituent 20 therein. The upper and lower half shells (11, 12) may be joined together via any suitable means, for example, the two half shells (11, 12) may be joined together via use of a glue, heat, and/or sonication.

Examples of the bone substituent suitable for use in the present disclosure include, but are not limited to, ceramic, bioglass, silica, strontium, magnesium, hydroxyapatite (HA) , tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate (TTCP) , and the like. According to some embodiments of the present disclosure, the bone substituent is composed of two materials at a ratio of 1: 1 to 10: 1, such as 1: 1, 1: 2, 1: 3, 1: 4, 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: 9, 9: 1, 9: 2, 9: 4, 9: 5, 9: 7, 9: 8, 9: 10, and 10: 1. In one preferred example, the bone substituent is a combination of HA and TCP in a ratio of 2: 3 by weight.

According to embodiments of the present disclosure, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 are present in the biodegradable bone composite 10 in a weight ratio between 1: 1 to 1: 19, such as 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 9, 1: 10, 1: 11, 1: 12, 1: 13, 1: 14, 1: 15, 1: 16, 1: 17, 1: 18, and 1: 19. In some embodiments, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 are present in the biodegradable bone composite 10 in a weight about 1: 1. In other embodiments, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 are present in the biodegradable bone composite 10 in a weight ratio about 1: 4. In further embodiments, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 are present in the biodegradable bone composite 10 in a weight ratio about 1: 19. Additionally, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 enclosed therein are preferably present in the biodegradable bone composite 10 in a volume ratio between 1: 1 to 1: 19, such as 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 9, 1: 10, 1: 11, 1: 12, 1: 13, 1: 14, 1: 15, 1: 16, 1: 17, 1: 18, and 1: 19. In some embodiments, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 enclosed therein are present in the biodegradable bone composite 10 in a volume about 1: 4. In other embodiments, the biodegradable thermoplastic polymeric shell (11, 112) and the bone substituent 20 enclosed therein are present in the biodegradable bone composite 10 in a volume ratio about 1: 9.

Additionally or optionally, the biodegradable bone composite may further include an agent selected from the group consisting of a contrast agent, an antibiotic, and a combination thereof. Preferably, the agent is encapsulated together with the bone substituent within the cavity or internal space enclosed by the shell.

2. Uses of the biodegradable bone composite

The second aspect of the present disclosure relates to uses of the biodegradable bone composite in the treatment of bone fracture or osteoporosis. According to preferred embodiments of the present disclosure, the biodegradable bone composite is heated until it turns into a molten mixture (i.e., liquefied and flowable) , which is then administered (e.g., via percutaneous injection) to a target site in need of such treatment (e.g., a fractured bone) .

According to preferred embodiments of the present disclosure, the biodegradable bone composite is heated at a temperature about 90℃ for 1 minute or until the thermoplastic polymeric outer shell melts and liquefies while the bone substituent enclosed therein remains in solid form. By this manner, the entire biodegradable bone composite becomes a molten mixture. With the flowability rendered by the melt and liquefied thermoplastic polymeric shell, the bone composite, now in the form of a molten mixture (with bone substituents enclosed by the liquefied polymeric shell) , may be easily applied (e.g., via percutaneous injection) to a target site in need of such treatment (e.g., a fractured bone) .

The molten mixture of the bone composite 10, once being applied to the target site, will solidify when the temperature returns to ambient temperature (e.g., human body temperature) . According to preferred embodiments of the present disclosure, the solidified bone composite 10 has an internal irregular web-like structure exhibiting a mechanical strength similar to that of a human cancellous bone, which is about 3-40 MPa, far below the mechanical strength of the well-known PMMA. Accordingly, the present bone composite 10 is suitable for enclosing and repairing bone fracture and/or treating osteoporosis.

In general, repairing bone fracture with a homogeneous mixture of PMMA and bone substituent would adversely limit the growth of osteoblasts at the repaired site. By contrast, the unique construction of the present bone composite, in which bone substituent is enclosed within a thermoplastic polymeric shell (i.e., without mixing the two materials) has the advantage of allowing the bone composite to be easily applied to the target site due to the flowability conferred by the melted thermoplastic outer shell, and the easy growth of osteoblasts into the bone substituent as the stress therein remains at a low level due to the fact that the bone substituent has not been mixed with the high stress thermoplastic polymer.

According to embodiments of the present disclosure, to repair a fractured bone or to treat osteoporosis by the present bone composite, a needle and a trocar are first guided to a target site (i.e., the site intended to be treated, such as a fractured bone) of a subject with the aid of X-ray, while a catheter having a plurality of the bone composite of the present invention disposed therein is heated (e.g., via use of a heater) until the bone composite of the present invention melts and liquefies, then the catheter containing the melted and liquefied bone composite therein is placed into the trocar under the guide of the needle, once in position, the catheter is squeezed to extrude the melted and liquefied bone composite out and into the target site, optionally, the squeezing and extruding step may be repeated several times until sufficient amounts of the present bone composite are administered to the target site. Once the temperature of the extruded bone composite returns to ambient temperature (i.e., human body temperature) , the bone composite would become solid again, then the trocar is removed from the target site.

The following Examples are provided to elucidate certain aspects of the present invention and to aid those of skilled in the art in practicing this invention. These Examples are in no way to be considered to limit the scope of the invention in any manner. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent.

EXAMPLES

Example 1 Preparation of the present bone composite

In this example, bone composites of the present disclosure were prepared in accordance with the formulation listed in Table 1 via compression extrusion. Specifically, two polymeric shells made of PCL were coupled together to form a capsule, which was filled with the designated bone substituent (e.g., a combination of 40%hydroxyapatite (HA) and 60%tricalcium phosphate (TCP) ) . Each polymeric shell had an outer diameter of 4 mm, an inside diameter of 3.8 mm, a height of 10 mm, and a thickness of 0.2 mm.

Table 1

Example 2 Characterization of the bone composite of Example 1

2.1 Ex vivo characterization of the bone composite of Example 1

The bone composites of Example 1 were independently placed in a catheter and heated at 90℃ for about 1 minute, the PCL shell would melt and liquefy, thus became flowable with the bone substituent enclosed therein. In other words, the entire bone composite turned into a molten mixture, with the outer shell being soft and flowable, while the bone substituent enclosed therein remained in solid form. Let the molten mixture cooled to room temperature (about 3 minutes) , then its internal structure and stress were observed and measured.

It was found that the bone composites of Example 1 independently had an irregular web-like internal structure with a mechanical strength similar to that of a human cancellous bone, which was about 3-40 MPa, far lower than that of PMMA (i.e., 250 MPa) , thereby would prevent adjacent bone from subsequent fracture and allow osteocytes to grow easily into the bone substituent. Accordingly, the bone composite of Example 1 is suitable for treating bone fracture and/or osteoporosis.

2.2 In vivo characterization of the bone composite of Example 1

In this example, effect of the bone composites of Example 1 as an implant was evaluated by an in vivo study. Specifically, Lanyu miniature pigs were randomly assigned into two groups. Cylindrical bone defects (each was about 10 mm in diameter and 10 mm in depth) were created on the distal femur of each pigs in both groups. The pigs in the experimental group were surgically implanted with the bone composites of Example 1 to repair the defects, and then let heal for a period of 12 months; while animals in the control group were let untreated for 12 months. After 12 months, animals were sacrificed and the distal femur of each pigs were harvested and subjected to computer tomography (CT) imaging analysis and Hemotoxylin &Eosin staining. Results are illustrated in FIG 3.

Regenerated bone tissue was found in the bone defect in the animals repaired with the bone composite of Example 1 (FIG 3, panel (A) ) , while bone defects remained visible in the control animal (FIG 3, panel (B) ) . The finding was further confirmed by Hemotoxylin &Eosin staining, in which bone tissue was found ingrowth into the implanted bone composite (FIG 3, panel (C) ) , while limited regeneration of bone tissue and loose trabecular structure were found in the defect of the control animal (FIG 3, panel (D) ) .

It will be understood that the above description of embodiments is given by way of example only and that various modifications may be made by those with ordinary skill in the art. The above specification, examples and data provide a complete description of the structure and use of exemplary embodiments of the invention. Although various embodiments of the invention have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those with ordinary skill in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this invention.

Claims

A biodegradable bone composite comprising,

a shell made of a biodegradable thermoplastic polymer; and

a bone substituent disposed within the shell;

wherein,

the biodegradable thermoplastic polymer has a molecular weight about 7,000 to 150,000 dalton; and

the shell and the bone substituent are present in a weight or volume ratio of about 1: 1 to 1: 19 in the biodegradable bone composite.
The biodegradable bone composite of claim 1, wherein

the biodegradable thermoplastic polymer is one or more of a material selected from the group consisting of silicone, polycaprolactone (PCL) , poly (glycolic acid) , polylactic acid (PLA) , poly (L-lactic acid) , poly (D-, L-lactic acid) , poly (lactic-co-glycolic acid) (PLGA) , polyhydroxybutyrate, polydioxanone, poly (ε-caprolactone-co-glycolide) , polyester amide (PEA) , polyethylene glycol (PEG) , polyphosphazene, polyorthoesters, polyanhydrides, and a combination thereof;

the bone substituent is one or more of a material selected from the group consisting of ceramic, bioglass, silica, strontium, magnesium, hydroxyapatite (HA) , tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate (TTCP) , and a combination thereof.
The biodegradable bone composite of claim 2, wherein

the biodegradable thermoplastic polymer is PCL;

the bone substituent is composed of HA and TCP in a ratio of 2: 3 by weight; and

the shell and the bone substituent are present in the weight ratio of 1: 4 or the volume ratio of 1: 9 in the biodegradable bone composite.
The biodegradable bone composite of claim 2, further comprising an agent selected from the group consisting of a contrast agent, an antibiotic, and a combination thereof; and the agent is encapsulated together with the bone substituent within the cavity enclosed by the shell.
Use of the biodegradable bone composite of claim 1 for the manufacture of a medicament for the treatment of bone fracture or osteoporosis, wherein the medicament becomes molten after being exposed to a temperature of 90℃ for 1 minute thereby allowing the biodegradable bone composite to be administered to the fractured bone in a molten state.
Use of claim 5, wherein the molten biodegradable bone composite is administered to the fractured bone via injection.
Use of claim 6, wherein

the biodegradable thermoplastic polymer is one or more of a material selected from the group consisting of silicone, polycaprolactone (PCL) , poly (glycolic acid) , polylactic acid (PLA) , poly (L-lactic acid) , poly (D-, L-lactic acid) , poly (lactic-co-glycolic acid) (PLGA) , polyhydroxybutyrate, polydioxanone, poly (ε-caprolactone-co-glycolide) , polyester amide (PEA) , polyethylene glycol (PEG) , polyphosphazene, polyorthoesters, polyanhydrides, and a combination thereof; and

the bone substituent is one or more of a material selected from the group consisting of ceramic, bioglass, silica, strontium, magnesium, hydroxyapatite (HA) , tricalcium phosphate (TCP) , calcium sulfate, dicalcium pyrophosphate, tetracalcium phosphate (TTCP) , and a combination thereof.
Use of claim 7, wherein

the biodegradable thermoplastic polymer is PCL;

the bone substituent is composed of HA and TCP in a ratio of 2: 3 by weight; and

the shell and the bone substituent are present in the weight ratio of 1: 4 or the volume ratio of 1: 9 in the biodegradable bone composite.
Use of claim 7, wherein the medicament further comprises an agent selected from the group consisting of a contrast agent, an antibiotic, and a combination thereof; and the agent is encapsulated together with the bone substituent within the cavity enclosed by the shell.